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Diabetes and gastrointestinal cancers (GI) are global health conditions with a massive burden on patients’ lives worldwide. The development of both conditions is influenced by several factors, such as diet, genetics, environment, and infection, which shows a potential link between them. Flavonoids are naturally occurring phenolic compounds present in fruits and vegetables. Once ingested, unabsorbed flavonoids reaching the colon undergo enzymatic modification by the gut microbiome to facilitate absorption and produce ring fission products. The metabolized flavonoids exert antidiabetic and anti-GI cancer properties, targeting major impaired pathways such as apoptosis and cellular proliferation in both conditions, suggesting the potentially dual effects of flavonoids on diabetes and GI cancers. This review summarizes the current knowledge on the impact of flavonoids on diabetes and GI cancers in four significant pathways. It also addresses the synergistic effects of selected flavonoids on both conditions. While this is an intriguing approach, more studies are required to better understand the mechanism of how flavonoids can influence the same impaired pathways with different outcomes depending on the disease.

The disease of cancer instills a sense of fear and dread among patients and the next of kin who are indirectly affected by the deteriorating quality of life of their loved ones [...]

Simple Summary Flavonoid’s consumption is reported to impact GI cancer progression positively. As 90% of flavonoids consumed, undergo metabolism and conversion by the human gut microbiome, understanding their enzymatic bioconversion and metabolism could advance the current knowledge of their anticancer activities. While it is reported that specific flavonoids target cancer-related pathways such as apoptosis, inflammation and cellular proliferation, efforts are required to assess the possibility of combining those specific flavonoids together or with current treatment such as chemotherapy and evaluate their effect on the pathogenesis of GI cancer. Additionally, Studies aimed to standardize flavonoids administered concentration, purification and isolation methods are required. Abstract Gastrointestinal (GI) cancer is a prevalent global health disease with a massive burden on health care providers. Internal and external factors such as obesity, smoking, diet (red meat), low socioeconomic status and infection with Helicobacter pylori are the critical risk factors of GI cancers. Flavonoids are natural phenolic compounds found abundantly in fruits and vegetables. Upon ingestion, 90% of flavonoids consumed require further enzymatic metabolism by the gut microbiome to enhance their bioavailability and absorption. Several epidemiological studies reported that consumption of flavonoids and their enzymatic conversion by gut microbes is strongly associated with the reduced risk of GI cancer development. This review summarizes the current knowledge on the enzymatic conversion of flavonoids by the human gut microbiome. It also addresses the underlying anti-GI cancer effects on metabolic pathways such as apoptosis and cellular proliferation. Overall, metabolites produced from flavonoid’s enzymatic conversion illustrate anti-GI cancer effects, but the mechanisms of action need further clarification.

Simple Summary Glioblastoma (GBM) is a tumor of the brain or spinal cord with poor clinical prognosis. Current interventions, such as chemotherapy and surgical tumor resection, are constrained by tumor invasion and cancer drug resistance. Dietary natural substances are therefore evaluated for their potential as agents in GBM treatment. Various substances found in fruits, vegetables, and other natural products restrict tumor growth and induce GBM cell death. These preclinical effects are promising but remain constrained by natural substances’ varying pharmacological properties. While many of the reviewed substances are available as over-the-counter supplements, their anti-GBM efficacy should be corroborated by clinical trials moving forward. Abstract Glioblastoma (GBM) is an aggressive, often fatal astrocyte-derived tumor of the central nervous system. Conventional medical and surgical interventions have greatly improved survival rates; however, tumor heterogeneity, invasiveness, and chemotherapeutic resistance continue to pose clinical challenges. As such, dietary natural substances—an integral component of the lifestyle medicine approach to chronic diseases—are examined as potential chemotherapeutic agents. These heterogenous substances exert anti-GBM effects by upregulating apoptosis and autophagy, inducing cell cycle arrest, interfering with tumor metabolism, and inhibiting proliferation, neuroinflammation, chemoresistance, angiogenesis, and metastasis. Although these beneficial effects are promising, natural substances’ efficacy in GBM is constrained by their bioavailability and blood–brain barrier permeability; various chemical formulations are proposed to improve their pharmacological properties. Many of the reviewed substances are available as over-the-counter dietary supplements, underscoring their viability as lifestyle interventions. However, clinical trials remain necessary to substantiate the in vitro and in vivo properties of natural substances.

Simple Summary Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating condition that severely reduces the quality of life of a considerable proportion of cancer patients. There is no cure for CIPN to date. Here, we explore the potential of flavonoids as pharmacological agents in combating CIPN. Flavonoids alleviate CIPN by reducing oxidative stress, inflammation, and neuronal damage, among other mechanisms. Future research should evaluate the efficacy and side effects of flavonoids in human models of CIPN. Abstract Purpose: This study aimed to assess the potential of flavonoids in combating CIPN. Methods: PubMed and Google Scholar were used, and studies that investigated flavonoids in models of CIPN and models of neuropathic pain similar to CIPN were included. Only studies investigating peripheral mechanisms of CIPN were used. Results: Flavonoids inhibit several essential mechanisms of CIPN, such as proinflammatory cytokine release, astrocyte and microglial activation, oxidative stress, neuronal damage and apoptosis, mitochondrial damage, ectopic discharge, and ion channel activation. They decreased the severity of certain CIPN symptoms, such as thermal hyperalgesia and mechanical, tactile, and cold allodynia. Conclusions: Flavonoids hold immense promise in treating CIPN; thus, future research should investigate their effects in humans. Specifically, precise pharmacological mechanisms and side effects need to be elucidated in human models before clinical benefits can be achieved.

Gastrointestinal cancer (GI) is a global health disease with a huge burden on a patient’s physical and psychological aspects of life and on health care providers. It is associated with multiple disease related challenges which can alter the patient’s quality of life and well-being. GI cancer development is influenced by multiple factors such as diet, infection, environment, and genetics. Although activating immune pathways and components during cancer is critical for the host’s survival, cancerous cells can target those pathways to escape and survive. As the gut microbiome influences the development and function of the immune system, research is conducted to investigate the gut microbiome–immune interactions, the underlying mechanisms, and how they reduce the risk of GI cancer. This review addresses and summarizes the current knowledge on the major immune cells and gut microbiome interactions. Additionally, it highlights the underlying mechanisms of immune dysregulation caused by gut microbiota on four major cancerous pathways, inflammation, cellular proliferation, apoptosis, and metastasis. Overall, gut-immune interactions might be a key to understanding GI cancer development, but further research is needed for more detailed clarification.

Despite the leaps and bounds in achieving success in the management and treatment of breast cancers through surgery, chemotherapy, and radiotherapy, breast cancer remains the most frequently occurring cancer in women and the most common cause of cancer-related deaths among women. Systemic therapeutic approaches, such as chemotherapy, although beneficial in treating and curing breast cancer subjects with localized breast tumors, tend to fail in metastatic cases of the disease due to (a) an acquired resistance to the chemotherapeutic drug and (b) the development of intrinsic resistance to therapy. The existence of cancer stem cells (CSCs) plays a crucial role in both acquired and intrinsic chemoresistance. CSCs are less abundant than terminally differentiated cancer cells and confer chemoresistance through a unique altered metabolism and capability to evade the immune response system. Furthermore, CSCs possess active DNA repair systems, transporters that support multidrug resistance (MDR), advanced detoxification processes, and the ability to self-renew and differentiate into tumor progenitor cells, thereby supporting cancer invasion, metastasis, and recurrence/relapse. Hence, current research is focusing on targeting CSCs to overcome resistance and improve the efficacy of the treatment and management of breast cancer. Studies revealed that metformin (1, 1-dimethylbiguanide), a widely used anti-hyperglycemic agent, sensitizes tumor response to various chemotherapeutic drugs. Metformin selectively targets CSCs and improves the hypoxic microenvironment, suppresses the tumor metastasis and inflammation, as well as regulates the metabolic programming, induces apoptosis, and reverses epithelial–mesenchymal transition and MDR. Here, we discuss cancer (breast cancer) and chemoresistance, the molecular mechanisms of chemoresistance in breast cancers, and metformin as a chemo-sensitizing/re-sensitizing agent, with a particular focus on breast CSCs as a critical contributing factor to acquired and intrinsic chemoresistance. The review outlines the prospects and directions for a better understanding and re-purposing of metformin as an anti-cancer/chemo-sensitizing drug in the treatment of breast cancer. It intends to provide a rationale for the use of metformin as a combinatory therapy in a clinical setting.

An incidence and mortality of cancer are rapidly growing worldwide, especially due to heterogeneous character of the disease that is associated with irreversible impairment of cellular homeostasis and function. Targeting apoptosis, one of cancer hallmarks, represents a potent cancer treatment strategy. Carotenoids are phytochemicals represented by carotenes, xanthophylls, and derived compounds such as apocarotenoids that demonstrate a broad spectrum of anti-cancer effects involving pro-apoptotic signaling through extrinsic and intrinsic pathways. As demonstrated in preclinical oncology research, the apoptotic modulation is performed at post-genomic levels. Further, carotenoids demonstrate additive/synergistic action in combination with conventional oncostatic agents. In addition, a sensitization of tumor cells to anti-cancer conventional treatment can be achieved by carotenoids. The disadvantage of anti-cancer application of carotenoids is associated with their low solubility and, therefore, poor bioavailability. However, this deficiency can be improved by using nanotechnological approaches, solid dispersions, microemulsions or biofortification that significantly increase the anti-cancer and pro-apoptotic efficacy of carotenoids. Only limited number of studies dealing with apoptotic potential of carotenoids has been published in clinical sphere. Pro-apoptotic effects of carotenoids should be beneficial for individuals at high risk of cancer development. The article considers the utility of carotenoids in the framework of 3P medicine.

Breast cancer (BC) is the most prevalent cancer in women. BC is heterogeneous, with distinct phenotypical and morphological characteristics. These are based on their gene expression profiles, which divide BC into different subtypes, among which the triple-negative breast cancer (TNBC) subtype is the most aggressive one. The growing interest in tumor metabolism emphasizes the role of altered glucose metabolism in driving cancer progression, response to cancer treatment, and its distinct role in therapy resistance. Alterations in glucose metabolism are characterized by increased uptake of glucose, hyperactivated glycolysis, decreased oxidative phosphorylation (OXPHOS) component, and the accumulation of lactate. These deviations are attributed to the upregulation of key glycolytic enzymes and transporters of the glucose metabolic pathway. Key glycolytic enzymes such as hexokinase, lactate dehydrogenase, and enolase are upregulated, thereby conferring resistance towards drugs such as cisplatin, paclitaxel, tamoxifen, and doxorubicin. Besides, drug efflux and detoxification are two energy-dependent mechanisms contributing to resistance. The emergence of resistance to chemotherapy can occur at an early or later stage of the treatment, thus limiting the success and outcome of the therapy. Therefore, understanding the aberrant glucose metabolism in tumors and its link in conferring therapy resistance is essential. Using combinatory treatment with metabolic inhibitors, for example, 2-deoxy-D-glucose (2-DG) and metformin, showed promising results in countering therapy resistance. Newer drug designs such as drugs conjugated to sugars or peptides that utilize the enhanced expression of tumor cell glucose transporters offer selective and efficient drug delivery to cancer cells with less toxicity to healthy cells. Last but not least, naturally occurring compounds of plants defined as phytochemicals manifest a promising approach for the eradication of cancer cells via suppression of essential enzymes or other compartments associated with glycolysis. Their benefits for human health open new opportunities in therapeutic intervention, either alone or in combination with chemotherapeutic drugs. Importantly, phytochemicals as efficacious instruments of anticancer therapy can suppress events leading to chemoresistance of cancer cells. Here, we review the current knowledge of altered glucose metabolism in contributing to resistance to classical anticancer drugs in BC treatment and various ways to target the aberrant metabolism that will serve as a promising strategy for chemosensitizing tumors and overcoming resistance in BC.

Metastasis represents a serious complication in the treatment of cancer. Flavonoids are plant secondary metabolites exerting various health beneficiary effects. The effects of flavonoids against cancer are associated not only with early stages of the cancer process, but also with cancer progression and spread into distant sites. Flavonoids showed potent anti-cancer effects against various cancer models in vitro and in vivo, mediated via regulation of key signaling pathways involved in the migration and invasion of cancer cells and metastatic progression, including key regulators of epithelial-mesenchymal transition or regulatory molecules such as MMPs, uPA/uPAR, TGF-β and other contributors of the complex process of metastatic spread. Moreover, flavonoids modulated also the expression of genes associated with the progression of cancer and improved inflammatory status, a part of the complex process involved in the development of metastasis. Flavonoids also documented clear potential to improve the anti-cancer effectiveness of conventional chemotherapeutic agents. Most importantly, flavonoids represent environmentally-friendly and cost-effective substances; moreover, a wide spectrum of different flavonoids demonstrated safety and minimal side effects during long-termed administration. In addition, the bioavailability of flavonoids can be improved by their conjugation with metal ions or structural modifications by radiation. In conclusion, anti-cancer effects of flavonoids, targeting all phases of carcinogenesis including metastatic progression, should be implemented into clinical cancer research in order to strengthen their potential use in the future targeted prevention and therapy of cancer in high-risk individuals or patients with aggressive cancer disease with metastatic potential.

Simple Summary Metabolic reprogramming is required for both malignant transformation and tumor development, including invasion and metastasis. Melatonin (5-methoxy-N-acetyltryptamine) is a methoxyindole that is synthesized in the pineal gland. Importantly, melatonin has anticancer effects by stimulating apoptosis, regulation of survival signaling, suppression of metastasis and angiogenesis and regulation of epigenetic modifications that contribute to malignant transformation. Furthermore, melatonin affects steps associated with the Warburg phenotype and suppresses the switch from oxidative phosphorylation to aerobic glycolysis through the regulation of critical enzymes and glucose transporters. Melatonin is involved in regulation of p53 and HIF-1, directly participate in signaling cascades that modulate aerobic glycolysis, gluconeogenesis, the tricarboxylic acid cycle and the pentose phosphate pathway. A significant impact of melatonin in the modulation of metabolic cascades represent a unique opportunity to inhibit pathways metabolic reprogramming. Abstract Metabolic reprogramming characterized by alterations in nutrient uptake and critical molecular pathways associated with cancer cell metabolism represents a fundamental process of malignant transformation. Melatonin (N-acetyl-5-methoxytryptamine) is a hormone secreted by the pineal gland. Melatonin primarily regulates circadian rhythms but also exerts anti-inflammatory, anti-depressant, antioxidant and anti-tumor activities. Concerning cancer metabolism, melatonin displays significant anticancer effects via the regulation of key components of aerobic glycolysis, gluconeogenesis, the pentose phosphate pathway (PPP) and lipid metabolism. Melatonin treatment affects glucose transporter (GLUT) expression, glucose-6-phosphate dehydrogenase (G6PDH) activity, lactate production and other metabolic contributors. Moreover, melatonin modulates critical players in cancer development, such as HIF-1 and p53. Taken together, melatonin has notable anti-cancer effects at malignancy initiation, progression and metastasing. Further investigations of melatonin impacts relevant for cancer metabolism are expected to create innovative approaches supportive for the effective prevention and targeted therapy of cancers.

Metformin, the most widely used anti-diabetic drug, also exhibits anti-cancer properties, however, the true potential of metformin as an anticancer drug remains largely unknown. In this study using mouse microvascular endothelial cells (MMECs), we investigated the effects of metformin alone or in combination with the glycolytic inhibitor, 2-deoxyglucose (2DG), on angiogenesis-a process known to be an integral part of tumor growth, cancer cell survival and metastasis. MMECs were exposed to 2DG (1&ndash, 10 mM) for 48 h in the absence or presence of metformin (2 mM). The status of angiogenic and anti-angiogenic marker proteins, proteins of the mTOR pathway and cell-cycle-related proteins were quantified by Western blot analysis. Assays for cell proliferation, migration and tubulogenesis were also performed. We observed robust up-regulation of anti-angiogenic thrombospondin-1 (TSP1) and increased TSP1-CD36 co-localization with a marked decrease in the levels of phosphorylated vascular endothelial growth factor receptor-2 (pVEGFR2, Y1175) in 2DG (5 mM) exposed cells treated with metformin (2 mM). Additionally, treatment with metformin and 2DG (5 mM) inhibited the Akt/mTOR pathway and down-regulated the cell-cycle-related proteins such as p-cyclin B1 (S147) and cyclins D1 and D2 when compared to cells that were treated with either 2DG or metformin alone. Treatment with a combination of 2DG (5 mM) and metformin (2 mM) also significantly decreased cell proliferation, migration and tubulogenic capacity when compared to cells that were treated with either 2DG or metformin alone. The up-regulation of TSP1, inhibition of cell proliferation, migration and tubulogenesis provides support to the argument that the combination of metformin and 2DG may prove to be an appropriate anti-proliferative and anti-angiogenic therapeutic strategy for the treatment of some cancers.

Among the different types of breast cancers, triple-negative breast cancers (TNBCs) are highly aggressive, do not respond to conventional hormonal/human epidermal growth factor receptor 2 (HER2)-targeted interventions due to the lack of the respective receptor targets, have chances of early recurrence, metastasize, tend to be more invasive in nature, and develop drug resistance. The global burden of TNBCs is increasing regardless of the number of cytotoxic drugs being introduced into the market each year as they have only moderate efficacy and/or unforeseen side effects. Therefore, the demand for more efficient therapeutic interventions, with reduced side effects, for the treatment of TNBCs is rising. While some plant metabolites/derivatives actually induce the risk of cancers, many plant-derived active principles have gained attention as efficient anticancer agents against TNBCs, with fewer adverse side effects. Here we discuss the possible oncogenic molecular pathways in TNBCs and how the purified plant-derived natural compounds specifically target and modulate the genes and/or proteins involved in these aberrant pathways to exhibit their anticancer potential. We have linked the anticancer potential of plant-derived natural compounds (luteolin, chalcones, piperine, deguelin, quercetin, rutin, fisetin, curcumin, resveratrol, and others) to their ability to target multiple dysregulated signaling pathways (such as the Wnt/β-catenin, Notch, NF-κB, PI3K/Akt/mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK) and Hedgehog) leading to suppression of cell growth, proliferation, migration, inflammation, angiogenesis, epithelial-mesenchymal transition (EMT) and metastasis, and activation of apoptosis in TNBCs. Plant-derived compounds in combination with classical chemotherapeutic agents were more efficient in the treatment of TNBCs, possibly with lesser side effects.

Neuroblastoma is the second most common paediatric cancer. It develops from undifferentiated simpatico-adrenal lineage cells and is mostly sporadic; however, the aetiology behind the development of neuroblastoma is still not fully understood. Intracellular calcium ([Ca2+]i) is a secondary messenger which regulates numerous cellular processes and, therefore, its concentration is tightly regulated. This review focuses on the role of [Ca2+]i in differentiation, apoptosis and proliferation in neuroblastoma. It describes the mechanisms by which [Ca2+]i is regulated and how it modulates intracellular pathways. Furthermore, the importance of [Ca2+]i for the function of anti-cancer drugs is illuminated in this review as [Ca2+]i could be a target to improve the outcome of anti-cancer treatment in neuroblastoma. Overall, modulations of [Ca2+]i could be a key target to induce apoptosis in cancer cells leading to a more efficient and effective treatment of neuroblastoma.

Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is the intrinsic or acquired drug resistance. Therefore, cancer drug resistance is a major impediment in medical oncology resulting in a failure of a successful cancer treatment. This mini-overview focuses on the interdependent relationship between intracellular calcium ([Ca2+]i) signaling and multidrug resistance of cancer cells, acquired upon treatment of tumors with anticancer drugs. We propose that [Ca2+]i signaling modulates gene expression of multidrug resistant (MDR) genes which in turn can be modulated by epigenetic factors which in turn leads to modified protein expression in drug resistant tumor cells. A precise knowledge of these mechanisms will help to develop new therapeutic strategies for drug resistant tumors and will improve current chemotherapy.

Cancer is the second leading cause of death globally. Although, there are many different approaches to cancer treatment, they are often painful due to adverse side effects and are sometimes ineffective due to increasing resistance to classical anti-cancer drugs or radiation therapy. Targeting delayed/inhibited apoptosis is a major approach in cancer treatment and a highly active area of research. Plant derived natural compounds are of major interest due to their high bioavailability, safety, minimal side effects and, most importantly, cost effectiveness. Flavonoids have gained importance as anti-cancer agents and have shown great potential as cytotoxic anti-cancer agents promoting apoptosis in cancer cells. In this review, a summary of flavonoids and their effectiveness in cancer treatment targeting apoptosis has been discussed.

Cancer is a main public health problem all over the world. It affects millions of humans no matter their age, gender, education, or social status. Although chemotherapy is the main strategy for the treatment of cancer, a major problem limiting its success is the intrinsic or acquired drug resistance. Therefore, cancer drug resistance is a major impediment in medical oncology resulting in a failure of a successful cancer treatment. This mini-overview focuses on the interdependent relationship between intracellular calcium ([Ca2+]i) signaling and multidrug resistance of cancer cells, acquired upon treatment of tumors with anticancer drugs. We propose that [Ca2+]i signaling modulates gene expression of multidrug resistant (MDR) genes which in turn can be modulated by epigenetic factors which in turn leads to modified protein expression in drug resistant tumor cells. A precise knowledge of these mechanisms will help to develop new therapeutic strategies for drug resistant tumors and will improve current chemotherapy.

Auranofin, a transition metal complex is used for the treatment of rheumatoid arthritis but is also an effective anti-cancer drug. We investigate the effects of Auranofin in inducing cell death by apoptosis and whether these changes are correlated to changes of intracellular calcium concentration ([Ca2+]i) in breast cancer cells (MCF-7). Cytotoxicity of Auranofin was evaluated using MTS assay and the Trypan blue dye exclusion method. With fluorescent dyes SR-FLICA and 7-AAD apoptotic death and necrotic death were differentiated by Flow cytometry. A concentration dependent decrease in the viability occurred and cells were shifted to the apoptotic phase. Intracellular calcium ([Ca2+]i) was recorded using florescence microscopy and a calcium sensitive dye (Fluo-4 AM) with a strong negative correlation (r = −0.713) to viability. Pharmacological modulators 2-APB (50 μM), Nimodipine (10 μM), Caffeine (10 mM), SKF 96365(20 μM) were used to modify calcium entry and release. Auranofin induced a sustained increase of [Ca2+]i in a concentration and time dependent manner. The use of different blockers of calcium channels did not reveal the source for the rise of [Ca2+]i. Overall, elevation of [Ca2+]i by Auranofin might be crucial for triggering Ca2+-dependent apoptotic pathways. Therefore, in anti-cancer therapy, modulating [Ca2+]i should be considered as a crucial factor for the induction of cell death in cancer cells.