Promising Anticancer Agent Research Articles

Thiazolopyrimidinium systems with a quaternized nitrogen atom as promising anticancer agents

Thiazolopyrimidinium systems with a quaternized nitrogen atom are attracting increasing attention in the development of new anticancer drugs. Their unique chemical structure and potential biological properties make them promising candidates for the development of effective drugs. In recent years, researches have shown that these compounds have significant activity against various types of tumors due to their ability to interact with cellular targets, disrupting processes critical for the survival and proliferation of tumor cells. This review examines the current state of researches on thiazolopyrimidines, including synthesis, mechanisms of action, and evaluation of their antitumor potential, with an emphasis on the importance of the quaternized nitrogen atom in their biological activity.

Molecular docking, DFT and antiproliferative properties of 4-(3,4-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine as potent anticancer agent with CDK2 and PIM1 inhibition potency.

Due to the limited effeteness and safety concerns associated with current cancer treatments, there is a pressing need to develop novel therapeutic agents. 4-(3,4-Dimethoxyphenyl)-3-(4-methoxyphenyl)-1-phenyl-1H-pyrazolo[3,4-b]pyridine (3) was synthesized and Initially screened on 59 cancer cell lines showed promising anticancer activity, so, it was chosen for a 5-dose experiment by the NCI/USA. The GI50 values ranged from 1.04 to 8.02 μM on the entire nine panels (57 cell lines), with a GI50 of 2.70 μM for (MG-MID) panel, indicating an encouraging action. To further explore the molecular attributes of compound 3, we optimized its structure using DFT with the B3LYP/6-31 + + G(d,p) basis set. We have considered vibrational analysis, bond lengths and angles, FMOs, and MEP for the structure. Additionally, pharmacokinetic assessments were conducted using various in-silico platforms to evaluate the compound safety. A molecular modeling study created a kinase profile on 44 different kinases. This allowed us to study our compound's binding affinity to these kinases and compare it to the co-crystallized one. Our findings revealed compound 3 exhibited better binding for half of the tested kinases, suggesting its potential as a multi-kinase inhibitor. To further validate our computational results, we tested compound 3 for its inhibitory effects on CDK2 and PIM1. Compound 3 exhibited an IC50 of 0.30 µM for CDK2 inhibition, making it five times less active than Roscovitine, which has an IC50 of 0.06 µM. However, compound 3 demonstrated slightly better inhibition of PIM1 compared to Staurosporine. These findings suggest that compound 3 is a promising anticancer agent with the potential for further development into a highly active compound.

Potential Anti-tumor Effects and Apoptosis-Inducing Mechanisms of Saponins: A Review.

The search for effective cancer therapies highlights saponins, natural plant-derived compounds, as promising anticancer agents. These compounds induce apoptosis in cancer cells by activating caspases, essential enzymes for cell death. For example, Soyasapogenol B from Glycine max and Astragaloside IV from Astragalus membranaceus effectively trigger apoptosis in cancer cells. Additionally, saponins, such as Compound K from American ginseng and Saikosaponin from Bupleurum falcatum, affect extrinsic and intrinsic pathways, including mitochondrial release of cytochrome C and activation of caspase-9. Ziyuglycoside II also acts on both pathways and activates the ROS/JNK pathway. Understanding these mechanisms provides promising prospects for developing more specific and safer anticancer therapies. The review utilized the ScienceDirect, PubMed, and Google Scholar databases. It was found that original articles and reviews from journals indexed in these sources emphasized the antitumor capabilities of saponins and discussed their role in apoptosis induction and caspase activation. The activation of caspases by saponins in the apoptotic pathway involves two main pathways: the extrinsic pathway is initiated by external signals that activate caspase-8, while the intrinsic pathway starts with internal stimuli, causing the release of cytochrome c and the activation of caspase-9. These pathways both lead to the activation of effector caspases (caspases 3, 6, and 7), culminating in apoptosis, an essential process for maintaining cellular balance and eliminating damaged cells. Identifying saponins in the context of cancer and their mechanisms of action is an ever-evolving field. Future research may lead to more targeted and personalized therapies, highlighting the collaboration between basic and clinical research in this promising area of medicine.

Family Malvaceae: a potential source of secondary metabolites with chemopreventive and anticancer activities supported with in silico pharmacokinetic and pharmacodynamic profiles.

Cancer is the second most widespread cause of mortality following cardiovascular disorders, and it imposes a heavy global burden. Nowadays, herbal nutraceutical products with a plethora of bioactive metabolites represent a foundation stone for the development of promising chemopreventive and anticancer agents. Certain members of the family Malvaceae have traditionally been employed to relieve tumors. The literature concerning the chemopreventive and anticancer effects of the plant species along with the isolated cytotoxic phytometabolites was reviewed. Based on the findings, comprehensive computational modelling studies were performed to explore the pharmacokinetic and pharmacodynamic profiles of the reported cytotoxic metabolites to present basis for future plant-based anticancer drug discovery. All the available information about the anticancer research in family Malvaceae and its cytotoxic phytometabolites were retrieved from official sources. Extensive search was carried out using the keywords Malvaceae, cancer, cytotoxicity, mechanism and signalling pathway. Pharmacokinetic study was performed on the cytotoxic metabolites using SWISS ADME model. Acute oral toxicity expressed as median lethal dose (LD50) was predicted using Pro Tox 3.0 web tool. The compounds were docked using AutoDock Vina platform against epidermal growth factor receptor (EGFR kinase enzyme) obtained from the Protein Data Bank. Molecular dynamic simulations and MMGBSA calculations were performed using GROMACS 2024.2 and gmx_MMPBSA tool v1.5.2. One hundred forty-five articles were eligible in the study. Several tested compounds showed safe pharmacokinetic properties. Also, the molecular docking study showed that the bioactive metabolites possessed agreeable binding affinities to EGFR kinase enzyme. Tiliroside (25), boehmenan (30), boehmenan H (31), and isoquercetin (22) elicited the highest binding affinity toward the enzyme with a score of -10.4, -10.4, -10.2 and -10.1Kcal/mol compared to the reference drug erlotinib having a binding score equal to -9Kcal/mol. Additionally, compounds 25 and 31 elicited binding free energies equal to -42.17 and -42.68Kcal/mol, respectively, comparable to erlotinib. Overall, the current study presents helpful insights into the pharmacokinetic and pharmacodynamic properties of the reported cytotoxic metabolites belonging to family Malvaceae members. The molecular docking and dynamic simulations results intensify the roles of secondary metabolites from medicinal plants in fighting cancer.

EGCG enhances antitumor effect of apatinib in nonsmall cell lung cancer by targeting VEGF signaling to inhibit glycolysis.

Nonsmall cell lung cancer (NSCLC), one of the most aggressive malignancies globally, is characterized by poor prognosis and limited life expectancy. Epigallocatechin-3-gallate (EGCG), a natural polyphenol found in green tea, has emerged as a promising anticancer agent due to its potent antitumor properties. However, the role and the underlying mechanisms of EGCG in NSCLC remain poorly understood. Hence, this research aimed to explore the effect of EGCG on the antitumor effect of apatinib in NSCLC throughvascular endothelial growth factor(VEGF)-regulated glycolysis. Cell Counting Kit-8 (CCK-8), 5-ethynyl-2'-deoxyuridine staining, wound healing, transwell, terminal deoxynucleotidyl transferase dUTP nick-end labeling, and flow cytometry assays were carried out to evaluate the proliferation, migration, invasion, and apoptosis of H1299 cells, respectively. Furthermore, western blot analysis was used to detect the expressions of VEGF, p-vascular endothelial growth factor receptor-2, hypoxia-inducible factor 1α, neuropilin-1, phosphorylated-phosphatidylinositol 3-kinase, and phosphorylated-AKT. The transfection efficiency of H1299 cells with VEGF overexpression plasmid was also assessed by western blot analysis. Glycolysis was analyzed by estimating extracellular acidification rate, lactate concentration, glucose uptake, and the expressions of lactate dehydrogenase A, pyruvate kinase M2, and hexokinase 2. The results demonstrated that VEGF activated glycolysis in NSCLC cells. EGCG alone and apatinib alone or in combination inhibited cell viability, proliferation, invasion, migration, and glycolysis whereas promoted apoptosis in NSCLC cells. EGCG regulated glycolysis levels in NSCLC through VEGF overexpression, and enhanced the antitumor effect of apatinib in NSCLC through VEGF-regulated glycolysis. Taken together, EGCG strengthened the protective effects of apatinib in NSCLC through glycolysis mediated by VEGF.

In Silico Investigation of Taurodispacamide A and Strepoxazine A from Agelas oroides S. as Potential Inhibitors of Neuroblastoma Targets Reveals Promising Anticancer Activity

In Silico Investigation of Taurodispacamide A and Strepoxazine A from Agelas oroides S. as Potential Inhibitors of Neuroblastoma Targets Reveals Promising Anticancer Activity

Aucubin Induces Apoptotic Cell Death Through Caspase-dependent Pathways in Human Osteosarcoma MG-63 Cells

Background Osteosarcomas (OSs) are predominantly generated by mesenchymal cells, which commonly develop in the distal and upper regions of the bones. OS has high mortality rates and treatment failures, mostly due to the presence of lung metastases. Purpose The present work aimed to scrutinize the anticancer potentials of aucubin against OS human osteosarcoma (MG-63) cells. Methods The proliferation of the control and aucubin-treated MG-63 cells was studied by an XTT assay. Various fluorescent staining assays were done to assess the endogenous reactive oxygen species (ROS) accumulation and apoptosis in the aucubin-treated MG-63 cells. The caspase-3, -8, and -9 activities were investigated using the assay kits. Results The XTT assay results confirmed that the aucubin treatment considerably reduced the MG-63 cells. The findings of the various fluorescent staining assays evidenced that the aucubin treatment remarkably promoted endogenous ROS accumulation and apoptosis in the OS cells. The caspase activities were also improved in the OS cells after the aucubin treatment. Conclusion The results of this work show that aucubin treatments inhibit cell proliferation and trigger apoptosis in MG-63 cells, suggesting its potential as a promising anticancer agent. These findings will facilitate the future development of aucubin as a talented anticancer agent to treat OS.

A Dual Action Platinum(IV) Complex with Self-assembly Property Inhibits Prostate Cancer through Mitochondrial Stress Pathway.

Platinum(IV) prodrugs are highly promising anticancer agents because they can selectively target tumors and minimize the adverse effects associated with their PtII congeners. In this study, we synthesized dual action PtIV complexes by linking oxoplatin with lithocholic acid. The synthesized compounds, designated as PL-I, PL-II, and PL-III, can spontaneously self-assemble in water, resulting in the formation of spherical shape nanoparticles. Among the developed complexes, PL-III appeared to be the most potent compound against all the tested cancer cell lines, with 10 fold higher cytotoxicity compared to cisplatin in PC3 cells. The complex arrests the cell cycle in the S and G2 phases and induces DNA damage. Additional mechanistic investigations demonstrate that PL-III predominantly localizes within the mitochondria and cytoplasm. Consequently, PL-III disrupts mitochondrial membrane potential, increases ROS production, and perturbs mitochondrial bioenergetics in PC3 cells. The complex induces apoptosis through the mitochondrial pathway by upregulating pro-apoptotic protein expression and downregulating anti-apoptotic protein expression from the BCl-2 protein family. These results demonstrate that higher cellular uptake and reduction of PL-III by biological reductants in PC3 cells resulted in a synergistic effect of lithocholic acid and cisplatin, which can be easily observed due to its unique cytotoxic mechanism. This further underscores the significance of dual-action PtIV complexes in enhancing the efficacy of cancer therapy.

Ni(II)-selenosemicarbazones complexes as promising anticancer and anti-tubercular agents: Synthesis, characterization, molecular docking and binding studies with HSA and ct-DNA

Reaction of nickel(II) acetate with selenosemicarbazones (2-HOxsesc, 3-MeHOxsesc, 6-ClHOxsesc, 3-HIndsesc, 3-AcHIndsesc, 9-HAnsesc, 1-HNapsesc, 2-HNapsesc) in 1:2 (M:L) molar ratio yielded complexes of formula, [Ni(sesc)2] 1–8 (sesc = 2-Oxsesc 1, 3-MeOxsesc 2, 6-ClOxsesc 3, 3-Indsesc 4, 3-AcIndsesc 5, 9-Ansesc 6, 1-Napsesc 7, 2-Napsesc 8).Complexes are characterized using elemental analysis, FTIR, NMR (1H and 13C) spectroscopy and Mass spectrometry. The full optimized energy for 2-HOxsesc and its complex was found through Density Functional Theory calculation using B3LYP level and predicted geometry parameters are compared with literature. Selenosemicarbazones and their complexes were tested for their anti-tuberculosis activity against M. tuberculosis H37RV strain and anticancer activity against PA-1 and DU145cell lines. The anti-TB activity of 3-AcHIndsesc (MIC = 25 μg/mL) got exceptionally enhanced on complexation with Ni(II) (complex 5, MIC = 0.8 μg/mL). Anticancer activity of ligands have got enhanced on complexation with Ni(II) metal ion and best results were obtained in case of complex 5 (PA-1, IC50 =1.28; DU145, IC50 =3.83). The binding constant of 6.5 × 103M-1 and 3 × 104M−1 obtained from absorption spectroscopy (UV–Vis) indicates strong binding of complex 5 with HSA and ct-DNA. The molecular interaction of 3-AcHIndsesc and complex 5 with mycobacterium tuberculosis enoyl reductase and DNA (PDB ID: 1BNA) were checked with docking studies. The docking studies with mycobacterium tuberculosis enoyl reductase and DNA (PDB ID: 1BNA) gave minimum binding energy of -8.9 Kcal/mol and -7.5 Kcal/mol respectively for complex 5. The docking results are in well agreement with experimental data.

Action Mechanism of Bioactive Compounds from Plants and Spices Mixture as promising Anticancer agents: In Silico Drug Design predictions targeting Cancer Cell proliferation through Cell Cycle Arrest Pathway

Action Mechanism of Bioactive Compounds from Plants and Spices Mixture as promising Anticancer agents: In Silico Drug Design predictions targeting Cancer Cell proliferation through Cell Cycle Arrest Pathway

Computational quest, synthesis and anticancer profiling of 3-methyl quinoxaline-2-one-based active hits against the tyrosine kinase

BackgroundCancer is the predominant cause of mortality and a remarkable obstacle to elevating life anticipation in every nation on globe. Hepatocellular carcinoma (HCC), a hyper-vascular tumour, develops and progresses due to angiogenesis, a key feature of malignancy. HCC exhibits high neoangiogenic activity because of the need to generate new blood vessels for tumour growth.MethodsThe present work includes the construction of virtual library of ligands, virtual screening using the Dockthor-VS server, ADMET study using the SwissADME and Osiris property explorer. All the synthesized compounds were characterized by UV, IR, NMR and mass spectroscopic techniques. MTT assay was done to find the IC50 of the synthesized compounds against HepG2 cell line. The more active compound found is subjected to the molecular dynamics simulation study.ResultsThe ligands exhibited good docking scores, ADMET profile compared to the reference drugs. The target compounds were obtained with the satisfactory yields of 66–82%. The best activity against the HepG2 cancer cell line is observed with the compound SA-4 with IUPAC name (2-(3-methyl-2-oxoquinoxalin-1(2H)-yl)-N-(5-(3-nitrophenyl)-5H-thiazolo[4,3-b] [1,3,4] thiadiazol-2-yl) acetamide). The experimental results obtained show correlation with the in silico results. MD simulation of the compound SA-4 indicates the moderate stability of the protein-ligand complex in real time environment.ConclusionThe results obtained suggest that the compound SA-4 has the potential to be a promising anticancer agent effective against the VEGFR-2 and FGFR-4.Graphical abstract

Cytotoxic Effect of Bajong LN Rice Methanol Extract on Human Squamous Cell Carcinoma, ORL-48

Oral squamous cell carcinoma (OSCC), a major oral cancer, significantly challenges treatments and impacts patient quality of life; current therapies often cause severe side effects, highlighting the urgent need for gentler alternatives. Rice stands as one of the primary cereal grains providing the daily caloric intake for more than half of the global population. Extensive research has demonstrated the significant health benefits derived from rice, attributed to its abundance of bioactive compounds. This study endeavours to explore the potential cytotoxic effects of Bajong LN rice, a pigmented purple rice indigenous to Sarawak, on human squamous cell carcinoma, ORL-48 cells. Cells were cultured in complete DMEM/F-12 media and incubated under standard culture conditions. Upon reaching 80% confluency, the cells were treated to varied concentrations (ranging from 0 μg/ml to 2000 μg/ml) of Bajong LN rice methanol extract (BLN-ME) and cisplatin. Subsequently, the cells were incubated for 48 and 72 hours, and their cytotoxicity was assessed using the MTS assay. Results demonstrated that cisplatin inhibited ORL-48 cells with an IC50 of 7.483 μg/ml and 3.877 μg/ml; and an IC80 of 40.649 μg/ml; and 17.543 μg/ml for 48 and 72 hours, respectively. Correspondingly, BLN-ME exhibited a notable cytotoxic effect against ORL-48 cells at 48- and 72-hour intervals, with an IC50 of 354.4 μg/ml and 342.0 μg/ml; and an IC80 of 450.3 μg/ml and 423.63 μg/ml, respectively. The cytotoxic activity of BLN-ME against ORL-48 cells was observed in both a time and dose-dependent manner. Morphological analysis and the Trypan blue exclusion assay corroborated the MTS assay's findings. Our preliminary findings provide the first scientific evidence of the cytotoxic effect of BLN-ME specifically against human squamous cell carcinoma, ORL-48 cells. This study suggests the potential of BLN-ME as a promising anti-cancer agent, presenting opportunities for further investigation into its underlying cytotoxic mechanisms.

Molecular Networking-Guided Discovery of a New Antitumor Pyranonaphthoquinone from Streptomyces tanashiensis DSM 731: Insights from Single-Molecule Stretching Assays.

Guided by molecular networking based on single-molecule stretching assay, an unprecedented pyranonaphthoquinone, methyl kalafunginate (1) and five known compounds 2-6 were isolated from Streptomyces tanashiensisDSM 731. Compound 1 was characterized through a combination of spectroscopic techniques, including 1D and 2D NMR analysis, ECD calculation, and X-ray crystallography. Interestingly, we discovered that compound 1 was spontaneously converted from kalafungin (4) in methanol solution. All isolated compounds were assessed for their cytotoxic potential against a panel of five human cancer cell lines: A549, HepG2, BxPC-3, SW620, and C4-2B. Compounds 1, 2, 4, and 5 exhibited remarkable cytotoxicity with IC50values below 2.382 μM, suggesting their potential as promising anticancer agents. These findings highlight the significance of using a combined approach of single-molecule stretching assays and molecular networking for efficiently discovering novel natural products with potential therapeutic applications.

Review on Thiazolo-triazole as a Promising Anticancer Agent

Thiazolo-Triazole is a fused ring heterocyclic system consisting of three nitrogen atoms and one Sulphur atom shows wide range of biological activities. Cancer is the second leading cause of death worldwide. In past few decades, there has been a crucial necessity for the design and development of innovative anticancer drugs that can diminish the serious health problems and unwanted side effects associated with presently used anticancer drugs. Many anticancer drugs are commercially accessible, but nonexistence of selectivity, target specificity, cytotoxicity, and development of resistance lead to serious side effects. Several experiments have been going on to develop compounds with negligible or no side effects. The thiazole and triazole heterocyclic are well-recognized to possess abundant pharmacological activities, including predominantly anticancer, as revealed by various investigations on anticancer compounds and the latest research findings pointed out that to study the anticancer potential of thiazolo-triazole compounds in single scaffold.

Rosmarinic acid attenuates glioblastoma cells and spheroids’ growth and EMT/stem-like state by PTEN/PI3K/AKT downregulation and ERK-induced apoptosis

BackgroundGlioblastoma (GB) is a highly malignant type of brain cancer with a poor prognosis. Therapeutic strategies for GB are still limited. Rosmarinic acid (RA), a polyphenolic compound, is a promising experimental anticancer agent, but its specific protein targets for GB remain unclear. PurposeThis study aimed to elucidate the anticancer effects of RA in 2D- and 3D-GB cells and the underlying mechanisms. Methods3D-tumor spheroids (mimics in vivo tumors) were obtained by the hanging-drop/agarose method. RA's anti-glioma activity on U-87MG (p53-wt/PTEN-mt) and LN229 (p53-mt/PTEN-wt) cells was evaluated through cell viability, colony-formation, migration/invasion/angiogenesis assays, fluorescence imaging, and spheroid growth analysis. The underlying mechanism of the anticancer effects of RA was investigated by Western blot and immunofluorescence analysis. The MEK inhibitor U0126 was used to block ERK phosphorylation. ResultsRA treatments exerted anti-proliferative and pro-apoptotic effects on human GB cells. RA dose-dependently reduced angiogenesis and intracellular ROS levels, suppressed glioma growth, and migration/invasion in 2D-culture and cancer stem cell (CSC)-like 3D-spheroid culture (SPC). Repeated therapy in SPC was more effective by leading to disrupted structure than a single treatment. Treatments in SPC also suppressed epithelial-mesenchymal transition (EMT) and CSC-like properties. Strikingly, RA downregulated the SIRT1/FOXO1/NF-κB axis independently of p53 or PTEN function in both gliomas. Immunofluorescence labeling revealed decreased SIRT1 and NF-κB-p65 and increased FOXO1 and GAPDH proteins in nuclear location (associated with apoptosis). Surprisingly, RA increased p-ERK1/2 levels, but priming with U0126 abolished RA-mediated p-ERK upregulation; thus, autophagy and apoptosis induction in GB cells were prevented, and the growth of GB spheroids accelerated. Specifically, RA also inhibited the PTEN/PI3K/AKT pathway in U-87MG cells. Due to genetic differences in cells, U-87MG cells were more sensitive to RA treatments than LN229 cells. Meanwhile, our positive control drug trial results with FDA-approved temozolomide (TMZ) used in GB treatment showed that our test compound rosmarinic acid exhibited higher therapeutic effects than TMZ at lower doses. ConclusionSuppression of EMT, downregulation of SIRT1/FOXO1/NF-κB axis, inhibition of PTEN/PI3K/AKT signaling pathway, and ERK-induced apoptosis and autophagy were determined to be involved in stopping glioma progression. Our findings for the first time, revealed that RA may have potential therapeutic use by having multiple targets in human brain cancer with further clinical studies.

Multi-target anticancer activity of compounds isolated from galls of Pistacia chinensis subsp. integerrima: A mechanistic investigation

The usage of Pistacia chinensis subsp. integerrima (J.L. Stewart) Rech. f. and its extracts in traditional medicine is well-documented, since this plant is known for its anti-infective, antidiabetic and antioxidant properties. Additionally, recent studies described the antiproliferative activity of its extracts on cancer cell models. Nevertheless, the mechanisms of action underlying this biological effect still have to be fully elucidated. In this study, we focused our attention on the characterization of the bioactivity profile of the flavonoids spinacetin (1) and patuletin (2) and of the triterpene pistagremic acid (3) extracted from the galls of P. integerrima. The compounds were tested in vitro against aldose reductase and thymidine phosphorylase, two targets that are attracting growing attention in the field of drug discovery due to their involvement in metabolism regulation and angiogenesis. Computational studies were used to rationalize experimental data, and the results support the potential of spinacetin (1) as a promising bioactive multi-target anticancer agent.

Synthesis, Molecular Docking, and Anticancer Screening of Ester-based Thiazole Derivatives.

This study investigates the potential of five compounds as novel anticancer agents. We examined their efficacy, mechanisms of action, and impact on various cancer cell lines, through a comprehensive set of experiments. Notably, compound 3e demonstrated superior activity compared to the positive control cisplatin, with a GI50 value of 6.3±0.7 μM against the breast cancer cell line (MCF-7). Compound 3b also displayed remarkable growth inhibition, yielding GI50 values of 8.7±0.2 μM (MCF-7) and 8.9±0.5 μM against the colon cancer cell line (HCT-116). Cell count experiments further confirmed the potent inhibitory effects of compounds 3e, 3b, and 3c on MCF-7 and HCT-116 cell growth. Compound 3e demonstrated a reduction of 55-60 % at GI50 and complete inhibition (100 %) at 2x GI50. Compound 3b exhibited 50-55 % reduction (GI50) and 90-95 % inhibition (2x GI50) in HCT-116 cells. Compound 3c displayed 75-80 % inhibition (2x GI50) and 35-40 % inhibition (GI50) in HCT-116 cells. In-depth mechanistic investigations unveiled valuable insights into the mode of action of compound 3e. The cell-cycle assay demonstrated G2/M phase arrest, DNA damage, and caspase-mediated apoptosis in both MCF-7 and HCT-116 cells. Caspase activation indicated a significant increase in apoptosis following exposure to compound 3e. Furthermore, compound 3e induced reactive oxygen species (ROS) production, influencing HCT-116 and MCF-7 cells differently. Elevated ROS production in HCT-116 cells and distinct effects in MCF-7 cells contribute to a deeper understanding of the cytotoxic mechanisms of compound 3e. Overall, these findings highlight the potential of the investigated compounds, particularly compound 3e, as effective inducers of apoptosis in cancer cells. Mechanistic insights into cell cycle arrest, caspase-mediated apoptosis, and ROS modulation provide a comprehensive understanding of their cytotoxic effects. This study offers significant contribution to the development of promising anticancer agents and their therapeutic applications.

Naturally Occurring Xanthones and Their Biological Implications.

Xanthones are chemical substances in higher plants, marine organisms, and lower microorganisms. The most prevalent naturally occurring sources of xanthones are those belonging to the families Caryophyllaceae, Guttiferae, and Gentianaceae. Structurally, xanthones (9H xanthan-9-one) are heterocyclic compounds with oxygen and a γ-pyrone component. They are densely packed with a two-benzene ring structure. The carbons in xanthones are numbered from their nucleus and biosynthetic construct. They have mixed shikimate-acetate (higher plants) and acetate-malonate (lower organisms) biosynthetic origins, which influence their classification. Based on the level of oxidation of the C-ring, they are classified into monomers, dimers, and heterodimers. While based on the level of oxygenation or the type of ring residue, they can be categorized into mono-, di-, tri-, tetra-, penta- and hexa-oxygenated xanthones, bis-xanthones, prenylated and related xanthones, xanthonolignoids, and other miscellaneous xanthones. This structural diversity has made xanthones exhibit considerable biological properties as promising antioxidant, antifungal, antimicrobial, and anticancer agents. Structure-activity relationship studies suggest C-1, C-3, C-6, and C-8 as the key positions that influence the biological activity of xanthones. Furthermore, the presence of functional groups, such as prenyl, hydroxyl, glycosyl, furan, and pyran, at the key positions of xanthones, may contribute to their spectrum of biological activity. The unique chemical scaffolds of xanthones, their notable biological activities, and the structure-activity relationships of some lead molecules were discussed to identify lead molecules as possible drug candidates.

Vitamin K3 derivative inhibits androgen receptor signaling in targeting aggressive prostate cancer cells.

Prostate cancer (PCa) is the second critical cause of cancer-related deaths, with African Americans dying at higher rates in the U.S. The main reasons for the higher mortality rate are ethnic differences and lack of understanding of prostate cancer biology and affordable treatments, as well as the financial burden of African American men to obtain the most effective and safe treatments. The effect of micronutrients, including Vitamin K, on various cancer cell lines has been widely studied, but the potential anticancer effect of VK3-OCH3, an analog of vitamin K3 (Menadione), on African American prostate cancer has not been evaluated. In this study, we compared the anticancer effect of VK3-OCH3 on targeting African American derived PCa cell lines namely RC77-T and MDA-PCa-2b. Our results show that VK3-OCH3 significantly inhibits the proliferation of both RC77-T and MDA-PCa-2b African American PCa cells and promotes apoptosis, and the underlying mechanism of cell death appears to be similar in both the cell lines. Notably, VK3-OCH3 inhibits colony-forming ability and induces apoptosis by blocking the cell cycle at G0 in African American PCa cells. VK3-OCH3 also acts as an anti-metastatic agent by inhibiting the migration ability of the metastatic properties of African American PCa cells. The cell death of African American PCa cells mediated by VK3-OCH3 is associated with the production of free radicals, such as intracellular and mitochondrial reactive oxygen species (ROS). Interestingly, antioxidants such as N-Acetylcysteine (NAC) and Glutathione (GSH) effectively negated the oxidative stress induced by VK3-OCH3 on PCa cell lines derived from African American patients. Of note, VK3-OCH3 reduces androgen receptor and prostate-specific antigen expression in these PCa cells. Furthermore, molecular dynamic studies reiterated that VK3-OCH3 strongly binds to the androgen receptor, suggesting that the androgen receptor is the potential molecular target of VK3-OCH3. In addition, Western blot analysis showed that VK3-OCH3 reduces the expression of androgen receptor, TRX2, and anti-apoptotic signaling molecules such as Bcl-2 and TCTP in the MDA-PCa-2b metastatic PCa cellular model. In conclusion, our results suggested that VK3-OCH3 is a promising anticancer agent that could potentially reduce the mortality rates of African American PCa patients, warranting further preclinical and translational studies.

Identification of sanguinarine as c-MYC transcription inhibitor through enhancing the G-quadruplex-NM23-H2 interactions

c-MYC is a proto-oncogene ubiquitously overexpressed in various cancers. The formation of G-quadruplex (G4) structures within the c-MYC promoter region can regulate its transcription by interfering with protein binding. Consequently, small molecules targeting c-MYC G4 have emerged as promising anticancer agents. Herein, we report that sanguinarine (SG) and its analogs exhibit a high affinity for c-MYC G4 and potently modulate G4-protein interactions within a natural product library. Notably, SG uniquely enhances NM23-H2 binding to c-MYC G4, both in vitro and in cellular contexts, leading to c-MYC transcriptional repression and subsequent inhibition of cancer cell growth in an NM23-H2-dependent manner. Mechanistic studies and molecular modeling suggest that SG binds to the c-MYC G4/NM23-H2 interface, acting as an orthosteric stabilizer of the DNA-protein complex and preventing c-MYC transcription. Our findings identify SG as a potent c-MYC transcription inhibitor and provide a novel strategy for developing G4-targeting anticancer therapeutics through modulation of G4-protein interactions.