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Despite significant advancements in chemotherapy, effective treatments for advanced cancer stages remain largely elusive due to chemoresistance. Resistance to anticancer agents in cancer cells can arise through various mechanisms, including multi-drug resistance, inhibition of apoptosis, modification of drug targets, and enhancement of DNA repair capabilities. Consequently, there is a critical need for agents that can suppress the molecular signatures responsible for drug resistance. Piperine, an active alkaloid extracted from Piper nigrum L. (black pepper), is one such agent that has been extensively studied for its potential in addressing chronic diseases, including cancer. Piperine's antineoplastic properties are mediated through the regulation of numerous key cellular signaling pathways and the modulation of various biological processes. Its capability to enhance drug bioavailability and counteract mechanisms of drug resistance, such as the inhibition of P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP-1), emphasizes its potential as an adjunct in cancer therapy. Research across various cancer types has demonstrated piperine's role in chemosensitization by targeting P-gp and MRP-1 and altering drug-metabolizing enzymes. This review provides a comprehensive analysis of piperine's pharmacological characteristics and its capacity to modulate several cellular signaling pathways involved in drug resistance. Furthermore, the review emphasizes how piperine, when used in conjunction with other chemotherapeutic agents or natural compounds, can enhance therapeutic effects, leading to improved outcomes in cancer treatment., Competing Interests: Declaration of competing interest The authors claim no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Due to the complex pathophysiological mechanisms involved in cancer progression and metastasis, current therapeutic approaches lack efficacy and have significant adverse effects. Therefore, it is essential to establish novel strategies for combating cancer. Phytochemicals, which possess multiple biological activities, such as antioxidant, anti-inflammatory, antimutagenic, immunomodulatory, antiproliferative, anti-angiogenesis, and antimetastatic properties, can regulate cancer progression and interfere in various stages of cancer development by suppressing various signaling pathways., Methods: The current systematic and comprehensive review was conducted based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria, using electronic databases, including PubMed, Scopus, and Science Direct, until the end of December 2023. After excluding unrelated articles, 111 related articles were included in this systematic review., Results: In this current review, the major signaling pathways of cancer metabolism are highlighted with the promising anticancer role of phytochemicals. This was through their ability to regulate the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) signaling pathway. The AMPK/PGC-1α signaling pathway plays a crucial role in cancer cell metabolism via targeting energy homeostasis and mitochondria biogenesis, glucose oxidation, and fatty acid oxidation, thereby generating ATP for cell growth. As a result, targeting this signaling pathway may represent a novel approach to cancer treatment. Accordingly, alkaloids, phenolic compounds, terpene/terpenoids, and miscellaneous phytochemicals have been introduced as promising anticancer agents by regulating the AMPK/PGC-1α signaling pathway. Novel delivery systems of phytochemicals targeting the AMPK/PGC-1α pathway in combating cancer are also highlighted in this review., (© 2024. The Author(s).)

Background: Betulinic acid (BA), which is a pentacyclic triterpenoid found in the bark of plane, birch, and eucalyptus trees, has emerged as a compound of significant interest in scientific research due to its potential therapeutic applications. BA has a range of well-documented pharmacological and biological effects, including antibacterial, immunomodulatory, diuretic, antiviral, antiparasitic, antidiabetic, and anticancer activities. Although numerous research studies have explored the potential anticancer effects of BA, there is a noticeable gap in the literature, highlighting the need for a more up-to-date and comprehensive evaluation of BA's anticancer potential., Purpose: The aim of this work is to critically assess the reported cellular and molecular mechanisms underlying the cancer preventive and therapeutic effects of BA., Methods: Relevant research on the inhibitory effects of BA against cancerous cells was searched using Science Direct, Scopus, Web of Science, and PubMed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines., Results: The anticancer properties of BA are mediated by the activation of cell death and cell cycle arrest, production of reactive oxygen species, increased mitochondrial permeability, modulation of nuclear factor-κB and Bcl-2 family signaling. Emerging evidence also underscores the combined anticancer effects of BA with other natural bioactive compounds or approved drugs. Notably, several novel BA nanoformulations have been found to exhibit encouraging antineoplastic activities., Conclusion: BA, whether used alone or in combination, or as a form of nanoformulation, shows significant potential for cancer prevention and treatment. Nevertheless, further detailed studies are necessary to confirm the therapeutic effectiveness of this natural compound., Competing Interests: Declaration of competing interest Given their role as Editor/Associate Editor/Editorial board members, Anupam Bishayee had no involvement in the peer-review of this article and has no access to information regarding its peer-review., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Significance: Peroxisome proliferator-activated receptors (PPARs) have a moderately preserved amino-terminal domain, an extremely preserved DNA-binding domain, an integral hinge region, and a distinct ligand-binding domain that are frequently encountered with the other nuclear receptors. PPAR-β/δ is among the three nuclear receptor superfamily members in the PPAR group. Recent Advances: Emerging studies provide an insight on natural compounds that have gained increasing attention as potential anticancer agents due to their ability to target multiple pathways involved in cancer development and progression. Critical Issues: Modulation of PPAR-β/δ activity has been suggested as a potential therapeutic strategy for cancer management. This review focuses on the ability of bioactive phytocompounds to impact reactive oxygen species (ROS) and redox signaling by targeting PPAR-β/δ for cancer therapy. The rise of ROS in cancer cells may play an important part in the initiation and progression of cancer. However, excessive levels of ROS stress can also be toxic to the cells and cancer cells with increased oxidative stress are likely to be more vulnerable to damage by further ROS insults induced by exogenous agents, such as phytocompounds and therapeutic agents. Therefore, redox modulation is a way to selectively kill cancer cells without causing significant toxicity to normal cells. However, use of antioxidants together with cancer drugs may risk the effect of treatment as both act through opposite mechanisms. Future Directions: It is advisable to employ more thorough and detailed methodologies to undertake mechanistic explorations of numerous phytocompounds. Moreover, conducting additional clinical studies is recommended to establish optimal dosages, efficacy, and the impact of different phytochemicals on PPAR-β/δ.

Litchi (Litchi chinensis Sonn.) is a tropical fruit with various health benefits. The objective of this study is to present a thorough analysis of the cancer preventive and anticancer therapeutic properties of litchi constituents and phytocompounds. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis criteria were followed in this work. Various litchi extracts and constituents were studied for their anticancer effects. In vitro studies showed that litchi-derived components reduced cell proliferation, induced cytotoxicity, and promoted autophagy via increased cell cycle arrest and apoptosis. Based on in vivo studies, litchi flavonoids and other extracted constituents significantly reduced tumor size, number, volume, and metastasis. Major signaling pathways impacted by litchi constituents were shown to stimulate proapoptotic, antiproliferative, and antimetastatic activities. Despite promising antineoplastic activities, additional research, especially in vivo and clinical studies, is necessary before litchi-derived products and phytochemicals can be used for human cancer prevention and intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies., (© 2024. The Author(s).)

Tumor cells employ multiple signaling mediators to escape the hypoxic condition and trigger angiogenesis and metastasis. As a critical orchestrate of tumorigenic conditions, hypoxia-inducible factor-1 (HIF-1) is responsible for stimulating several target genes and dysregulated pathways in tumor invasion and migration. Therefore, targeting HIF-1 pathway and cross-talked mediators seems to be a novel strategy in cancer prevention and treatment. In recent decades, tremendous efforts have been made to develop multi-targeted therapies to modulate several dysregulated pathways in cancer angiogenesis, invasion, and metastasis. In this line, natural compounds have shown a bright future in combating angiogenic and metastatic conditions. Among the natural secondary metabolites, we have evaluated the critical potential of phenolic compounds, terpenes/terpenoids, alkaloids, sulfur compounds, marine- and microbe-derived agents in the attenuation of HIF-1, and interconnected pathways in fighting tumor-associated angiogenesis and invasion. This is the first comprehensive review on natural constituents as potential regulators of HIF-1 and interconnected pathways against cancer angiogenesis and metastasis. This review aims to reshape the previous strategies in cancer prevention and treatment., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Plasticity of phenotypic traits refers to an organism's ability to change in response to environmental stimuli. As a result, the response may alter an organism's physiological state, morphology, behavior, and phenotype. Phenotypic plasticity in cancer cells describes the considerable ability of cancer cells to transform phenotypes through non-genetic molecular signaling activities that promote therapy evasion and tumor metastasis via amplifying cancer heterogeneity. As a result of metastable phenotypic state transitions, cancer cells can tolerate chemotherapy or develop transient adaptive resistance. Therefore, new findings have paved the road in identifying factors and agents that inhibit or suppress phenotypic plasticity. It has also investigated novel multitargeted agents that may promise new effective strategies in cancer treatment. Despite the efficiency of conventional chemotherapeutic agents, drug toxicity, development of resistance, and high-cost limit their use in cancer therapy. Recent research has shown that small molecules derived from natural sources are capable of suppressing cancer by focusing on the plasticity of phenotypic responses. This systematic, comprehensive, and critical review analyzes the current state of knowledge regarding the ability of phytocompounds to target phenotypic plasticity at both preclinical and clinical levels. Current challenges/pitfalls, limitations, and future perspectives are also discussed., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The high incidence of oral cancer combined with excessive treatment cost underscores the need for novel oral cancer preventive and therapeutic options. The value of natural agents, including plant secondary metabolites (phytochemicals), in preventing carcinogenesis and representing expansive source of anticancer drugs have been established. While fragmentary research data are available on antioral cancer effects of phytochemicals, a comprehensive and critical evaluation of the potential of these agents for the prevention and intervention of human oral malignancies has not been conducted according to our knowledge. This study presents a complete and critical analysis of current preclinical and clinical results on the prevention and treatment of oral cancer using phytochemicals. Our in-depth analysis highlights anticancer effects of various phytochemicals, such as phenolics, terpenoids, alkaloids, and sulfur-containing compounds, against numerous oral cancer cells and/or in vivo oral cancer models by antiproliferative, proapoptotic, cell cycle-regulatory, antiinvasive, antiangiogenic, and antimetastatic effects. Bioactive phytochemicals exert their antineoplastic effects by modulating various signaling pathways, specifically involving the epidermal growth factor receptor, cytokine receptors, toll-like receptors, and tumor necrosis factor receptor and consequently alter the expression of downstream genes and proteins. Interestingly, phytochemicals demonstrate encouraging effects in clinical trials, such as reduction of oral lesion size, cell growth, pain score, and development of new lesions. While most phytochemicals displayed minimal toxicity, concerns with bioavailability may limit their clinical application. Future directions for research include more in-depth mechanistic in vivo studies, administration of phytochemicals using novel formulations, investigation of phytocompounds as adjuvants to conventional treatment, and randomized clinical trials., (© 2023 Wiley Periodicals LLC.)

The tumor microenvironment (TME) plays a pivotal role in cancer development and progression. In this line, revealing the precise mechanisms of the TME and associated signaling pathways of tumor resistance could pave the road for cancer prevention and efficient treatment. The use of nanomedicine could be a step forward in overcoming the barriers in tumor-targeted therapy. Novel delivery systems benefit from enhanced permeability and retention effect, decreasing tumor resistance, reducing tumor hypoxia, and targeting tumor-associated factors, including immune cells, endothelial cells, and fibroblasts. Emerging evidence also indicates the engagement of multiple dysregulated mediators in the TME, such as matrix metalloproteinase, vascular endothelial growth factor, cytokines/chemokines, Wnt/β-catenin, Notch, Hedgehog, and related inflammatory and apoptotic pathways. Hence, investigating novel multitargeted agents using a novel delivery system could be a promising strategy for regulating TME and drug resistance. In recent years, small molecules from natural sources have shown favorable anticancer responses by targeting TME components. Nanoformulations of natural compounds are promising therapeutic agents in simultaneously targeting multiple dysregulated factors and mediators of TME, reducing tumor resistance mechanisms, overcoming interstitial fluid pressure and pericyte coverage, and involvement of basement membrane. The novel nanoformulations employ a vascular normalization strategy, stromal/matrix normalization, and stress alleviation mechanisms to exert higher efficacy and lower side effects. Accordingly, the nanoformulations of anticancer monoclonal antibodies and conventional chemotherapeutic agents also improved their efficacy and lessened the pharmacokinetic limitations. Additionally, the coadministration of nanoformulations of natural compounds along with conventional chemotherapeutic agents, monoclonal antibodies, and nanomedicine-based radiotherapy exhibits encouraging results. This critical review evaluates the current body of knowledge in targeting TME components by nanoformulation-based delivery systems of natural small molecules, monoclonal antibodies, conventional chemotherapeutic agents, and combination therapies in both preclinical and clinical settings. Current challenges, pitfalls, limitations, and future perspectives are also discussed., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Epithelial-mesenchymal transition (EMT) is a complex process with a primordial role in cellular transformation whereby an epithelial cell transforms and acquires a mesenchymal phenotype. This transformation plays a pivotal role in tumor progression and self-renewal, and exacerbates resistance to apoptosis and chemotherapy. EMT can be initiated and promoted by deregulated oncogenic signaling pathways, hypoxia, and cells in the tumor microenvironment, resulting in a loss-of-epithelial cell polarity, cell-cell adhesion, and enhanced invasive/migratory properties. Numerous transcriptional regulators, such as Snail, Slug, Twist, and ZEB1/ZEB2 induce EMT through the downregulation of epithelial markers and gain-of-expression of the mesenchymal markers. Additionally, signaling cascades such as Wnt/β-catenin, Notch, Sonic hedgehog, nuclear factor kappa B, receptor tyrosine kinases, PI3K/AKT/mTOR, Hippo, and transforming growth factor-β pathways regulate EMT whereas they are often deregulated in cancers leading to aberrant EMT. Furthermore, noncoding RNAs, tumor-derived exosomes, and epigenetic alterations are also involved in the modulation of EMT. Therefore, the regulation of EMT is a vital strategy to control the aggressive metastatic characteristics of tumor cells. Despite the vast amount of preclinical data on EMT in cancer progression, there is a lack of clinical translation at the therapeutic level. In this review, we have discussed thoroughly the role of the aforementioned transcription factors, noncoding RNAs (microRNAs, long noncoding RNA, circular RNA), signaling pathways, epigenetic modifications, and tumor-derived exosomes in the regulation of EMT in cancers. We have also emphasized the contribution of EMT to drug resistance and possible therapeutic interventions using plant-derived natural products, their semi-synthetic derivatives, and nano-formulations that are described as promising EMT blockers., (© 2023 Wiley Periodicals LLC.)

Background: Drug resistance is a serious challenge in cancer treatment that can render chemotherapy a failure. Understanding the mechanisms behind drug resistance and developing novel therapeutic approaches are cardinal steps in overcoming this issue. Clustered regularly interspaced short palindrome repeats (CRISPR) gene-editing technology has proven to be a useful tool to study cancer drug resistance mechanisms and target the responsible genes. In this review, we evaluated original research studies that used the CRISPR tool in three areas related to drug resistance, namely screening resistance-related genes, generating modified models of resistant cells and animals, and removing resistance by genetic manipulation. We reported the targeted genes, study models, and drug groups in these studies. In addition to discussing different applications of CRISPR technology in cancer drug resistance, we analyzed drug resistance mechanisms and provided examples of CRISPR's role in studying them. Although CRISPR is a powerful tool for examining drug resistance and sensitizing resistant cells to chemotherapy, more studies are required to overcome its disadvantages, such as off-target effects, immunotoxicity, and inefficient delivery of CRISPR/cas9 into the cells., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mina Mirian reports financial support was provided by Isfahan University of Medical Sciences. Mina Mirian reports a relationship with Isfahan University of Medical Sciences that includes: employment., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Cancer is amongst the deadliest and most disruptive disorders, having a much higher death rate than other diseases worldwide. Human cancer rates continue to rise, thereby posing the most significant concerns for medical health professionals. In the last two decades, researchers have gone past several milestones in tackling cancer while gaining insight into the role of apoptosis in cancer or targeting various biomarker tools for prognosis and diagnosis. Apoptosis which is still a topic full of complexities, can be controlled considerably by B-cell lymphoma 2 (BCL-2) and its family members. Therefore, targeting proteins of this family to prevent tumorigenesis, is essential to focus on the pharmacological features of the anti-apoptotic and pro-apoptotic members, which will help to develop and manage this disorder. This review deals with the advancements of various epigenetic regulators to target BCL-2 family proteins, including the mechanism of several microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Similarly, a rise in natural and synthetic molecules' research over the last two decades has allowed us to acquire insights into understanding and managing the transcriptional alterations that have led to apoptosis and treating various neoplastic diseases. Furthermore, several inhibitors targeting anti-apoptotic proteins and inducers or activators targeting pro-apoptotic proteins in preclinical and clinical stages have been summarized. Overall, agonistic and antagonistic mechanisms of BCL-2 family proteins conciliated by epigenetic regulators, natural and synthetic agents have proven to be an excellent choice in developing cancer therapeutics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Guava ( Psidium guajava L.) tree (Myrtaceae family) bears fruit rich in vitamins, fiber, and other nutrients. While native to Latin America, guava is grown in many tropical and subtropical regions across the globe where it has long been used in traditional medicine to treat a myriad of ailments. Guava has been shown to exhibit a number of biological and pharmacological activities, such as antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, antidiabetic, and anticancer properties. Several parts of the plant, including the leaves, fruits, seeds, peels, pulp, bark, and oil, produce phytochemicals with medicinal properties. Emerging research has found that guava bioactive phytochemicals exert antitumorigenic effects against various human malignancies through multiple mechanisms. While there are numerous individual studies that document the anticancer effects of guava constituents, an up-to-date, comprehensive, and critical review of available research data has not been performed. Therefore, the purpose of this review is to present a complete analysis of the cancer preventive and anticancer therapeutic potential of guava-derived products and guava constituents, with a focus on the cellular and molecular mechanisms of action. The bioavailability, pharmacokinetics, and toxicity of guava as well as limitations, challenges, and future directions of research have also been discussed.

Cancer is a leading cause of morbidity and mortality across the globe. Emerging evidence suggests that consumption of a well-balanced diet containing a wide variety of vegetables, fruits, and whole grains can prevent the development of, halt, or reverse cancer progression. Carica papaya L. (papaya) has a wide distribution throughout many countries. Although the fruits of C. papaya are primarily consumed as food, various parts of this tree, including the bark, fruits, latex, seeds, and roots, have been used in traditional medicine for health promotion and disease mitigation. While numerous individual studies have investigated anticancer efficacies of various products and constituents of C. papaya , an up-to-date, comprehensive, and critical evaluation of available research data covering its role in the prevention and intervention of various human malignancies has not been conducted according to our knowledge. The purpose of this review is to present a systematic, comprehensive, and critical analysis of the cancer-preventive potential of C. papaya extracts, fractions, and isolated phytochemicals with a special emphasis on the cellular and molecular mechanisms of action. Moreover, the bioavailability, pharmacokinetics, and safety profiles of individual phytochemicals of C. papaya, as well as current limitations, challenges, and future directions of research, have also been discussed.

Senescence-like cell cycle arrest is a critical state of cancer initiation and progression. Senescence is an irreversible cell cycle arrest in response to stress induced by extrinsic and intrinsic stimuli, including oxidative/genotoxic stress, oncogenic activation, irradiation, mitochondrial malfunction, or chemotherapeutic drugs. Several signaling pathways are involved in senescence-like cell cycle arrest, which is primarily induced by the activation of p53/p21-dependent apoptotic pathways and suppressing p16INK4A/retinoblastoma protein (pRB)-dependent oncogenic pathways. p21 is necessary for proper cell cycle advancement, is involved in cell death, and mediates p53-dependent cell cycle arrest caused by DNA damage. pRB's role in tumor suppression is through modulation of the G1 checkpoint in the cell cycle, as it has the ability to block S-phase entry and cell growth. The aforementioned pathways are also highly interconnected with significant crosstalk, such as cyclin-dependent kinases (CDK)/cyclin complexes, and the dimerization partner, RB-like, E2F and multi-vulval class B (DREAM) complex. The primary regulators of transcription are p53 and pRB, which maintain the senescent state through negative control of the cell cycle and process of tumorigenesis. Because CDK inhibitors comprise negative regulators of cell cycle progress, they are fundamental parts of each route. Prolonged overexpression of any of these four fundamental elements (p16, p53, p21, and pRB) suffices to induce senescence, demonstrating how the regulatory DREAM complex causes senescence and how its malfunction results in cell cycle progression. The present chapter aims at revealing the pivotal mechanisms behind the senescence-like cell cycle arrest in cancer., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Chlorogenic acid (CA), also known as 5-O-caffeoylquinic acid, is a dietary phenolic acid produced by various plant species. CA, is the most ubiquitous compound among the phenolic acid group, is also present in tea and green coffee extracts. Its consumption reduces the risk of numerous diseases as validated by preclinical and clinical studies. CA possesses a wide range of pharmacological properties, such as hepatoprotective, antimicrobial, immunomodulatory, antioxidant, antidiabetic, and anticancer activities. It has been extensively used in the food, chemical, medicine, and health care industries. Available reports revealed that CA can exert anticancer activity by inhibiting the cell cycle, triggering apoptosis, and suppressing the proliferation of cancer cells. It upregulates the expression of nuclear factor of activated T cells 2 (NFATC2) and NFATC3 genes involved in immune pathway and downregulates B cell-specific moloney murine leukemia virus integration site 1 protein and SRY-box transcription factor 2 gene expression to facilitate tumor cell destruction. It promotes intracellular DNA impairment and topoisomerase I- and topoisomerase-II-DNA complex formation that perform a key function in apoptosis. In addition, CA has been documented to be an effective natural anticancer drug and was approved by the China Food and Drug Administration. Several previously published reports have provided fragmented summary of various anticancer activities of CA. Therefore, this review aims to deliver up-to-date and comprehensive assessment about the natural sources of CA, its bioavailability, metabolism, and anticancer property with an emphasis on the molecular mechanisms associated with several signaling pathways in tumor cells., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Many substances derived from nutritional or medicinal plants have been studied for their chemopreventive and antineoplastic properties. Among those studied, Ficus carica has shown to have a significant ability to inhibit tumor formation and development of cancer cells through modulating various signaling mechanisms and interaction including a large number of cell signaling molecules., Purpose: The goal of this study is to provide a critical and complete evaluation of F. carica's anticancer capacity in various malignancies, as well as related molecular targets., Methods: Research was conducted electronically on scholarly scientific databases, including Science Direct, PubMed, and Scopus. Published papers were analyzed and investigated using the keywords, Ficus carica, figs, cancer, malignancies and tumor based on established selection criteria. In this systematic review, 27 individual studies were considered., Results: Treatment with F. carica alone or in combination with other medications was linked to anticancer activity with significant evidence. Furthermore, F. carica has been shown to use multitargeted pathways to prevent cancer initiation and development by modulating numerous dysregulated signaling cascades involved in cell proliferation, cell cycle regulation, apoptosis, autophagy inflammatory processes, metastasis, invasion, and angiogenesis., Conclusion: Our findings suggest that F. carica and its phytochemicals have the potential for cancer prevention and therapy. Nonetheless, additional mechanistic studies with pure compounds derived from F. carica and well-designed clinical trials are needed to advance our knowledge to clinical application., (Copyright © 2022. Published by Elsevier GmbH.)

The marine environment is important yet generally underexplored. It contains new sources of functional constituents that can affect various pathways in food processing, storage, and fortification. Bioactive secondary metabolites produced by marine microorganisms may have significant potential applications for humans. Various components isolated from disparate marine microorganisms, including fungi, microalgae, bacteria, and myxomycetes, showed considerable biological effects, such as anticancer, antioxidant, antiviral, antibacterial, and neuroprotective activities. Growing studies are revealing that potential anticancer effects of marine agents could be achieved through the modulation of several organelles. Mitochondria are known organelles that influence growth, differentiation, and death of cells via influencing the biosynthetic, bioenergetic, and various signaling pathways related to oxidative stress and cellular metabolism. Consequently, mitochondria play an essential role in tumorigenesis and cancer treatments by adapting to alterations in environmental and cellular conditions. The growing interest in marine-derived anticancer agents, combined with the development and progression of novel technology in the extraction and cultures of marine life, led to revelations of new compounds with meaningful pharmacological applications. This is the first critical review on marine-derived anticancer agents that have the potential for targeting mitochondrial function during tumorigenesis. This study aims to provide promising strategies in cancer prevention and treatment.

Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2), the redox-sensitive transcription factor, plays a key role in stress-defense and detoxification. Nrf2 is tightly controlled by its negative regulator cum sensor Kelch-[ECH]-associated protein 1 (Keap1). Nrf2 is well known for its dual nature owing to its cancer preventive and cancer promoting abilities. Modulation of this biphasic nature of Nrf2 signaling by phytochemicals may be a potential cancer preventive and anticancer therapeutic strategy. Phytocompounds may either act as Nrf2-activator or Nrf2-inhibitor depending on their differential concentration and varied cellular environment. Tea is not just the most popular global beverage with innumerable health-benefits but has well-established chemopreventive and chemotherapeutic effects. Various types of tea infusions contain a wide range of bioactive compounds, such as polyphenolic catechins and flavonols, which are endowed with potent antioxidant properties. Despite of their rapid biotransformation and poor bioavailability, regular tea consumption is risk-reductive for several cancer forms. Tea catechins show their dual Nrf2-modulatory effect by directly acting on Nrf2-Keap1 or their upstream regulators and downstream effectors in a highly case-specific manner. In this review, we have tried to present a comprehensive evaluation of the Nrf2-mediated chemopreventive and chemotherapeutic applications of tea in various preclinical cancer models, the Nrf2-modulatory mechanisms, and the limitations which need to be addressed in future research., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Epigallocatechin gallate (EGCG), also known as epigallocatechin-3-gallate, is an ester of epigallocatechin and gallic acid. EGCG, abundantly found in tea, is a polyphenolic flavonoid that has the potential to affect human health and disease. EGCG interacts with various recognized cellular targets and inhibits cancer cell proliferation by inducing apoptosis and cell cycle arrest. In addition, scientific evidence has illustrated the promising role of EGCG in inhibiting tumor cell metastasis and angiogenesis. It has also been found that EGCG may reverse drug resistance of cancer cells and could be a promising candidate for synergism studies. The prospective importance of EGCG in cancer treatment is owed to its natural origin, safety, and low cost which presents it as an attractive target for further development of novel cancer therapeutics. A major challenge with EGCG is its low bioavailability which is being targeted for improvement by encapsulating EGCG in nano-sized vehicles for further delivery. However, there are major limitations of the studies on EGCG, including study design, experimental bias, and inconsistent results and reproducibility among different study cohorts. Additionally, it is important to identify specific EGCG pharmacological targets in the tumor-specific signaling pathways for development of novel combined therapeutic treatments with EGCG. The present review highlights the ongoing development to identify cellular and molecular targets of EGCG in cancer. Furthermore, the role of nanotechnology-mediated EGCG combinations and delivery systems will also be discussed., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Senescence is a special state of tumor suppression induced by cell cycle arrest. However, releasing senescence-associated secretory phenotypes by senescent cells could provide tumorigenic conditions and epigenetic changes in neighboring cells. The conventional anticancer drugs activate therapy-induced senescence by several mechanisms which include an increase in mitochondrial biogenesis and reactive oxygen species, up-regulation of tumor suppressor proteins (e.g., p53, p21, p38, and p16) and modulation of dysregulated signaling mediators, including senescence-associated β-galactosidase, ataxia-telangiectasia mutated/ATM and Rad3-related, checkpoint kinase1/2, phosphatidylinositol 3-kinases/Akt, Ras/Raf pathway, and extracellular signal-regulated kinase/mitogen-activated protein kinase. On the other hand, conventional anticancer agents induce the secretion of procarcinogenic molecules, including inflammatory mediators, such as nuclear factor-κB, tumor necrosis factor-α, and interleukins, and angiogenic mediators, namely vascular endothelial growth factor, in the tumor microenvironment. This condition urges the need for finding novel alternative therapies, novel senolytics, senescence inducers and combination therapies in the regulation of senescence towards the regulation of multiple tumorigenic conditions. This comprehensive review highlights the therapeutic targets and signaling pathways in the senescence of tumor cells. The critical roles of anticancer drug-induced senescence, senolytics, and associated combined administrations are evaluated in the attenuation of cellular senescence pathways to achieve cancer prevention and efficient treatment. Current challenges/pitfalls, limitations, and future research are also discussed., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The medicinal plant Scutellaria baicalensis, commonly known as Chinese skullcap or Huang-Qin, has been used as a traditional medicine for several thousand years. The roots of this plant contain bioactive compounds, such as wogonin (WOG), wogonoside, baicalein, and baicalin. The aim of this article is to evaluate the therapeutic potential and mechanisms of action of WOG against different cancers. Numerous in vitro and in vivo studies have revealed that WOG exerts immense therapeutic potential against bladder cancer, breast cancer, cholangiocarcinoma, cervical cancer, colorectal cancer, gallbladder cancer, gastric cancer, glioblastoma, head and neck cancer, hepatic cancer, leukemia, lung cancer, lymphoma, melanoma, multiple myeloma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, and renal cancer by regulating various cell signaling pathways. WOG, in combination with established chemotherapeutic drugs, improves the efficacy of treatment and lowers toxicity. Nevertheless, human trials are warranted to validate these findings. Numerous preclinical studies, combined with an extensive margin of safety and no severe side effects, underscore WOG's therapeutic potential as an anticancer drug. These studies propound the use of WOG as a potential anticancer candidate; however, further high-quality studies are required to firmly establish the clinical efficacy of WOG for the prevention and treatment of human malignancies., (© 2022 John Wiley & Sons Ltd.)

The phosphatidylinositol 3-kinase (PI3K)-Akt and the mammalian target of rapamycin (mTOR) represent two vital intracellular signaling pathways, which are associated with various aspects of cellular functions. These functions play vital roles in quiescence, survival, and growth in normal physiological circumstances as well as in various pathological disorders, including cancer. These two pathways are so intimately connected to each other that in some instances these are considered as one unique pathway crucial for cell cycle regulation. The purpose of this review is to emphasize the role of PI3K-Akt-mTOR signaling pathway in different cancer conditions and the importance of natural products targeting the PI3K-Akt-mTOR signaling pathway. This review also aims to draw the attention of scientists and researchers to the assorted beneficial effects of the numerous classes of natural products for the development of new and safe drugs for possible cancer therapy. We also summarize and critically analyze various preclinical and clinical studies on bioactive compounds and constituents, which are derived from natural products, to target the PI3K-Akt-mTOR signaling pathway for cancer prevention and intervention., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Due to the high number of annual cancer-related deaths, and the economic burden that this malignancy affects today's society, the study of compounds isolated from natural sources should be encouraged. Most cancers are the result of a combined effect of lifestyle, environmental factors, and genetic and hereditary components. Recent literature reveals an increase in the interest for the study of phytochemicals from traditional medicine, this being a valuable resource for modern medicine to identify novel bioactive agents with potential medicinal applications. Phytochemicals are components of traditional medicine that are showing promising application in modern medicine due to their antitumor activities. Recent studies regarding two major mechanisms underlying cancer development and regulation, apoptosis and autophagy, have shown that the signaling pathways of both these processes are significantly interconnected through various mechanisms of crosstalk. Phytochemicals are able to activate pro-autophagic and pro-apoptosis mechanisms. Understanding the molecular mechanism involved in apoptosis-autophagy relationship modulated by phytochemicals plays a key role in development of a new therapeutic strategy for cancer treatment. The purpose of this review is to outline the bioactive properties of the natural phytochemicals with validated antitumor activity, focusing particularly on their role in the regulation of apoptosis and autophagy crosstalk that triggers the uncontrolled expansion of tumor cells. Furthermore, we have also critically discussed the limitations and challenges of existing research strategies and the prospective research directions in this field., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Several signaling pathways and basic metabolites are responsible for the control of metabolism in both normal and cancer cells. As emerging hallmarks of cancer metabolism, the abnormal activities of these pathways are of the most noticeable events in cancer. This altered metabolism expedites the survival and proliferation of cancer cells, which have attracted a substantial amount of interest in cancer metabolism. Nowadays, targeting metabolism and cross-linked signaling pathways in cancer has been a hot topic to investigate novel drugs against cancer. Despite the efficiency of conventional drugs in cancer therapy, their associated toxicity, resistance, and high-cost cause limitations in their application. Besides, considering the numerous signaling pathways cross-linked with cancer metabolism, discovery, and development of multi-targeted and safe natural compounds has been a high priority. Natural secondary metabolites have exhibited promising anticancer effects by targeting dysregulated signaling pathways linked to cancer metabolism. The present review reveals the metabolism and cross-linked dysregulated signaling pathways in cancer. The promising therapeutic targets in cancer, as well as the critical role of natural secondary metabolites for significant anticancer enhancements, have also been highlighted to find novel/potential therapeutic agents for cancer treatment., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Human exposure to environmental toxicants with diverse mechanisms of action is a growing concern. In addition to well-recognized carcinogens, various chemicals in environmental and occupational settings have been suggested to impact health, increasing susceptibility to cancer by inducing genetic and epigenetic changes. Accordingly, in this review, we have discussed recent insights into the pathological mechanisms of these chemicals, namely their effects on cell redox and calcium homeostasis, mitochondria and inflammatory signaling, with a focus on the possible implications for multi-stage carcinogenesis and its reversal by polyphenols. Plant-derived polyphenols, such as epigallocatechin-gallate, resveratrol, curcumin and anthocyanins reduce the incidence of cancer and can be useful nutraceuticals for alleviating the detrimental outcomes of harmful pollutants. However, development of therapies based on polyphenol administration requires further studies to validate the biological efficacy, identifying effective doses, mode of action and new delivery forms. Innovative microphysiological testing models are presented and specific proposals for future trials are given. Merging the current knowledge of multifactorial actions of specific polyphenols and chief environmental toxicants, this work aims to potentiate the delivery of phytochemical-based protective treatments to individuals at high-risk due to environmental exposure., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The current era of cancer research has been continuously advancing upon identifying novel aspects of tumorigenesis and the principal mechanisms behind the unleashed proliferation, invasion, drug resistance and immortality of cancer cells in hopes of exploiting these findings to achieve a more effective treatment for cancer. In pursuit of this goal, the identification of the first components of an extremely important regulatory pathway in Drosophila melanogaster that largely determines cell fate during the developmental stages, ended up in the discovery of the highly sophisticated Hippo signaling cascade. Soon after, it was revealed that deregulation of the components of this pathway either via mutations or through epigenetic alterations can be observed in a vast variety of tumors and these alterations greatly contribute to the neoplastic transformation of cells, their survival, growth and resistance to therapy. As more hidden aspects of this pathway such as its widespread entanglement with other major cellular signaling pathways are continuously being uncovered, many researchers have sought over the past decade to find ways of therapeutic interventions targeting the major components of the Hippo cascade. To date, various approaches such as the use of exogenous targeting miRNAs and different molecular inhibitors have been recruited herein, among which naturally occurring compounds have shown a great promise. On such a basis, in the present work we review the current understanding of Hippo pathway and the most recent evidence on targeting its components using natural plant-derived phytochemicals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Recently, long intergenic non-protein coding RNA 01133 ( LINC01133 ) was identified as a novel transcript in cancers. It modulates various hallmarks of cancers and acts as oncogenic in some cancers while tumor-suppressive in others. Furthermore, the expression of LINC01133 correlates with tumor size, advanced tumor node metastasis stage and lymphatic node metastasis, Ki-67 levels and overall survival of patients. Herein, the authors provide an in-depth analysis describing how LINC01133 modulates the multiple cancer-associated signaling pathways and the pathogenesis of various malignancies and treatment regimens. Based on the role played by LINC01133 , the authors propose LINC01133 as both a potential biomarker and a therapeutic target in cancer.

Background: Cancer is the world's second leading cause of death, but a significant advancement in cancer treatment has been achieved within the last few decades. However, major adverse effects and drug resistance associated with standard chemotherapy have led towards targeted treatment options., Objectives: Transforming growth factor-β (TGF-β) signaling plays a key role in cell proliferation, differentiation, morphogenesis, regeneration, and tissue homeostasis. The prime objective of this review is to decipher the role of TGF-β in oncogenesis and to evaluate the potential of various natural and synthetic agents to target this dysregulated pathway to confer cancer preventive and anticancer therapeutic effects., Methods: Various authentic and scholarly databases were explored to search and obtain primary literature for this study. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria was followed for the review., Results: Here we provide a comprehensive and critical review of recent advances on our understanding of the effect of various bioactive natural molecules on the TGF-β signaling pathway to evaluate their full potential for cancer prevention and therapy., Conclusion: Based on emerging evidence as presented in this work, TGF-β-targeting bioactive compounds from natural sources can serve as potential therapeutic agents for prevention and treatment of various human malignancies., (© 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Senescence suppresses tumor growth, while also developing a tumorigenic state in the nearby cells that is mediated by senescence-associated secretory phenotypes (SASPs). The dual function of cellular senescence stresses the need for identifying multi-targeted agents directed towards the promotion of cell senescence in cancer cells and suppression of the secretion of pro-tumorigenic signaling mediators in neighboring cells. Natural secondary metabolites have shown favorable anticancer responses in recent decades, as some have been found to target the senescence-associated mediators and pathways. Furthermore, phenolic compounds and polyphenols, terpenes and terpenoids, alkaloids, and sulfur-containing compounds have shown to be promising anticancer agents through the regulation of paracrine and autocrine pathways. Plant secondary metabolites are potential regulators of SASPs factors that suppress tumor growth through paracrine mediators, including growth factors, cytokines, extracellular matrix components/enzymes, and proteases. On the other hand, ataxia-telangiectasia mutated, ataxia-telangiectasia and Rad3-related, extracellular signal-regulated kinase/mitogen-activated protein kinase, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, nuclear factor-κB, Janus kinase/signal transducer and activator of transcription, and receptor tyrosine kinase-associated mediators are main targets of candidate phytochemicals in the autocrine senescence pathway. Such a regulatory role of phytochemicals on senescence-associated pathways is associated with cell cycle arrest and the attenuation of apoptotic/inflammatory/oxidative stress pathways. The current systematic review highlights the critical roles of natural secondary metabolites in the attenuation of autocrine and paracrine cellular senescence pathways, while also elucidating the chemopreventive and chemotherapeutic capabilities of these compounds. Additionally, we discuss current challenges, limitations, and future research indications., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Natural products, with incredible chemical diversity, have been widely studied for their antitumor potential. Quercetin (QU) and quercetin glycoside (rutin), both polyphenolic flavonoids, stick out amongst the natural products, through various studies. Rutin (RU) and its aglycone (QU) have various biological properties that include antioxidant, anti-inflammatory, and anticarcinogenic activities. However, several side effects have restricted the efficacy of these polyphenolic flavonoids, which makes it necessary to use new strategies involving low and pharmacological doses of QU and RU, either alone or in combination with other anticancer drugs., Purpose: The aim of this study is to present a comprehensive and critical evaluation of the anticancer ability of different nano-formulations of RU and QU for improved treatment of various malignancies., Methods: Studies were recognized via systematic searches of ScienceDirect, PubMed, and Scopus databases. Eligibility checks were conducted based upon predefined selection criteria. Ninety articles were included in this study., Results: There was conclusive evidence for the association between anticancer activity and treatment with RU or QU. Furthermore, studies indicated that nano-formulations of RU and QU have greater anticancer activities in comparison to either agent alone, which leads to increased efficiency for treating cancer., Conclusion: The results of this systematic review demonstrate the anticancer activities of nano-formulations of RU and QU and their molecular mechanisms through preclinical studies. This paper also attempts to contribute to further research by addressing the current limitations/challenges and proposing additional studies to realize the full potential of RU- and QU-based formulations for cancer treatment., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Curcumin, the key bioactive phytochemical present in turmeric (Curcuma longa L.), is the most studied natural compound in cancer. Preclinical studies (in vitro and in vitro) and clinical trials have demonstrated curcumin's effectiveness as an anti-inflammatory agent. The existing evidence supports that curcumin inhibits the proliferation of many types of cancer cells and can play an important role in cancer therapy. This study analyses the existing evidence in the literature on finalized clinical trials (2010-2020) related to the effect of curcumin and turmeric-derived products that focused on different types of cancers, such as chronic myeloid leukemia, multiple myeloma, prostate, colorectal and pancreatic cancer as well as cancer therapy-related complications, including oral mucositis and radiation dermatitis. Original English language articles and clinical trials published between 2010 and 2020 were searched using mainstream scholarly databases, such as PubMed, ScienceDirect, Google Scholar, and ClinicalTrials.gov. The keywords, such as "curcumin," "turmeric," "cancer," "anti-inflammatory," and "clinical trials," were used in various combinations. A total of 21 clinical trials were selected, reviewed, and included in this study. Sixteen out of 21 clinical trials were associated with the effectiveness of curcumin or turmeric on various types of cancer, and the other five clinical trials were related to the evaluation of the efficacy of curcumin or turmeric in relieving the side effects of cancer chemotherapy and radiotherapy. The emerging data from the clinical trials confirm that curcumin has the potential for cancer prevention and intervention. However, it is not yet clear whether long-term curcumin supplementation has similar benefits., Competing Interests: None

Garlic (Allium sativum L.) is one of the oldest plants cultivated for its dietary and medicinal values. This incredible plant is endowed with various pharmacological attributes, such as antimicrobial, antiarthritic, antithrombotic, antitumor, hypoglycemic, and hypolipidemic activities. Among the various beneficial pharmacological effects of garlic, the anticancer activity is presumably the most studied. The consumption of garlic provides strong protection against cancer risk. Taking into account the multi-targeted actions and absence of considerable toxicity, a few active metabolites of garlic are probably to play crucial roles in the killing of cancerous cells. Garlic contains several bioactive molecules with anticancer actions and these include diallyl trisulfide, allicin, diallyl disulfide, diallyl sulfide, and allyl mercaptan. The effects of various garlic-derived products, their phytoconstituents and nanoformulations have been evaluated against skin, prostate, ovarian, breast, gastric, colorectal, oral, liver, and pancreatic cancers. Garlic extract, its phytocompounds and their nanoformulations have been shown to inhibit the different stages of cancer, including initiation, promotion, and progression. Besides, these bioactive metabolites alter the peroxidation of lipid, activity of nitric oxide synthetase, nuclear factor-κB, epidermal growth factor receptor, and protein kinase C, cell cycle, and survival signaling. The current comprehensive review portrays the functions of garlic, its bioactive constituents and nanoformulations against several types of cancers and explores the possibility of developing these agents as anticancer pharmaceuticals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Emerging scientific evidence indicates that inflammation is a critical component of tumor promotion and progression. Most cancers originate from sites of chronic irritation, infections and inflammation, underscoring that the tumor microenvironment is largely orchestrated by inflammatory cells and pro-inflammatory molecules. These inflammatory components are intimately involved in neoplastic processes which foster proliferation, survival, invasion, and migration, making inflammation the primary target for cancer prevention and treatment. The influence of inflammation and the immune system on the progression and development of cancer has recently gained immense interest. The Wnt/β-catenin signaling pathway, an evolutionarily conserved signaling strategy, has a critical role in regulating tissue development. It has been implicated as a major player in cancer development and progression with its regulatory role on inflammatory cascades. Many naturally-occurring and small synthetic molecules endowed with inherent anti-inflammatory properties inhibit this aberrant signaling pathway, making them a promising class of compounds in the fight against inflammatory cancers. This article analyzes available scientific evidence and suggests a crosslink between Wnt/β-catenin signaling and inflammatory pathways in inflammatory cancers, especially breast, gastrointestinal, endometrial, and ovarian cancer. We also highlight emerging experimental findings that numerous anti-inflammatory synthetic and natural compounds target the crosslink between Wnt/β-catenin pathway and inflammatory cascades to achieve cancer prevention and intervention. Current challenges, limitations, and future directions of research are also discussed., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest. The work has been approved by all authors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cancer remains to be the second highest cause of mortality in our society, falling just short of heart disease. Despite major advancement in cancer therapy over the past decade, momentum has been gaining for an alternative approach of using naturally-occurring and dietary agents for cancer prevention and management. Research on pomegranate (Punica granatum L.), a fruit of the Punicaceae family, has shown enormous potential for cancer prevention and intervention. In addition to a rich source of polyphenols, including flavonoids and ellagitannins, in its juice, pomegranate also houses hundreds of other phytochemicals in its pericarp, seed, flower, bark, flowers and leaves. These phytochemicals provide powerful antiproliferative, anti-inflammatory, antioxidant, anti-invasive, antimigratory, anti-angiogenic and anti-metastatic effects without significant toxicity. This makes the use of its various extracts a very attractive strategy to our current battle against cancer. This review article presents a systematic, comprehensive and critical review of research on pomegranate-derived products in both cancer prevention and intervention. It discusses the chemical constituents of pomegranate, the results of both preclinical (in vitro, ex vivo and in vivo) and clinical studies on the anticancer effect of pomegranate phytochemicals and molecular targets in numerous types of cancers, such as breast, gastrointestinal tract (oral, colon, liver and pancreas), gynecological (uterine and ovarian), hematological (lymphoma, leukemia and myeloma), lung, neurological (glioma), urogenital (bladder and prostate), bioavailability, pharmacokinetics and safety of pomegranate constituents. In order to guide the direction of future research, we have also included current limitations and challenges in the field and our post analysis recommendation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Vegetables of the Allium genus, such as garlic (Allium sativum L.), onions, shallots, leaks, and chives, have been used for many years for food consumption and for medicinal purposes. Historical medical texts have indicated the therapeutic applications of garlic as an antitumor, laxative, diuretic, antibacterial and antifungal agent. Specifically, garlic's antitumor abilities have been traced back 3500 years as a chemotherapeutic agent used in Egypt. Other beneficial effects of garlic consumption include lowering blood pressure, blood cholesterol, sugar and lipids. The processing and aging of garlic result in the production of non-toxic organosulfur by-products. These sulfur-containing compounds, such as allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, alliin, S-allylcysteine, and S-allylmercaptocysteine, impact various stages of carcinogenesis. The anticancer mechanisms of action of these garlic-derived phytochemicals include altering mitochondrial permeability, inhibiting angiogenesis, enhancing antioxidative and proapoptotic properties, and regulating cell proliferation. All these effects of garlic's sulfur-compounds have been demonstrated in various human cancers. The intent of this literature research is to explore the potential of garlic-derived products and bioactive organosulfur compounds as cancer chemopreventive and chemotherapeutic agents. This investigation employs criteria for systematic review and critically analyzes published in vitro, in vivo and clinical studies. Concerns and limitations that have arisen in past studies regarding standards of measurement, bioavailability, and method of delivery are addressed. Overall, it is hoped that through this systematic and comprehensive review, future researchers can be acquainted with the updated data assembled on anticancer properties of garlic and its phytoconstituents., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Xanthohumol (XH) is an important prenylated flavonoid that is found within the inflorescence of Humulus lupulus L. (Hop plant). XH is an important ingredient in beer and is considered a significant bioactive agent due to its diverse medicinal applications, which include anti-inflammatory, antimicrobial, antioxidant, immunomodulatory, antiviral, antifungal, antigenotoxic, antiangiogenic, and antimalarial effects as well as strong anticancer activity towards various types of cancer cells. XH acts as a wide ranging chemopreventive and anticancer agent, and its isomer, 8-prenylnaringenin, is a phytoestrogen with strong estrogenic activity. The present review focuses on the bioactivity of XH on various types of cancers and its pharmacokinetics. In this paper, we first highlight, in brief, the history and use of hops and then the chemistry and structure-activity relationship of XH. Lastly, we focus on its prominent effects and mechanisms of action on various cancers and its possible use in cancer prevention and treatment. Considering the limited number of available reviews on this subject, our goal is to provide a complete and detailed understanding of the anticancer effects of XH against different cancers.

Cancer is an anomalous growth and differentiation of cells known to be governed by oncogenic factors. Plant-based natural metabolites have been well recognized to possess chemopreventive properties. Deguelin, a natural rotenoid, is among the class of bioactive phytoconstituents from a diverse range of plants with potential antineoplastic effects in different cancer subtypes. However, the precise mechanisms of how deguelin inhibits tumor progression remains elusive. Deguelin has shown promising results in targeting the hallmarks of tumor progression via inducing tumor apoptosis, cell cycle arrest, and inhibition of angiogenesis and metastasis. Based on initial scientific excerpts, deguelin has been reported to inhibit tumor growth via different signaling pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, serine/threonine protein kinase B (also known as Akt), mammalian target of rapamycin, nuclear factor-κB, matrix metalloproteinase (MMP)-2, MMP-9 and caspase-3, caspase-8, and caspase-9. This review summarizes the mechanistic insights of antineoplastic action of deguelin to gain a clear understanding of its therapeutic effects in cancer. The anticancer potential of deguelin with respect to its efficacy in targeting tumorigenesis via nanotechnological approaches is also investigated. The initial scientific findings have presented deguelin as a promising antitumorigenic agent which can be used for monotherapy as well as synergistically to augment efficacy of chemotherapeutic treatment regimes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The dysregulation of Notch signaling is associated with a wide variety of different human cancers. Notch signaling activation mostly relies on the activity of the γ-secretase enzyme that cleaves the Notch receptors and releases the active intracellular domain. It is well-documented that γ-secretase inhibitors (GSIs) block the Notch activity, mainly by inhibiting the oncogenic activity of this pathway. To date, several GSIs have been introduced clinically for the treatment of various diseases, such as Alzheimer's disease and various cancers, and their impacts on Notch inhibition have been found to be promising. Therefore, GSIs are of great interest for cancer therapy. The objective of this review is to provide a systematic review of in vitro and in vivo studies for investigating the effect of GSIs on various cancer stem cells (CSCs), mainly by modulation of the Notch signaling pathway. Various scholarly electronic databases were searched and relevant studies published in the English language were collected up to February 2020. Herein, we conclude that GSIs can be potential candidates for CSC-targeting therapy. The outcome of our study also indicates that GSIs in combination with anticancer drugs have a greater inhibitory effect on CSCs.

Application of natural product-based nanoformulations for the treatment of different human diseases, such as cancer, is an emerging field. The conventional cancer therapeutic modalities, including surgery, chemotherapy, immunotherapy, radiotherapy has limited achievements. A larger number of drawbacks are associated with these therapies, including damage to proliferating healthy tissues, structural deformities, systemic toxicity, long-term side effects, resistance to the drug by tumor cells, and psychological problems. The advent of nanotechnology in cancer therapeutics is recent; however, it has progressed and transformed the field of cancer treatment at a rapid rate. Nanotherapeutics have promisingly overcome the limitations of conventional drug delivery system, i.e., low aqueous solubility, low bioavailability, multidrug resistance, and non-specificity. Specifically, natural product-based nanoformulations are being intentionally studied in different model systems. Where it is found that these nanoformulations has more proximity and reduced side effects. The nanoparticles can specifically target tumor cells, enhancing the specificity and efficacy of cancer therapeutic modalities which in turn improves patient response and survival. The integration of phytotherapy and nanotechnology in the clinical setting may improve pharmacological response and better clinical outcome of patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The development of cancer is a complex phenomenon driven by various extrinsic as well as intrinsic risk factors including epigenetic modifications. These post-translational modifications are encountered in diverse cancer cells and appear for a relatively short span of time. These changes can significantly affect various oncogenic genes and proteins involved in cancer initiation and progression. Histone lysine acetylation and deacetylation processes are controlled by two opposing classes of enzymes that modulate gene regulation either by adding an acetyl moiety on a histone lysine residue by histone lysine acetyltransferases (KATs) or via removing it by histone deacetylases (KDACs). Deregulated KAT activity has been implicated in the development of several diseases including cancer and can be targeted for the development of anti-neoplastic drugs. Here, we describe the predominant epigenetic changes that can affect key KAT superfamily members during carcinogenesis and briefly highlight the pharmacological potential of employing lysine acetyltransferase inhibitors (KATi) for cancer therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mangifera indica L. (mango), a long-living evergreen plant belonging to the Anacardiaceae family, has been cultivated for thousands of years in the Indian subcontinent for its excellent fruits which represent a rich source of fiber, vitamin A and C, essential amino acids, and a plethora of phytochemicals. M. indica is extensively used in various traditional systems of medicine to prevent and treat several diseases. The health-promoting and disease-preventing effects of M. indica are attributed to a number of bioactive phytochemicals, including polyphenols, terpenoids, carotenoid and phytosterols, found in the leaf, bark, edible flesh, peel, and seed. M. indica has been shown to exhibit various biological and pharmacological activities, such as antioxidant, anti-inflammatory, immunomodulatory, antimicrobial, antidiabetic, antiobesity, and anticancer effects. There are a few studies conducted that have indicated the nontoxic nature of mango constituents. However, while there are numerous individual studies investigating anticancer effects of various constituents from the mango tree, an up-to-date, comprehensive and critical review of available research data has not been performed according to our knowledge. The purpose of this review is to present a comprehensive and critical evaluation of cancer preventive and anticancer therapeutic potential of M. indica and its phytochemicals with special focus on the cellular and molecular mechanisms of action. The bioavailability, pharmacokinetics, and safety profile of individual phytocomponents of M. indica as well as current limitations, challenges, and future directions of research have also been discussed.

Ferulic acid (4-hydroxy-3-methoxycinnamic acid, FA), a hydroxycinnamic acid derived from various seeds, nuts, leaves, and fruits, exists in a free form as well as is covalently conjugated with polysaccharides, glycoproteins, polyamines, lignin, and hydroxy fatty acids of plant cell walls. It exhibits a variety of pharmacological effects, such as antioxidant, anti-inflammatory, vasodilatory, antithrombotic, antimicrobial, anti-allergic, antiviral, hepatoprotective, and anticancer activities. FA induces the expression of cell cycle-related proteins, such as p53 and p21, and reduces cyclin D1 and cyclin E levels. Moreover, FA triggers apoptosis and autophagic cell death depending on intracellular reactive oxygen species production in various cancer cell lines. The potential apoptotic action of FA is mediated by altered expression of procaspase-3, procaspase-8, procaspase-9, poly (ADP ribose) polymerase, Bcl-2, and Bax. It blocks the activation of both the canonical Smad and noncanonical extracellular-signal-regulated kinase/Akt (protein kinase B) pathways in various cancer cells. However, due to low solubility and permeability, its availability to biological systems is limited. Therefore, encapsulation of FA into chitosan tripolyphosphate nanoparticles may enhance its cytocompatibility, solubility, and anticancer potential. The nanohybrids of FA and double layered hydroxide exhibit cellular delivery properties of intercalated molecules on cancer cell lines. This chapter summarizes the anticancer efficacy of FA with an emphasis on the role of apoptosis, and underlying molecular mechanisms involving various signaling pathways in tumor cells., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Significance: Phytochemicals are important dietary constituents with antioxidant properties. They affect various signaling pathways involved in the overall maintenance of interior milieu of the cell. Arsenic, an environmental toxicant, is well known for its deleterious consequences, such as various diseases, including cancers in humans. Mitochondria are the cell's powerhouse that fuel all metabolic energy requirements. Dysfunctional mitochondria due to stressors may lead to abnormal functioning of the organelle, hampering the crucial cellular cross talks and ultimately leading to cancer. Application of phytochemicals against arsenic-induced mitochondrial disorders may be a preventive measure to counteract the ruinous impacts of the metalloid. Recent Advances: In recent years, extensive research on the role of mitochondria in cancer gives a better understanding of the areas the organelle covers in maintaining a healthy cell or in inducing carcinogenicity. Detailed knowledge of the mitochondrial governances would enable researchers to administer numerous phytochemicals to ameliorate altered oxidative phosphorylation, mitochondrial membrane potential (MMP), mitochondrial oxidative stress, unfolded protein response, glycolysis, or even apoptosis. Critical Issues: In this review, we have addressed how various phytochemicals belonging to diverse classes combat against arsenic-induced mitochondrial oxidative stress, depletion of MMP, cell cycle abrogation, apoptosis, glycolytic damages, oncogenic regulations, chaperones, mitochondrial complexes, and mitochondrial membrane pore formation in both in vitro and in vivo models. Future Directions: Insightful application of mitoprotective phytochemicals against arsenic-induced mitochondrial oxidative stress and carcinogenesis may guide researchers to develop preclinical chemopreventive agents to fight arsenic toxicity in humans.

Epithelial mesenchymal transition (EMT) is a complex process through which epithelial (E) cells lose their adherens junctions, transform into mesenchymal (M) cells and attain motility, leading to metastasis at distant organs. Nowadays, the concept of EMT has shifted from a binary phase of interconversion of pure E to M cells and vice versa to a spectrum of E/M transition states preferably coined as hybrid/partial/intermediate EMT. Hybrid EMT, being a plastic transient state, harbours cells which co-express both E and M markers and exhibit high tumourigenic properties, leading to stemness, metastasis, and therapy resistance. Several preclinical and clinical studies provided the evidence of co-existence of E/M phenotypes. Regulators including transcription factors, epigenetic regulators and phenotypic stability factors (PSFs) help in maintaining the hybrid state. Computational and bioinformatics approaches may be excellent for identifying new factors or combinations of regulatory elements that govern the different EMT transition states. Therapeutic intervention against hybrid E/M cells, though few, may evolve as a rational strategy against metastasis and drug resistance. This review has attempted to present the recent advancements on the concept and regulation of the process of hybrid EMT which generates hybrid E/M phenotypes, evidence of intermediate EMT in both preclinical and clinical setup, impact of partial EMT on promoting tumourigenesis, and future strategies which might be adapted to tackle this phenomenon.

Cancer is a prevalent cause of mortality around the world. Aberrated activation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway promotes tumorigenesis. Natural agents, including phytochemicals, exhibit potent anticancer activities via various mechanisms. However, the therapeutic potency of phytoconstituents as inhibitors of JAK/STAT signaling against cancer has only come into focus in recent days. The current review highlights phytochemicals that can suppress the JAK/STAT pathway in order to impede cancer cell growth. Various databases, such as PubMed, ScienceDirect, Web of Science, SpringerLink, Scopus, and Google Scholar, were searched using relevant keywords. Once the authors were in agreement regarding the suitability of a study, a full-length form of the relevant article was obtained, and the information was gathered and cited. All the complete articles that were incorporated after the literature collection rejection criteria were applied were perused in-depth and material was extracted based on the importance, relevance, and advancement of the apprehending of the JAK/STAT pathway and their relation to phytochemicals. Based on the critical and comprehensive analysis of literature presented in this review, phytochemicals from diverse plant origins exert therapeutic and cancer preventive effects, at least in part, through regulation of the JAK/STAT pathway. Nevertheless, more preclinical and clinical research is necessary to completely comprehend the capability of modulating JAK/STAT signaling to achieve efficient cancer control and treatment.

Inflammatory gastrointestinal (GI) diseases and malignancies are associated with growing morbidity and cancer-related mortality worldwide. GI tumor and inflammatory cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinase 1 (SphK1) and SphK2, that generate sphingosine-1-phosphate (S1P), a highly bioactive compound. Many inflammatory responses, including lymphocyte trafficking, are directed by circulatory S1P, present in high concentrations in both the plasma and the lymph of cancer patients. High fat and sugar diet, disbalanced intestinal flora, and obesity have recently been linked to activation of inflammation and SphK/S1P/S1P receptor (S1PR) signaling in various GI pathologies, including cancer. SphK1 overexpression and activation facilitate and enhance the development and progression of esophageal, gastric, and colon cancers. SphK/S1P axis, a mediator of inflammation in the tumor microenvironment, has recently been defined as a target for the treatment of GI disease states, including inflammatory bowel disease and colitis. Several SphK1 inhibitors and S1PR antagonists have been developed as novel anti-inflammatory and anticancer agents. In this review, we analyze the mechanisms of SphK/S1P signaling in GI tissues and critically appraise recent studies on the role of SphK/S1P/S1PR in inflammatory GI disorders and cancers. The potential role of SphK/S1PR inhibitors in the prevention and treatment of inflammation-mediated GI diseases, including GI cancer, is also evaluated., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest. The work has been approved by all authors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Often, even the most effective antineoplastic drugs currently used in clinic do not efficiently allow complete healing due to the related toxicity. The reason for the toxicity lies in the lack of selectivity for cancer cells of the vast majority of anticancer agents. Thus, the need for new potent anticancer compounds characterized by a better toxicological profile is compelling. Lectins belong to a particular class of non-immunogenic glycoproteins and have the characteristics to selectively bind specific sugar sequences on the surface of cells. This property is exploited to exclusively bind cancer cells and exert antitumor activity through the induction of different forms of regulated cell death and the inhibition of cancer cell proliferation. Thanks to the extraordinary biodiversity, marine environments represent a unique source of active natural compounds with anticancer potential. Several marine and freshwater organisms, ranging from the simplest alga to the most complex vertebrate, are amazingly enriched in these proteins. Remarkably, all studies gathered in this review show the impressive anticancer effect of each studied marine lectin combined with irrelevant toxicity in vitro and in vivo and pave the way to design clinical trials to assess the real antineoplastic potential of these promising proteins. It provides a concise and precise description of the experimental results, their interpretation as well as the experimental conclusions that can be drawn.

Angiogenesis, the process of formation and recruitment of new blood vessels from pre-existing vessels, plays an important role in the development of cancer. Therefore, the use of antiangiogenic agents is one of the most critical strategies for the treatment of cancer. In addition, the complexity of cancer pathogenicity raises the need for multi-targeting agents. Coumarins are multi-targeting natural agents belonging to the class of benzopyrones. Coumarins have several biological and pharmacological effects, including antimicrobial, antioxidant, anti-inflammation, anticoagulant, anxiolytic, analgesic, and anticancer properties. Several reports have shown that the anticancer effect of coumarins and their derivatives are mediated through targeting angiogenesis by modulating the functions of vascular endothelial growth factor as well as vascular endothelial growth factor receptor 2, which are involved in cancer pathogenesis. In the present review, we focus on the antiangiogenic effects of coumarins and related structure-activity relationships with particular emphasis on cancer.