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A highly selective, sensitive caffeic acid (CA) detection based on calcium oxide nanoparticles (CaO NPs) derived from extract of Moringa oleifera leaves decorated graphitic carbon nitride covalently grafted poly vinyl alcohol (CaO/g-C3N4/PVA) nanocomposite modified glassy carbon electrode (GCE) was studied. A facile sonochemical method was adapted to synthesis nanomaterials and characterized by HR-TEM (High resolution transmission electron microscopy), FT-IR (Fourier transform infrared spectroscopy), XRD (X-ray diffraction), FE-SEM (Field emission scanning electron microscopy), EDX (Energy dispersive X-ray analysis), Mapping and BET (Brunauer-Emmett-Teller) analysis, and electrochemical techniques. The nanocomposite modified GCE exhibited an excellent catalytic performance to the oxidation of CA under optimized conditions owing to better electron transfer efficiency, conductivity and high surface area of the electrode material. The present electrochemical sensor showed high selectivity towards the determination of 10 µM CA in the presence of 100-fold higher concentrations of interferents. The modified CA sensor exhibited a wide sensing linear range from 0.01 µM to 70 µM and the detection limit (LOD) was found to be 0.0024 µM (S/N = 3) in 0.1 M phosphate buffer saline (PBS) as a supporting electrolyte at pH 7.0. The fabricated CA sensor provides an excellent stability, reproducibility and selectivity for the determination of CA. The modified CA sensor was applied to real blood plasma samples and obtained good recovery (97.6-100.1%) results. [ABSTRACT FROM AUTHOR]

Microfluid-derived liposomes (M-Lipo) exhibit great potential as drug and functional substance carriers in pharmaceutical and food science. However, the low liposome membrane stability, attributed to the liquid core, limits their application range. Oleosin, a natural surfactant protein, can improve the stability of the lipid nanoparticle membrane against various environmental stresses, such as heat, drying, and pH change; in addition, it can enable sustained drug release. Here, we proposed the fabrication of oleosin-coated M-Lipo (OM-Lipo) through self-assembly on a microfluidic chip and the evaluation of its anticancer drug (carmustine) delivery efficiency. Nanoparticle characterization revealed that the oleosin coating slightly lowered the membrane potential of M-Lipo and greatly improved their dispersibility. Additionally, the in vitro drug release profile showed that the oleosin coating improved the sustained release of the hydrophobic drug from the phospholipid bilayer in body temperature. Our results suggest that OM-Lipo has sufficient potential in various fields, based on its easy production, excellent stability, and biocompatibility. [ABSTRACT FROM AUTHOR]

Cisplatin, the pioneering heavy metal compound, stands out as a potent drug for the treatment of various solid tumors. However, its clinical utility is hampered by notable toxicity and adverse effects, particularly nephrotoxicity. The potency of rutecarpine, a phytochemical, in mitigating cisplatin‐induced nephrotoxicity was assessed in the present study. In this experimental setup, healthy male Wistar rats were grouped into four and Group I rats served as the control group, receiving only vehicle control. Group II rats were subjected to cisplatin treatment alone, administered intraperitoneally at a dosage of 7 mg/kg body weight on the 19th, 20th, and 21st days. Group III and IV rats were orally administered with rutecarpine at doses of 10 and 20 mg/kg body weight, respectively, starting from Day 1 and continuing daily for 21 days. Additionally, they were injected intraperitoneally with cisplatin at the same dosage and schedule as Group II. Relative kidney weight and renal biochemical markers blood urea nitrogen, lactate dehydrogenase, serum urea, and creatinine were measured to assess rutecarpine inhibitory potency against cisplatin toxicity. Markers of oxidative damage and antioxidants levels were quantified in the ruteacarpine‐ and cisplatin‐treated rats. The study investigated the anti‐inflammatory property of rutecarpine in cisplatin‐induced nephrotoxicity by analyzing inflammatory cytokines. Renal tissue levels of monocyte chemoattractant protein‐1, intercellular adhesion molecule‐1, high‐mobility group box 1, and nuclear factor kappa B, key markers of nephrotoxicity, were quantified to assess rutecarpine's potential to mitigate cisplatin‐triggered damage. Histopathological examinations were performed to confirm the impact of rutecarpine against cisplatin‐induced nephrotoxicity. Treatment with rutecarpine notably reduced renal biochemical markers, prevented renal edema, and attenuated oxidative stress‐induced damage in cisplatin‐treated rats. Both inflammatory and nephrotoxicity markers showed significant decreases in rats treated with rutecarpine along with cisplatin. Histological analysis affirmed that rutecarpine pretreatment effectively prevented cisplatin‐induced nephrotoxicity. The study findings demonstrate that rutecarpine ameliorates cisplatin‐triggered nephrotoxicity through its antioxidant and anti‐inflammatory properties, suggesting that rutecarpine supplementation alongside cisplatin treatment could potentially reduce nephrotoxicity in cancer patients. [ABSTRACT FROM AUTHOR]

NLRP1 is predominantly overexpressed in breast cancer tissue, and the evaluated activation of NLRP1 inflammasome is associated with tumor growth, angiogenesis, and metastasis. Therefore, targeting NLRP1 activation could be a crucial strategy in anticancer therapy. In this study, we investigated the hypothesis that NLRP1 pathway may contribute to the cytotoxic effects of celecoxib and nimesulide in MDA-MB-231 cells. First of all, IC50 values and inhibitory effects on the colony-forming ability of drugs were evaluated in cells. Then, the alterations in the expression levels of NLRP1 inflammasome components induced by drugs were investigated. Subsequently, the release of inflammatory cytokine IL-1β and the activity of caspase-1 in drug-treated cells were measured. According to our results, celecoxib and nimesulide selectively inhibited the viability of MDA-MB-231 cells. These drugs remarkably inhibited the colony-forming ability of cells. The expression levels of NLRP1 inflammasome components decreased in celecoxib-treated cells, accompanied by decreased caspase-1 activity and IL-1β release. In contrast, nimesulide treatment led to the upregulation of the related protein expressions with unchanged caspase-1 activity and increased IL-1β secretion. Our results indicated that the NLRP1 inflammasome pathway might contribute to the antiproliferative effects of celecoxib in MDA-MB-231 cells but is not a crucial mechanism for nimesulide. [ABSTRACT FROM AUTHOR]

Anticancer drug discovery needs serious attention to overcome the high mortality rate caused by cancer. There are still many obstacles to treating this disease, such as the high cost of chemotherapeutic drugs, the resulting side effects from the drug, and the occurrence of multidrug resistance. Herbaceous plants are a reservoir of natural compounds that can be anticancer drugs with novel mechanisms of action. Piperine, a bioactive compound derived from Piper species, is gaining attention due to its unique dual role in directly inhibiting tumor growth and enhancing the bioavailability of chemotherapeutic drugs. Unlike conventional treatments, Piperine exhibits a novel mechanism of action by modulating multiple signaling pathways, including apoptosis and autophagy, with low toxicity. Additionally, Piperine acts as a bioenhancer by improving the absorption and effectiveness of other anticancer agents, reducing the required dosage, and minimizing side effects. Therefore, this review aims to visualize a summary of Piperine sources, phytochemistry, chemical structure–anticancer activity relationship, anticancer activities of semi‐synthetic derivatives, pharmacokinetic and bioavailability, in vitro and in vivo preclinical studies, mechanism of antitumor action, human clinical trials, toxicity, side effects, and safety of Piperine. References were collected from the Pubmed/MedLine database (https://pubmed.ncbi.nlm.nih.gov/) with the following keywords: “Piperine anticancer,” “Piperine derivatives,” “Piperine antitumor mechanism” and “Piperine pharmacokinetic and bioavailability,” after filter process by inclusion and exclusion criteria, 101 were selected from 444 articles. From 2013 to 2023, there were numerous studies regarding preclinical studies of Piperine of various cell lines, including breast cancer, prostate cancer, lung cancer, melanoma, cervical cancer, gastric cancer, osteosarcoma, colon cancer, hepatocellular carcinoma, ovarian cancer, leukemia, colorectal cancer, and hypopharyngeal carcinoma. In vivo, the anticancer study has also been conducted on some animal models, such as Ehrlich carcinoma‐bearing mice, Ehrlich ascites carcinoma cells‐bearing Balbc mice, hepatocellular carcinoma‐bearing Wistar rat, A375SM cells‐bearing mice, A375P cells‐bearing mice, SNU‐16 cells‐bearing BalbC mice, and HGC‐27‐bearing baby mice. Treatment with this compound leads to cell proliferation inhibition and induction of apoptosis. Piperine has been used for clinical trials of diseases, but no cancer patient report exists. Various semi‐synthetic derivatives of Piperine show efficacy as an anticancer drug across multiple cell lines. Piperine shows promise for use in cancer clinical trials, either as a standalone treatment or as a bioenhancer. Its bioenhancer properties may enhance the efficacy of existing chemotherapeutic agents, providing a valuable foundation for developing new anticancer therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Niclosamide, a drug originally used to treat parasitic infections, has shown potential as a possible cancer treatment, but poor absorptive and solubility properties are believed to limit its effectiveness. Researchers are exploring modified structures of the drug along with advanced delivery methods, particularly nanotechnology, to improve niclosamide's absorption profile and improve its specificity in regard to targeting cancerous cells. These efforts intend to produce more effective tumor-targeting compounds, which can be employed as pharmacological cancer treatment options when appropriate. If successful, these efforts will provide new tools for scientists and doctors, offering a novel approach regarding the treatment of a variety of different cancers and contribute to the elucidation of oncobiology. Inhibition of multiple cancer-related pathways has made niclosamide a promising candidate for the treatment of various cancers. However, its clinical application has been significantly limited by poor bioavailability. This review will discuss current findings on improving niclosamide bioavailability through modification of its chemical structure and utilization of novel nanotechnologies, like electrospraying and supercritical fluids, to improve drug delivery. For example, niclosamide derivatives, such as o-alkylamino-tethered niclosamide derivates, niclosamide ethanolamine salt, and niclosamide piperazine salt, have demonstrated increased water solubility without compromising anticancer activity in vitro. Additionally, this review briefly discusses recent findings on the first pass metabolism of niclosamide in vivo, the role of cytochrome P450-mediated hydroxylation, UDP-glucuronosyltransferase mediated glucuronidation, and how enzymatic inhibition could enhance niclosamide bioavailability. Ultimately, there is a need for researchers to synthesize, evaluate, and improve upon niclosamide derivatives while experimenting with the employment of nanotechnologies, such as targeted delivery and nanoparticle modification, as a way to improve drug administration. Researchers should strive to improve drug-target accuracy, its therapeutic index, and increase the drug's efficacy as an anti-neoplastic agent. [ABSTRACT FROM AUTHOR]

Triptolide, a bioactive diterpene tri-epoxide extracted from Tripterygium wilfordii Hook F (TWHF), exhibits notable pharmacological activities, including anti-inflammatory, immunosuppressive, antifertility, and anticancer effects. Despite its promising therapeutic potential, clinical applications of triptolide are significantly limited by its poor water solubility and substantial toxicity, particularly hepatotoxicity, nephrotoxicity, and cardiotoxicity. These toxic effects are difficult to separate from many of its desired therapeutic effects, the Yin and Yang of triptolide applications. Triptolide’s therapeutic and toxic effects are linked to its inhibitory interactions with XPB, a DNA helicase essential for transcription by RNA polymerase II (RNAPII) and nucleotide excision repair (NER). By irreversibly binding to XPB, triptolide inhibits its ATPase activity, leading to global repression of transcription and impaired NER, which underlies its cytotoxic and antitumor properties. Recent developments, including triptolide prodrugs such as Minnelide and derivatives like glutriptolides, aim to enhance its pharmacokinetic properties and reduce toxicity. This review critically examines triptolide’s chemical structure, therapeutic applications, toxicological profile, and molecular interactions with XPB and other protein targets to inform future strategies that maximize therapeutic efficacy while minimizing adverse effects. [ABSTRACT FROM AUTHOR]

Purpose: Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are relatively common toxicities that interfere with the quality of life (QoL) of patients with cancer. Anti-inflammatory tripeptide cream (ATPC) is a complex formulation of anti-inflammatory tripeptides, the CD99-agonist Binterin and the Wnt-antagonist Winhibin. The present study aimed to assess the therapeutic effects of ATPC in HFS/HFSR associated with anticancer drugs. Materials and Methods: This was a single-center, randomized, double-blind, placebo-controlled trial. Patients who developed grade 1 HFS/HFSR after systemic anticancer treatments were enrolled, and randomly assigned to receive either ATPC or placebo cream (PC) and followed up at 3-week intervals for up to 9 weeks. Primary endpoint was the development of grade ≥ 2 HFS/HFSR. Results: Between April 2019 and July 2022, 60 patients (31 in the ATPC and 29 in the PC group) completed the study. The incidence of grade ≥ 2 HFS/HFSR was significantly lower in the ATPC than in the PC group (25.8% vs. 51.7%, p=0.039). The ATPC showed trends towards a better QoL score, assessed by a HFSR and QoL questionnaire at 9 weeks (26.0 vs. 29.9, p=0.574), and a lower frequency of discontinuation, interruption, or dose reduction of anticancer drugs (51.6% vs. 58.6%, p=0.586) than the PC group over 9 weeks, though without statistical significance. Conclusion: Our results showed that ATPC significantly decreased the development of grade ≥ 2 HFS/HFSR in patients already with HFS/HFSR. Therefore, ATPC may be an effective treatment for HFS/HFSR associated with anticancer drugs. [ABSTRACT FROM AUTHOR]

Background: Cancer is uncontrolled cell proliferation that has the potential to invade other tissues and cells. The first three most prevalent cancers are breast, lung, and colon cancer. The widest family of kinase enzymes is receptor tyrosine kinases (RTKs) which are aimed by several chemotherapy medicines. The vascular endothelial growth factor (VEGFR), a well-known type IV tyrosine kinase receptor, is an effective biological target for the development of angiogenesis-related cancer treatments. The hepatocyte growth factor (also known as mesenchymal–epithelial transition factor) triggers the activation of the c-Met tyrosine kinase receptor, which controls several biological processes including cell division, survival, and proliferation. Main body: In this review, we summarized the various dual inhibitors of VEGFR and c-MET receptors which are active for therapeutic action against cancer. Combination of some VEGFR and c-Met inhibitors also shows synergistic action. The developed dual inhibitors of VEGFR and c-MET such as quinolones and quinazolines derivatives, pyridine and pyrimidine derivatives, oxindole moiety and triazine derivatives are most potent for the same. Dual inhibitors of VEGFR and c-MET hold significant promise in improving cancer therapy by enhancing treatment efficacy, reducing resistance, and potentially improving patient outcomes. Clinical trials are currently being conducted on a few of them and other compounds are being under investigation. Inhibiting VEGFR and c-Met pathway activity will be discussed as novel therapeutic strategies for advanced development in treating cancer. The research progress in this review is fetched up to the current year. Conclusion: Apart from the development of cancer treatment still cancer is listed as a deadly disease, due to its toxicity and resistance to treatment. Hence, the novel approach is necessary to overcome the cancer. The VEGFR and c-MET inhibitors as dual inhibitors may be more significant in future clinical anticancer treatments. [ABSTRACT FROM AUTHOR]

Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways. [ABSTRACT FROM AUTHOR]

Among the low-dimensional carbon-based systems, bilayer graphene garners great interest. In contrast to monolayer graphene, infinite bilayer graphene displays a gap in the electronic spectrum, establishing a link with semiconducting materials utilized in conventional electronics. Graphene nanosheets (GNS) are used for biological purposes, including drug delivery, illness detection, biosensing, drug targeting treatment, photothermal therapy, and tissue engineering. In this study, bilayer circumcoronene (CC2L) and boron nitride bilayer circumcoronene (BNCC2L) are utilized as carriers for the anticancer drug hydroxyurea (HU) and the effect of impurity phosphorus (PHIS) on the electrical and optical characteristics of all complex structures. We calculated several electronic and optical characteristics using the density functional theory (DFT) method offered by the QuantumATK software package. From the results, adding two phosphor impurity molecules (2PH) to CC2L led to a decreasing energy gap from 0.766 to 0.061 eV and adding two phosphor impurity molecules (2PH) to BNCC2L led to a decreasing energy gap from 4.945 to 1.055 eV. Due to its greater total energy, the HU/2PH-BNCC2L structure became more stable and less reactive than other structures. The HU/1PHIS-CC2L structure exhibits a large absorption peak with a magnitude of 4.08 × 105cm−1 at 1.9 eV in the (xx and yy) directions. The adsorption energy of HU/2PH-CC2L is − 3.036 eV which makes it have more stable complex structures than other nanomaterials, making it more likely to deliver HU molecule than other nanomaterials. [ABSTRACT FROM AUTHOR]

Abstract A highly selective, sensitive caffeic acid (CA) detection based on calcium oxide nanoparticles (CaO NPs) derived from extract of Moringa oleifera leaves decorated graphitic carbon nitride covalently grafted poly vinyl alcohol (CaO/g-C3N4/PVA) nanocomposite modified glassy carbon electrode (GCE) was studied. A facile sonochemical method was adapted to synthesis nanomaterials and characterized by HR-TEM (High resolution transmission electron microscopy), FT-IR (Fourier transform infrared spectroscopy), XRD (X-ray diffraction), FE-SEM (Field emission scanning electron microscopy), EDX (Energy dispersive X-ray analysis), Mapping and BET (Brunauer-Emmett-Teller) analysis, and electrochemical techniques. The nanocomposite modified GCE exhibited an excellent catalytic performance to the oxidation of CA under optimized conditions owing to better electron transfer efficiency, conductivity and high surface area of the electrode material. The present electrochemical sensor showed high selectivity towards the determination of 10 µM CA in the presence of 100-fold higher concentrations of interferents. The modified CA sensor exhibited a wide sensing linear range from 0.01 µM to 70 µM and the detection limit (LOD) was found to be 0.0024 µM (S/N = 3) in 0.1 M phosphate buffer saline (PBS) as a supporting electrolyte at pH 7.0. The fabricated CA sensor provides an excellent stability, reproducibility and selectivity for the determination of CA. The modified CA sensor was applied to real blood plasma samples and obtained good recovery (97.6-100.1%) results.

Abstract Background Cancer is uncontrolled cell proliferation that has the potential to invade other tissues and cells. The first three most prevalent cancers are breast, lung, and colon cancer. The widest family of kinase enzymes is receptor tyrosine kinases (RTKs) which are aimed by several chemotherapy medicines. The vascular endothelial growth factor (VEGFR), a well-known type IV tyrosine kinase receptor, is an effective biological target for the development of angiogenesis-related cancer treatments. The hepatocyte growth factor (also known as mesenchymal–epithelial transition factor) triggers the activation of the c-Met tyrosine kinase receptor, which controls several biological processes including cell division, survival, and proliferation. Main body In this review, we summarized the various dual inhibitors of VEGFR and c-MET receptors which are active for therapeutic action against cancer. Combination of some VEGFR and c-Met inhibitors also shows synergistic action. The developed dual inhibitors of VEGFR and c-MET such as quinolones and quinazolines derivatives, pyridine and pyrimidine derivatives, oxindole moiety and triazine derivatives are most potent for the same. Dual inhibitors of VEGFR and c-MET hold significant promise in improving cancer therapy by enhancing treatment efficacy, reducing resistance, and potentially improving patient outcomes. Clinical trials are currently being conducted on a few of them and other compounds are being under investigation. Inhibiting VEGFR and c-Met pathway activity will be discussed as novel therapeutic strategies for advanced development in treating cancer. The research progress in this review is fetched up to the current year. Conclusion Apart from the development of cancer treatment still cancer is listed as a deadly disease, due to its toxicity and resistance to treatment. Hence, the novel approach is necessary to overcome the cancer. The VEGFR and c-MET inhibitors as dual inhibitors may be more significant in future clinical anticancer treatments.

Context: Non-Small Cell Lung Cancer (NSCLC) is the most common lung cancer type, with 80-85% prevalence. Usually, NSCLC is treated by chemotherapy and radiotherapy in collaboration with gefitinib or other anticancer drugs. Those treatments have many adverse effects, such as shortness of breath, bleeding, fever, hair loss, and radiation pneumonitis. Lack of treatment options and numerous mutations greatly contribute to lung cancer's shocking death toll. Therefore, potential EGFR mutant inhibitors need to be analyzed. Aims: To identify potential inhibitors of an epidermal growth factor receptor (EGFR) mutant derived from Calophyllum inophyllum L. leaf using an in silico approach. Methods: In silico analysis and literature study were carried out. Secondary metabolite compounds from C. inophyllum were obtained through the PubChem database, and their biological activity and ADMET were analyzed. Molecular docking with EGFR wild-type (5FED) and mutant (5HG7) was carried out using PyRx. Furthermore, amino acid residues were analyzed using Discovery Studio. Results: Based on overall screening and molecular docking, a non-toxic compound with a low binding affinity with EGFR mutant protein is 4-[2-(4-nitrophenyl)ethylcarbamoyl]benzenesulfonyl. Moreover, interactions and hydrogen bonds at Ala743, Gly796, Leu718, Phe856, Leu844, and Val726 are known to play a crucial role in ATP binding inhibition toward the tyrosine kinase domain, resulting in EGFR mutant inhibition. Conclusions: 4-[2-(4-nitrophenyl)ethylcarbamoyl]benzenesulfonyl is one of the potential candidates as an EGFR mutant protein by ATP binding inhibition. However, in vitro and in vivo research needs to be performed to confirm these results.

Abstract Anticancer drugs may affect the incidence of dementia by modulating the common pathophysiology between cancer and dementia. However, there is a paucity of research that focused on anticancer drugs with different mechanisms of action and their associations with subtypes of dementia. Therefore, we aimed to investigate the incidence of dementia according to various groups of anticancer drugs. From the Korea National Health Insurance Service database, our retrospective population-based cohort study enrolled 116,506 cancer patients aged 65 years and older who received anticancer drugs between January 1, 2008 and December 31, 2018. The hazard ratio was determined using Cox proportional hazards regression models, comparing each group of anticancer drugs to all other anticancer drugs, after adjusting for covariates. Antimetabolites (HR = 0.91; 95% CI 0.84–0.97) and molecular targeted therapies (HR = 0.60; 95% CI 0.49–0.74) were associated with a decreased incidence of dementia of the Alzheimer type (DAT), but not with vascular dementia. Among molecular targeted therapies, epidermal growth factor receptor inhibitors (HR = 0.60; 95% CI 0.46–0.79) and multikinase inhibitors (HR = 0.49; 95% CI 0.27–0.89) were associated with a low incidence of DAT only. Our findings highlight the potential for targeted repurposing of anticancer drugs to prevent dementia.

Abstract The size of the drug particles is one of the essential factors for the proper absorption of the drug compared to the dose of the drug. When particle size is decreased, drug uptake into the body increases. Recent studies have revealed that the rapid expansion of supercritical solution with cosolvent plays a significant role in preparing micron and submicron particles. This paper examines the preparation of Erlotinib hydrochloride nanoparticles using a supercritical solution through the cosolvent method for the first time. An examination of the parameters of temperature (318–338 K), pressures (15–25 MPa) and nozzle diameter (300–700 μm) was investigated by Box-Behnken design, and their respective effects on particle size revealed that the nozzle diameter has a more significant impact on particle size than the other parameters. The smallest particles were produced at temperature 338 K, pressure 20 MPa, and nozzle diameter 700 μm. Besides, the ERL nanoparticles were characterized using SEM, DLS, XRD, FTIR, and DSC analyses. Finally, the results showed that the average size of the ERL particles decreased from 31.6 μm to 200–1100 nm.

The determination of sunitinib (STB) as a significant anticancer drug is very important. In the present research, a novel and effective electrochemical sensing device for STB was manufactured using the modification of a glassy carbon electrode (GCE) with the 2D layered metal-organic framework-carbon nanotubes (2DMOF-CNTs) nanocomposite. The electro-oxidation of STB exhibited a notable enhancement in the anodic current at +0.70 V, which may be due to the catalytic character of the 2DMOF-CNTs modifier. The key experimental parameters affecting the efficiency of the STB sensor including amount of 2DMOF-CNTs and solution pH of were evaluated and optimized. The 2DMOF-CNTs/GCE demonstrated a linear response in detecting STB, covering a range from 0.02 µM to 30 µM. In addition, the established sensor showed a good detection limit of 5 nM based on signal-to-noise ratio of 3. The successful evaluation of the practical implementation of the 2DMOF-CNTs/GCE for STB detection in serum samples as the real sample was accomplished. The novel electrochemical device possesses several remarkable properties, such as broad linear range, low limit of detection, quick analysis time, high selectivity, and convenient operation.

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N′-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1, and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10−5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration. [ABSTRACT FROM AUTHOR]

Specific cancer therapy remains a problem to be solved. Breast and colorectal cancer are among the cancers with the highest prevalence and mortality rates. Although there are some therapeutic options, there are still few effective agents for those cancers, which constitutes a clinical problem that requires further research efforts. Lysosomes play an important role in cancer cells' survival, and targeting lysosomes has gained increased interest. In recent years, our team has been synthetizing and testing novel benzo[a]phenoxazine derivatives, as they have been shown to possess potent pharmacological activities. Here, we investigated the anticancer activity of three of the most potent derivatives from our library, C9, A36, and A42, on colorectal- and breast-cancer-derived cell lines, and compared this with the effect on non-neoplastic cell lines. We observed that the three compounds were selective for the cancer cells, namely the RKO colorectal cancer cell line and the MCF7 breast cancer cell line. In both models, the compounds reduced cell proliferation, cell survival, and cell migration, accumulated on the lysosome, and induced cell death accompanied by lysosomal membrane permeabilization (LMP), increasing the intracellular pH and ROS accumulation. Our results demonstrated that these compounds specifically target lysosomes from cancer cells, making them promising candidates as LMP inducers for cancer therapy. [ABSTRACT FROM AUTHOR]

Lactate dehydrogenase A (LDHA) is highly expressed in many tumor cells and promotes the conversion of pyruvate to lactic acid in the glucose pathway, providing energy and synthetic precursors for rapid proliferation of tumor cells. Therefore, inhibition of LDHA has become a widely concerned tumor treatment strategy. However, the research and development of highly efficient and low toxic LDHA small molecule inhibitors still faces challenges. To discover potential inhibitors against LDHA, virtual screening based on molecular docking techniques was performed from Specs database of more than 260,000 compounds and Chemdiv-smart database of more than 1,000 compounds. Through molecular dynamics (MD) simulation studies, we identified 12 potential LDHA inhibitors, all of which can stably bind to human LDHA protein and form multiple interactions with its active central residues. In order to verify the inhibitory activities of these compounds, we established an enzyme activity assay system and measured their inhibitory effects on recombinant human LDHA. The results showed that Compound 6 could inhibit the catalytic effect of LDHA on pyruvate in a dose-dependent manner with an EC50 value of 14.54 ± 0.83 µM. Further in vitro experiments showed that Compound 6 could significantly inhibit the proliferation of various tumor cell lines such as pancreatic cancer cells and lung cancer cells, reduce intracellular lactic acid content and increase intracellular reactive oxygen species (ROS) level. In summary, through virtual screening and in vitro validation, we found that Compound 6 is a small molecule inhibitor for LDHA, providing a good lead compound for the research and development of LDHA related targeted anti-tumor drugs. [ABSTRACT FROM AUTHOR]

Graphene, known for its outstanding physical and chemical properties, is widely used in various fields, including electronics and biomedicine. Reduced graphene oxide (rGO) is preferred for electrochemical applications due to its enhanced water solubility and dispersion. Electrochemically reduced graphene oxide (ErGO) is particularly advantageous as it can be prepared under mild conditions and simplifies sensor fabrication; however, ErGO-based electrochemical sensors often lack specificity. Bioreceptors like proteins, enzymes, and DNA/RNA aptamers are incorporated to provide high specificity. This study introduces a guanine (G)/cytosine (C)-modified ErGO electrode (G/C@ErGO-GCE) for the sensitive electrochemical detection of doxorubicin (DOX) with good selectivity. The G/C mixture acts as a bioreceptor and is anchored on the ErGO-GCE surface via π-π interactions. The G/C@ErGO-GCE was characterized using scanning electron microscopy, contact angle measurement, Raman spectroscopy, and electrochemical methods. The sensor demonstrated excellent dynamic range (DPV: 10 nM to 1 µM, CA: 30 nM to 1.3 µM), sensitivity (DPV: 2.17 µA/µM, CA: 6.79 µA/µM), limit of detection (DPV: 84 nM, CA: 34 nM), and selectivity for DOX detection, highlighting its potential for biomedical applications and pharmacokinetic studies. [ABSTRACT FROM AUTHOR]

A series of twenty alkyl derivatives (2–21) of 4-amino benzoic acid (1, PABA) have been prepared using potassium carbonate and opportune alkylating agents under simple and mild reaction conditions. Compounds (16–21) are reported for the first time. Electron impact mass spectrometry (EIMS), Fourier transform infrared (FTIR) and Proton nuclear magnetic resonance (1H-NMR) spectroscopic techniques were adopted for the characterization of these analogues. In the present study, the cytotoxic screening of sixteen compounds (3, 5–11, 13 and 15–21) was also achieved against lung (NCI-H460) and oral squamous carcinoma (CAL-27) cell lines. Compound 20 has shown magnificent inhibitory properties against NCI-H460 cell line (IC50 15.59 and 20.04 µM, respectively) at a lower dose than that of the control (cisplatin; IC50 21.00 µM). One-way analysis of variance (ANOVA), t-test and Pearson correlation coefficient (PCC) have been performed to determine the reliability of current data through statistical package for the social sciences (SPSS). [ABSTRACT FROM AUTHOR]

Platinum‐based chemotherapeutic agents are widely used in the treatment of cancer. However, their effectiveness is limited by severe adverse reactions, drug resistance, and poor water solubility. This study focuses on the synthesis and characterization of new water‐soluble cationic monofunctional platinum(II) complexes starting from the [PtCl(η1‐C2H4OEt)(phen)] (1, phen=1,10‐phenanthroline) precursor, specifically [Pt(NH3)(η1‐C2H4OEt)(phen)]Cl (2), [Pt(1‐hexyl‐1H‐imidazole)(η1‐C2H4OEt)(phen)]Cl (3), and [Pt(1‐hexyl‐1H‐benzo[d]imidazole)(η1‐C2H4OEt)(phen)]Cl (4), which deviate from traditional requirements for antitumor activity. These complexes were evaluated for their cytotoxic effects in comparison to cisplatin, using immortalized cervical adenocarcinoma cells (HeLa), human renal carcinoma cells (Caki‐1), and normal human renal cells (HK‐2). While complex 2 showed minimal effects on the cell lines, complexes 3 and 4 demonstrated higher cytotoxicity than cisplatin. Notably, complex 4 displayed the highest cytotoxicity in both cancer and normal cell lines. However, complex 3 exhibited the highest selectivity for renal tumor cells (Caki‐1) among the tested complexes, compared to healthy cells (HK‐2). This resulted in a significantly higher selectivity than that of cisplatin and complex 4. Therefore, complex 3 shows potential as a leading candidate for the development of a new generation of platinum‐based anticancer drugs, utilizing biocompatible imidazole ligands while demonstrating promising anticancer properties. [ABSTRACT FROM AUTHOR]

While drug therapy plays a crucial role in cancer treatment, many anticancer drugs, particularly cytotoxic and molecular-targeted drugs, cause severe side effects, which often limit the dosage of these drugs. Efforts have been made to alleviate these side effects by developing derivatives, analogues, and liposome formulations of existing anticancer drugs and by combining anticancer drugs with substances that reduce side effects. However, these approaches have not been sufficiently effective in reducing side effects. Molecular hydrogen (H2) has shown promise in this regard. It directly reduces reactive oxygen species, which have very strong oxidative capacity, and indirectly exerts antioxidant, anti-inflammatory, and anti-apoptotic effects by regulating gene expression. Its clinical application in various diseases has been expanded worldwide. Although H2 has been reported to reduce the side effects of anticancer drugs in animal studies and clinical trials, the underlying molecular mechanisms remain unclear. Our comprehensive literature review revealed that H2 protects against tissue injuries induced by cisplatin, oxaliplatin, doxorubicin, bleomycin, and gefitinib. The underlying mechanisms involve reductions in oxidative stress and inflammation. H2 itself exhibits anticancer activity. Therefore, the combination of H2 and anticancer drugs has the potential to reduce the side effects of anticancer drugs and enhance their anticancer activities. This is an exciting prospect for future cancer treatments. [ABSTRACT FROM AUTHOR]

The determination of sunitinib (STB) as a significant anticancer drug is very important. In the present research, a novel and effective electrochemical sensing device for STB was manufactured using the modification of a glassy carbon electrode (GCE) with the 2D layered metal-organic framework-carbon nanotubes (2DMOF-CNTs) nanocomposite. The electro-oxidation of STB exhibited a notable enhancement in the anodic current at +0.70 V, which may be due to the catalytic character of the 2DMOF-CNTs modifier. The key experimental parameters affecting the efficiency of the STB sensor including amount of 2DMOF-CNTs and solution pH of were evaluated and optimized. The 2DMOF-CNTs/GCE demonstrated a linear response in detecting STB, covering a range from 0.02 µM to 30 µM. In addition, the established sensor showed a good detection limit of 5 nM based on signal-to-noise ratio of 3. The successful evaluation of the practical implementation of the 2DMOF-CNTs/GCE for STB detection in serum samples as the real sample was accomplished. The novel electrochemical device possesses several remarkable properties, such as broad linear range, low limit of detection, quick analysis time, high selectivity, and convenient operation. [Display omitted] • An effective sensing assay was proposed for voltammetric determination of sunitinib drug. • The novel sunitinib sensor possesses a broad linear range and low limit of detection. • The method was successfully utilized for sunitinib determination in serum and urine samples. [ABSTRACT FROM AUTHOR]

Cyclodextrins (CDs) are cyclic oligosaccharides able to form noncovalent water-soluble complexes useful in many different applications for the solubilization, delivery, and greater bioavailability of hydrophobic drugs. The complexation of 5-fluorouracil (5-FU) with natural or synthetic cyclodextrins permits the solubilization of this poorly soluble anticancer drug. In this theoretical work, the complexes between β-CD and 5-FU are investigated using molecular mechanics (MM) and molecular dynamics (MD) simulations in water. The inclusion complexes are formed thanks to the favorable intermolecular interactions between β-CD and 5-FU. Both 1:1 and 1:2 β-CD/5-FU stoichiometries are investigated, providing insight into their interaction geometries and stability over time in water. In the 1:2 β-CD/5-FU complexes, the intermolecular interactions affect the drug's mobility, suggesting a two-step release mechanism: a fast release for the more exposed and hydrated drug molecule, with greater freedom of movement near the β-CD rims, and a slow one for the less-hydrated and well-encapsulated and confined drug. MD simulations study the intermolecular interactions between drugs and specific carriers at the atomistic level, suggesting a possible release mechanism and highlighting the role of the impact of the drug concentration on the kinetics process in water. A comparison with experimental data in the literature provides further insights. [ABSTRACT FROM AUTHOR]

Maintaining cellular redox homeostasis is critical for cell viability and growth, with disruptions implicated in cellular responses to chemicals and drugs. This study investigates the interactions between acylfulvenes (AFs), a class of DNA alkylating drugs, and thioredoxin (Trx), a key redox regulating enzyme. AFs are semi-synthetic derivatives of the natural product illudin S. While their cytotoxic properties are widely attributed to DNA alkylation, they also react with cellular thiols, such as Trx, and the implications of these interactions remain poorly understood. Through biochemical assays with isolated E. Coli Trx, and cellular experiments in a human cell line (HeLa), we elucidate AFs’ impact on Trx activity and cellular levels. AFs, particularly hydroxymethylacylfulvene (HMAF), inhibited Trx activity by covalently modifying its active site cysteines. Drug exposure also altered cellular Trx levels and nuclear accumulation. In contrast, illudin S, which has a less selective toxicity profile for cancer cells, minimally inhibited isolated Trx. These data underscore Trx as a potential target contributing to the chemotherapeutic potential of AFs and provide insights into molecular interactions governing their impact on cancer cells.

Abstract A series of 20 novel gefitinib derivatives incorporating the 1,2,3-triazole moiety were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H1299, A549) and human lung adenocarcinoma cells (NCI-H1437) as non-small cell lung cancer. In comparison to gefitinib, Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds 7a and 7j demonstrated the most pronounced effects, with an IC50 value of 3.94 ± 0.17 µmol L−1 (NCI-H1299), 3.16 ± 0.11 µmol L−1 (A549), and 1.83 ± 0.13 µmol L−1 (NCI-H1437) for 7a, and an IC50 value of 3.84 ± 0.22 µmol L−1 (NCI-H1299), 3.86 ± 0.38 µmol L−1 (A549), and 1.69 ± 0.25 µmol L−1 (NCI-H1437) for 7j. These two compounds could inhibit the colony formation and migration ability of H1299 cells, and induce apoptosis in H1299 cells. Acute toxicity experiments on mice demonstrated that compound 7a exhibited low toxicity in mice. Based on these results, it is proposed that 7a and 7j could potentially be developed as novel drugs for the treatment of lung cancer.

Glucose transporters GLUT1 belong to the major facilitator superfamily and are essential to human glucose uptake. The overexpression of GLUT1 in tumor cells designates it as a pivotal target for glycoconjugate anticancer drugs. However, the interaction mechanism of glycoconjugate drugs with GLUT1 remains largely unknown. Here, we employed all-atom molecular dynamics simulations, coupled to steered and umbrella sampling techniques, to examine the thermodynamics governing the transport of glucose and two glycoconjugate drugs (i.e., 6-D-glucose-conjugated methane sulfonate and 6-D-glucose chlorambucil) by GLUT1. We characterized the specific interactions between GLUT1 and substrates at different transport stages, including substrate recognition, transport, and releasing, and identified the key residues involved in these procedures. Importantly, our results described, for the first time, the free energy profiles of GLUT1-transporting glycoconjugate drugs, and demonstrated that H160 and W388 served as important gates to regulate their transport via GLUT1. These findings provide novel atomic-scale insights for understanding the transport mechanism of GLUT1, facilitating the discovery and rational design of GLUT1-targeted anticancer drugs. [ABSTRACT FROM AUTHOR]

A series of 20 novel gefitinib derivatives incorporating the 1,2,3-triazole moiety were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H1299, A549) and human lung adenocarcinoma cells (NCI-H1437) as non-small cell lung cancer. In comparison to gefitinib, Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds 7a and 7j demonstrated the most pronounced effects, with an IC50 value of 3.94 ± 0.17 µmol L−1 (NCI-H1299), 3.16 ± 0.11 µmol L−1 (A549), and 1.83 ± 0.13 µmol L−1 (NCI-H1437) for 7a, and an IC50 value of 3.84 ± 0.22 µmol L−1 (NCI-H1299), 3.86 ± 0.38 µmol L−1 (A549), and 1.69 ± 0.25 µmol L−1 (NCI-H1437) for 7j. These two compounds could inhibit the colony formation and migration ability of H1299 cells, and induce apoptosis in H1299 cells. Acute toxicity experiments on mice demonstrated that compound 7a exhibited low toxicity in mice. Based on these results, it is proposed that 7a and 7j could potentially be developed as novel drugs for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

Pectin is a natural anionic hetero-polysaccharide substantially found in fruits and cell wall of plants. Nanomaterials of natural polysaccharides are the excellent carriers for targeting specific drug delivery due to multivalent interaction of sugar molecules. Pectin-based nanoforms manifest good stability, safety, low immunogenicity, low toxicity, hydrophilicity, gelling ability and biodegradability, which propose their applicability in various biomedical application. Pectin-based nanoparticles can inhibit the growth of several pathogenic bacteria including Staphylococcus aureus, Escherichia coli and Aspergillus japonicus. In addition, it also exhibits strong antioxidant property which can scavenge free radicals and help to prevent or manage various disease conditions. Its role in the detoxification of metals and carcinogens as well as its anti-carcinogenic qualities have made it of great interest to cancer researchers. The pectin-based nanocarrier offer a promising platform for the delivery of a wide range of drugs including chemotherapeutic drugs with good pharmacokinetics and controlled drug release. This review describes the neoteric evidence of pectin and their nano-formulations in biomedical applications as an antimicrobial, antioxidant, anticancer agents and a key role in drug delivery mechanisms. [ABSTRACT FROM AUTHOR]

Protein phosphorylation is a prevalent translational modification, and its dysregulation has been implicated in various diseases, including cancer. Despite its significance, there is a lack of specific inhibitors of the FCP/SCP-type Ser/Thr protein phosphatase Scp1, characterized by high specificity and affinity. In this study, we focused on adnectin, an antibody-mimetic protein, aiming to identify Scp1-specific binding molecules with a broad binding surface that target the substrate-recognition site of Scp1. Biopanning of Scp1 was performed using an adnectin-presenting phage library with a randomized FG loop. We succeeded in identifying FG-1Adn, which showed high affinity and specificity for Scp1. Ala scanning analysis of the Scp1-binding sequence in relation to the FG-1 peptide revealed that hydrophobic residues, including aromatic amino acids, play important roles in Scp1 recognition. Furthermore, FG-1Adn was found to co-localize with Scp1 in cells, especially on the plasma membrane. In addition, Western blotting analysis showed that FG-1Adn increased the phosphorylation level of the target protein of Scp1 in cells, indicating that FG-1Adn can inhibit the function of Scp1. These results suggest that FG-1Adn can be used as a specific inhibitor of Scp1. [ABSTRACT FROM AUTHOR]

The current study aims to develop and validate an analytical quality by design approach‐based high‐performance thin‐layer chromatographic (HPTLC) method for the analysis of Axitinib tablet samples. The chromatographic conditions in the TLC method were optimized using a three‐level full factorial design. The mobile phase composition and chamber saturation time served as the independent variables for optimization. The mobile phase used for TLC separation on pre‐coated aluminum plates with silica gel 60 F254 consisted of a mixture of ethyl acetate and isopropyl alcohol in a ratio of 9:1 (v/v). Axitinib was quantified at 330 nm using the densitometric method. Axitinib peak from tablet formulation was verified against the reference standard by comparing its single band at Rf 0.44 ± 0.02. Linearity was found to exist between 100 and 600 ng/band, with a correlation coefficient (r2) of 0.9978. The percentage recovery was obtained as 98.21%–99.05%. The system was validated by determining the parameters according to the guidelines of the International Council for Harmonization of Technical Conditions for Medical Products for Human Use. The proposed TLC method can be effectively applied to routine quality control of a pharmaceutical product. [ABSTRACT FROM AUTHOR]

Endophytes are considered one of the major sources of bioactive compounds used in different aspects of health care including cancer treatment. When colonized, they either synthesize these bioactive compounds as a part of their secondary metabolite production or augment the host plant machinery in synthesising such bioactive compounds. Hence, the study of endophytes has drawn the attention of the scientific community in the last few decades. Among the endophytes, endophytic fungi constitute a major portion of endophytic microbiota. This review deals with a plethora of anti-cancer compounds derived from endophytic fungi, highlighting alkaloids, lignans, terpenes, polyketides, polyphenols, quinones, xanthenes, tetralones, peptides, and spirobisnaphthalenes. Further, this review emphasizes modern methodologies, particularly omics-based techniques, asymmetric dihydroxylation, and biotic elicitors, showcasing the dynamic and evolving landscape of research in this field and describing the potential of endophytic fungi as a source of anticancer drugs in the future. [ABSTRACT FROM AUTHOR]

Aims To identify a marine L-asparaginase with clinically desirable attributes and characterize the shortlisted candidate through in silico tools Methods and results Marine bacterial strains (number = 105) isolated from marine crabs were evaluated through a stepwise strategy incorporating the crucial attributes for therapeutic safety. The results demonstrated the potential of eight bacterial species for extracellular L-asparaginase production. However, only one isolate (Bacillus altitudinis CMFRI/Bal-2) showed clinically desirable attributes, viz. extracellular production, type-II nature, lack of concurrent L-glutaminase and urease activities, and presence of ansZ (functional gene for clinical type). The enzyme production was 22.55 ± 0.5 µM/mg protein/min within 24 h without optimization. The enzyme also showed good activity and stability in pH 7–8 and temperature 37°C, predicting the functioning inside the human body. The Michealis-Menten constant (Km) was 14.75 µM. Detailed in silico analysis based on functional gene authenticating the results of in vitro characterization and predicted the nonallergenic characteristic of the candidate. Docking results proved the higher affinity of the shortlisted candidate to L-asparagine than L-glutamine and urea. Conclusion Comprehensively, the study highlighted B. altitudinis t ype II asparaginase as a competent candidate for further research on clinically safe asparaginases. [ABSTRACT FROM AUTHOR]

Marine-derived bisindoles exhibit structural diversity and exert anti-cancer influence through multiple mechanisms. Comprehensive research has shown that the development success rate of drugs derived from marine natural products is four times higher than that of other natural derivatives. Currently, there are 20 marine-derived drugs used in clinical practice, with 11 of them demonstrating anti-tumor effects. This article provides a thorough review of recent advancements in anti-tumor exploration involving 167 natural marine bisindole products and their derivatives. Not only has enzastaurin entered clinical practice, but there is also a successfully marketed marine-derived bisindole compound called midostaurin that is used for the treatment of acute myeloid leukemia. In summary, investigations into the biological activity and clinical progress of marine-derived bisindoles have revealed their remarkable selectivity, minimal toxicity, and efficacy against various cancer cells. Consequently, they exhibit immense potential in the field of anti-tumor drug development, especially in the field of anti-tumor drug resistance. In the future, these compounds may serve as promising leads in the discovery and development of novel cancer therapeutics. [ABSTRACT FROM AUTHOR]

Objective: PDZ‐binding kinase (PBK) has been reported as a poor prognostic factor and is a promising molecular target for anticancer therapeutics. Here, we aimed to investigate the effect of specific PBK inhibitor OTS514 on the survival of OSCC cells. Methods: Four OSCC cell lines (HSC‐2, HSC‐3, SAS, and OSC‐19) were used to examine the effect of OTS514 on cell survival and apoptosis. DNA microarray analysis was conducted to investigate the effect of OTS514 on gene expression in OSCC cells. Gene set enrichment analysis was performed to identify molecular signatures related to the antiproliferative effect of OTS514. Results: OTS514 decreased the cell survival of OSCC cells dose‐dependently, and administration of OTS514 readily suppressed the HSC‐2‐derived tumor growth in immunodeficient mice. Treatment with OTS514 significantly increased the number of apoptotic cells and caspase‐3/7 activity. Importantly, OTS514 suppressed the expression of E2F target genes with a marked decrease in protein levels of E2F1, a transcriptional factor. Moreover, TP53 knockdown attenuated OTS514‐induced apoptosis. Conclusion: OTS514 suppressed the proliferation of OSCC cells by downregulating the expression of E2F target genes and induced apoptosis by mediating the p53 signaling pathway. These results highlight the clinical application of PBK inhibitors in the development of molecular‐targeted therapeutics against OSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: We summarize the current knowledge of the signaling pathways involved in anticancer drug-induced cell death. We discuss the common signaling pathways of apoptotic cell death, antiapoptotic pathways, non-apoptotic cell death mechanisms (autophagic, necrotic, and other), signaling pathways involved in the death of drug-sensitive and -resistant tumor cells (with emphasis on c-Jun/activator protein 1 and crosstalk with mitochondrial and endoplasmic reticulum pathways), and therapeutic implications of the modification of signaling pathways leading to cell death (with emphasis on cell death-related gene targeting, interactions of drug resistance factors in drug-resistant cells, and the unfolded protein response pathway). We provide suggestions for the restoration of these altered signaling pathways to potentially restore the drug sensitivity of tumor cells. Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1–mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy. [ABSTRACT FROM AUTHOR]

Background: Accelerated approval (AA) program expedites access to promising drugs for life-threatening conditions, particularly in oncology. However, challenges arise from the trade-off between faster access and the certainty of clinical benefits. We examined the differences between the indications for successful conversion of AA to regular approval (RA) and those withdrawn from the perspective of whether the confirmatory trial was appropriately designed and conducted to verify the efficacy estimated in the pivotal trial for AA (AA trial). Methods: All the anticancer drugs approved by the United States (US) Food and Drug Administration (FDA) between January 2016 and December 2019 were identified on the FDA website. From these, we selected drugs granted AA for solid tumors based on single-arm trials. We compared the characteristics of the AA and confirmatory trials between products that were successfully converted to RA and those that were withdrawn. Results: Twenty-four AA indications were identified, of which 11 were converted to RA and 6 were withdrawn. The magnitude of the objective response rate (ORR) in both the AA and confirmatory trials was not a factor that clearly determined the conversion or withdrawal of AA. However, if the experimental arm did not achieve a certain level of ORR over the control arm in the confirmatory trial, it was thought to increase the uncertainty of successful conversion to RA. Conclusion: A relatively high ORR compared with that of the control arm in the confirmatory trial, after AA, is important for successfully obtaining RA. [ABSTRACT FROM AUTHOR]

Immune-related drug delivery systems (DDSs) in humanized mouse models are at the forefront of cancer research and serve as bridges between preclinical studies and clinical applications. These systems offer unique platforms for exploring new therapies and understanding their interactions with human cells and the immune system. Here, we focus on a DDS and a peripheral blood mononuclear cell (PBMC)-engrafted humanized mouse model that we recently developed, and consider some of the key components, challenges, and applications to advance these systems towards better cancer treatment on the basis of a better understanding of the immune response. Our DDS is unique and has a dual function, an anticancer effect and a capacity to fine-tune the immune reaction. The PBL-NOG-hIL-4-Tg mouse system is superior to other available humanized mouse systems for the development of such multifunctional DDSs because it supports the rapid reconstruction of an individual donor’s immunity and avoids the onset of graft-versus-host disease.

Cancer research has advanced tremendously with the identification of causative genes, proteins, and signaling pathways. Numerous antitumor drugs have been designed and screened for cancer therapeutics; however, designing target-specific drugs for malignant cells with minimal side effects is challenging. Recently, energy-sensing- and homeostasis-associated molecules and signaling pathways playing a role in proliferation, apoptosis, autophagy, and angiogenesis have received increasing attention. Energy-metabolism-based studies have shown the contribution of energetics to cancer development, where tumor cells show increased glycolytic activity and decreased oxidative phosphorylation (the Warburg effect) in order to obtain the required additional energy for rapid division. The role of energy homeostasis in the survival of normal as well as malignant cells is critical; therefore, fuel intake and expenditure must be balanced within acceptable limits. Thus, energy-sensing enzymes detecting the disruption of glycolysis, AMP, ATP, or GTP levels are promising anticancer therapeutic targets. Here, we review the common energy mediators and energy sensors and their metabolic properties, mechanisms, and associated signaling pathways involved in carcinogenesis, and explore the possibility of identifying drugs for inhibiting the energy metabolism of tumor cells. Furthermore, to corroborate our hypothesis, we performed meta-analysis based on transcriptomic profiling to search for energy-associated biomarkers and canonical pathways.

Platinum complexes are potential antitumor drugs in chemotherapy. Their impact on tumor treatment could be greatly strengthened by combining with immunotherapy. Increasing evidences indicate that the antitumor activity of platinum complexes is not limited to chemical killing effects, but also extends to immunomodulatory actions. This review introduced the general concept of chemoimmunotherapy and summarized the progress of platinum complexes as chemoimmunotherapeutic agents in recent years. Platinum complexes could be developed into inducers of immunogenic cell death, blockers of immune checkpoint, regulators of immune signaling pathway, and modulators of tumor immune microenvironment, etc. The synergy between chemotherapeutic and immunomodulatory effects reinforces the antitumor activity of platinum complexes, and helps them circumvent the drug resistance and systemic toxicity. The exploration of platinum complexes for chemoimmunotherapy may create new opportunities to revive the discovery of metal anticancer drugs. [ABSTRACT FROM AUTHOR]

In Sri Lanka as well as the rest of the globe, cancer is the top cause of mortality. One of the key medicines in treating tumors is anticancer medications and delivery dendrimers. To prevent the formation of the rapid proliferation of cancer cells, several tests were carried out. Because of this, research on dendrimers and anti-cancer medications is crucial. Topological indices (TIs) are molecular descriptors numerical values corresponding to the physical characteristics of a molecule's chemical structure. It costs money to determine a molecule's physical characteristics in a lab since it takes a lot of materials, medications, and time. Therefore, the relevant information about molecules may be obtained by computing TIs. This study's goals are to compute hitherto uncalculated eccentricity-based TIs for various anticancer structures and to use curvilinear regression models to forecast the physical characteristics of particular anticancer medications. These anticancer medications were given different TIs developed in this work, allowing the researchers to understand the physical, physicochemical, and chemical characteristics related to them. In addition comparative study of the novel indices with some well-known and mostly used indices in structure–property modeling and anticancer drugs in performed. [ABSTRACT FROM AUTHOR]

Adrucil is a chemotherapy drug commonly used in various types of cancers, including lung cancer. However, it may have some side effects on the respiratory system and other tissues. Therefore, delivery of this drug on a suitable nanocarrier can reduce daily dose and diminishes its side effects on the respiratory system. In this work, Ga-doped ZnO nanoparticles are prepared via sedimentation method and specified by some analytical techniques. Then, Adrucil molecules are loaded onto the surface of nanomaterial and loading/release properties are investigated under the in vitro conditions. After that, the electronic sensitivity and effectiveness of Ga-doped ZnO nanocluster bearing Adrucil were investigated theoretically with the B3LYP/wB97XD density functional theory (DFT) according to Lanl2DZ basis set. Furthermore, an MTT experiment was planned to investigate cytocompatibility of drug-loaded material on the lung cancer cells A549. This study confirmed that the drug-loaded material has a higher antiproliferative activity compared to free drug against A549 cancer cells. Ga-doped ZnO nanoparticles are synthesized and characterized by SEM, TEM, XRD, and FT-IR. Then, the prepared nanomaterial was utilized for loading of Adrucil. The results indicated that the performed nanomaterial encapsulated with Adrucil may act as an efficient anticancer drug delivery carrier. The calculated geometrical parameters and electronic properties indicated that the Ga-doped Zn12O12 represent higher sensitivity to Adrucil compared to the pristine ZnO nanocluster. [ABSTRACT FROM AUTHOR]

Dual crosslinked interpenetrating polymer network (IPN) beads of sodium alginate reinforced with curdlan-grafted poly-N-isopropylacrylamide/montmorillonite [Cud-g-PNIPA-/MMT] nanocomposites were accomplished for effective delivery of erlotinib HCl (ERL) to triple-negative breast cancer (TNBC) cells. Different beads exhibited variable size (1.30–1.47 mm) and excellent drug entrapment efficiency (DEE, 49.35–93.01%), which were influenced by the contents of reinforcing clay (MMT) in the composites. The SEM photographs also displayed the spherical morphology of the beads, and the results of infrared, thermal, and X-ray diffraction studies conferred a compatible environment of ERL in the matrices. Moreover, the sustained drug release profiles (Q8h, 73.79–84.24%) of various matrices were best fitted in the Korsmeyer-Peppas kinetic model with Fickian diffusion-driven mechanism. Furthermore, the beads demonstrated temperature-responsive swelling behavior and their molar masses between crosslinks ( M ¯ c) estimated by Flory-Rehner equation were enhanced with temperature. The beads containing 20% MMT (F-3) displayed a faster biodegradability than the control matrices (F-1, 0% MMT). The mucin adsorption ability of F-1 and F-3 followed Freundlich isotherm and Langmuir isotherm, respectively. As compared to pristine drug, F-3 bestowed an increased sensitivity on MDA-MB-231 cells. Thus, the Cud/alginate IPN beads could be employed as efficient drug carriers for TNBC therapy. [ABSTRACT FROM AUTHOR]

SHetA2 is a promising, orally active small molecule with anticancer properties that target heat shock proteins. In this study, we aimed to investigate the pharmacodynamic (PD) effects of SHetA2 using preclinical in vitro and in vivo models of ovarian cancer and establish a physiologically based pharmacokinetic (PBPK)/PD model to describe their relationships with SHetA2 concentrations in mice. We found that daily oral administration of 60 mg/kg SHetA2 for 7 days resulted in consistent plasma PK and tissue distribution, achieving tumor drug concentrations required for growth inhibition in ovarian cancer cell lines. SHetA2 effectively induced cyclin D1 degradation in cancer cells in a dose-dependent manner, with up to 70% reduction observed and an IC50 of 4~5 µM. We identified cyclin D1 as a potential PD marker for SHetA2, based on a well-correlated time profile with SHetA2 PK. Additionally, we examined circulating levels of ccK18 as a non-invasive PD marker for SHetA2-induced apoptotic activity and found it unsuitable due to high variability. Using a PBPK/PD model, we depicted SHetA2 levels and their promoting effects on cyclin D1 degradation in tumors following multiple oral doses. The model suggested that twice-daily dosing regimens would be effective for sustained reduction in cyclin D1 protein. Our study provides valuable insights into the PK/PD of SHetA2, facilitating future clinical trial designs and dosing schedules. [ABSTRACT FROM AUTHOR]

Here, the potential of Si76, C76, Al38N38, V-Si76, V-C76 and V-Al38N38 nanocages to transfer the Mechlorethamine are examined by computational methods. Results shown that the water as polar solvent is increased the adsorption energy and enthalpy of Mechlorethamine on Si76, C76, Al38N38, V-Si76, V-C76 and V-Al38N38 nanocages ca 0.12 eV to 0.23 eV. Results shown that the HOMO of Mechlorethamine-nanocage complex is located on Mechlorethamine and LUMO of Mechlorethamine-nanocage complex is located on nanocages. The calculated ΔGadsorption of anticancer drug on Si76, C76, Al38N38, V-Si76, V-C76, V-Al38N38 are -3.06, -2.85, -2.97, -3.75, -3.53 and -3.61 eV. The V-Al38N38 and V-Si76 have higher Eadsorption to transfer the Mechlorethamine than C76 ca 0.17 eV to 0.21 eV. The recovery time (τ) values of complexes of V-Si76, V-C76, V-Al38N38 with anticancer drug are higher than Si76, C76 and Al38N38 ca 3.12 s to 5.49 s. Results indicated that the V-Al38N38 and V-Si76 are effective nanostructures to deliver the Mechlorethamine as anticancer drug. [ABSTRACT FROM AUTHOR]

Purpose In the modern era of precision medicine, next-generation sequencing (NGS) is employed for a variety of clinical purposes. The aim of this study was to investigate the trends and clinical characteristics of NGS testing in South Korea. Materials and Methods This nationwide, population-based, retrospective cohort study examined National Health Insurance Service claims data from 2017 to 2021 for NGS and from 2008 to 2021 for gene-targeted anticancer drugs. Results Among the total 98,748 claims, there were 51,407 (52.1%) solid cancer panels, 30,173 (30.5%) hereditary disease panels, and 17,168 (17.4%) hematolymphoid cancer panels. The number of annual claims showed a persistent upward trend, exhibiting a 5.4-fold increase, from 5,436 in 2017 to 29,557 in 2021. In the solid cancer panel, colorectal cancer was the most common (19.2%), followed by lung cancer (18.8%). The annual claims for targeted cancer drugs have increased 25.7-fold, from 3,932 in 2008 to 101,211 in 2020. Drugs for the treatment of lung cancer accounted for 488,819 (71.9%) claims. The number of patients who received non-hereditary NGS testing has substantially increased, and among them, the count of patients prescribed targeted anticancer drugs consistently rose from 508 (13.9%) in 2017 to 2,245 (12.3%) in 2020. Conclusion This study highlights the rising nationwide demand for comprehensive genetic testing for disease diagnosis and treatment following NGS reimbursement by the National Health Insurance in South Korea, in addition to the need for greater utilization of targeted anticancer drugs. [ABSTRACT FROM AUTHOR]