Promising Anticancer Agent Research Articles

Trichostatin C Synergistically Interacts with DNMT Inhibitor to Induce Antineoplastic Effect via Inhibition of Axl in Bladder and Lung Cancer Cells.

Aberrant epigenetic modifications are fundamental contributors to the pathogenesis of various cancers. Consequently, targeting these aberrations with small molecules, such as histone deacetylase (HDAC) inhibitors and DNA methyltransferase (DNMT) inhibitors, presents a viable strategy for cancer therapy. The objective of this study is to assess the anti-cancer efficacy of trichostatin C (TSC), an analogue of trichostatin A sourced from the fermentation of Streptomyces sp. CPCC 203909. Our investigations reveal that TSC demonstrates potent activity against both human lung cancer and urothelial bladder cancer cell lines, with IC50 values in the low micromolar range. Moreover, TSC induces apoptosis mediated by caspase 3/7 and arrests the cell cycle at the G2/M phase. When combined with the DNMT inhibitor decitabine, TSC exhibits a synergistic anti-cancer effect. Additionally, protein analysis elucidates a significant reduction in the expression of the tyrosine kinase receptor Axl. Notably, elevated concentrations of TSC correlate with the up-regulation of the transcription factor forkhead box class O1 (FoxO1) and increased levels of the proapoptotic proteins Bim and p21. In conclusion, our findings suggest TSC as a promising anti-cancer agent with HDAC inhibitory activity. Furthermore, our results highlight the potential utility of TSC in combination with DNMT inhibitors for cancer treatment.

Abstract 3328: Oridonin derivative compounds target STATs to inhibit triple-negative breast cancer

Abstract Breast cancer remains the second leading cause of cancer related deaths in women. Despite the development of targeted treatments and immunotherapies, triple-negative breast cancer (TNBC) continues to evade effective treatment. TNBC lacks sufficient expression of druggable markers, ER, PR, and Her2, and exhibits especially aggressive characteristics including later diagnosis, lower survival rate, and higher rates of metastasis and reoccurrence. Currently, cytotoxic chemotherapy and radiation remain the standard of care for TNBC. Our work utilizes compounds from nature to develop therapies for TNBC with improved efficacy and safety. Oridonin, a natural kaurene-type diterpenoid enriched in the medicinal herb Rabdosia rubescens, is a promising anticancer agent, but exhibits limited bioavailability and potency. Our team successfully developed oridonin derivative CYD0618 compound that exhibits significantly improved solubility and anticancer activity. This study aims to characterize the mechanism of action of CYD0618 on TNBC cells. We found that CYD0618 reduces the proliferation of TNBC cells in vitro with IC50s at the nanomolar level. We also found CYD0618 has high potency against TNBC in vivo. Within a xenograft mouse model, CYD0618 suppresses the growth of TNBC tumors and extends animal survival. Using Western blot to probe for putative targets, we found CYD0618 reduces activation of STAT3, a transcription factor critically involved in proliferation, survival, and transformation of epithelial cells. Because STAT3 is constitutively active in ~70% of human cancers, there has been a tremendous effort to develop STAT3 targeting therapies; however, none has achieved FDA approval. In addition to STAT3, we show CYD0618 also suppresses other STAT transcription factors. Compared to selective STAT3 degradation by PROTAC treatment, poly-STAT targeting by CYD0618 exhibits superior activity against TNBC cells. Our study identifies CYD0618 as a novel poly-STAT inhibitor with promising activity against TNBC. Citation Format: Gabrielle Vontz, Jun Li, Zhipin Liang, Ruixia Ma, Pingyuan Wang, Haiying Chen, Jia Zhou, Qiang Shen. Oridonin derivative compounds target STATs to inhibit triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3328.

Abstract 5262: MBO enhances anti-tumor immunity in pancreatic ductal adenocarcinoma by inducing immunogenic apoptosis

Abstract Pancreatic ductal adenocarcinoma (PDAC) poses significant therapeutic challenges due to its aggressive nature and limited treatment options. In this study, we explored the anti-cancer potential of MBO, a compound selected through drug repurposing strategy based on its cytotoxic ability and modulation of key survival pathways in PDAC. Our preliminary in vitro experiments demonstrated MBO's potent cytotoxicity against various PDAC cell lines, inhibiting cellular growth and clonogenicity. MBO induced G1 phase cell cycle arrest in a concentration-dependent manner. In the next step, in vivo, studies using xenograft and orthotopic mouse models confirmed MBO's ability to suppress tumor growth and increase CD8+ T cell infiltration. MBO demonstrated a favorable tumor suppressive activity wherein it suppressed tumor growth by approximately 49% and 56% in xenograft and orthotopic models, respectively. A CD8+ T cell depletion experiment revealed partial dependence on CD8+ T cells for MBO's overall anti-tumor efficacy. Further, combining MBO with anti-PD1 therapy exhibited a synergistic effect, enhancing overall T cell infiltration, particularly CD8+ T cells. Our mechanistic studies revealed that MBO induced immunogenic apoptosis, as evidenced by increased expression of immunogenic cell death markers (HSP90 and calreticulin) and apoptotic markers. To further delineate the mechanism, we performed RPPA profiling. RPPA analysis indicated MBO's impact on mitochondrial gene expression and stress response pathways, suggesting its involvement in disrupting cellular survival mechanisms along with stress-induced immunogenic marker expression. Overall, this study demonstrates MBO as a promising anti-cancer agent with the potential to serve as an immune adjuvant. Particularly, in combination with immunotherapies, MBO can serve as a potential option to improve immunotherapeutic response in PDAC tumors providing valuable insights for developing novel therapeutic strategies in PDAC. Citation Format: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava. MBO enhances anti-tumor immunity in pancreatic ductal adenocarcinoma by inducing immunogenic apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5262.

Abstract 5980: Cancer therapeutic and prevention strategy targeting mutated mitochondria DNA

Abstract As the energy factory for the cell, the mitochondrion, through its role of ATP production by oxidative phosphorylation, can be regarded as the guardian of well regulated cellular metabolism; the integrity of mitochondrial functions, however, is particularly vulnerable in cancer due to the lack of superstructures such as histone and lamina folds to protect the mitochondrial genome from unintended exposure, which consequently elevates risks of mutation. In cancer, mechanisms responsible for enforcing quality control surveillance for identifying and eliminating defective mitochondria are often poorly regulated, and certain uneliminated mitochondrial DNA (mtDNA) mutations and polymorphisms can be advantageous for the proliferation, progression, and metastasis of tumor cells and disseminated into microenvironment cells through extracellular vesicle and tunnel nano tube. Such pathogenic mtDNA aberrations are likely to increase and frequently be homoplasmic in metastatic cancer cells and, intriguingly, in normal cells in the tumor microenvironments as well. Distinct characteristics of these abnormalities in mtDNA may provide a new path for cancer therapy. We recently tested this hypothesis with a few PIP-TPP conjugates targeting mtDNA mutations to induce mutants reduction in heteoplasmic cells or apoptosis in homoplasmic or near homoplasmic cells in vivo model without major adverse effects. This finding reaffirms the feasibility of such a PIP-TPP-based mtDNA-targeting approach for anticancer therapy as well as perhaps cancer risk prevention. However, the absence of known mtDNA mutation hotspots limits the clinical application of somatic mutation-targeted PIP-TPPs. Thus, we designed CCCh-1005-TPP to selectively target a frequent ATP6 gene variant and often oncogenically homoplasmic in the associated with hypertrophic cardiomyopathy, colon, breast and ovarian cancer risk and found its anticancer effect in mouse xenograft models. Here we study preclinical trial of CCCh-1005-TPP, a promising novel anti-cancer agent for clearing abnormal mtDNA by reactivating mitochondrial quality control surveillance of mitophagy. Given those mechanistic insights may provide a promising therapeutic or maybe preventive approach of the pathogenic mtDNA removal in homoplasmic or heteroplasmic cells. Additional caveat is that this strategy may also use not only for cancer but also many other mitochondria related diseases, such as neurodegenerative, diabetic, renal, muscle and hearing loss diseases as well as aging. Citation Format: Hiroki Nagase. Cancer therapeutic and prevention strategy targeting mutated mitochondria DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5980.

Abstract 1818: Novel efficient isolation and water-soluble prodrug preparation of anti-cancer natural product narciclasine

Abstract Narciclasine is a promising anti-cancer agent produced by plants of the family Amaryllidaceae. Narciclasine has been shown to be a potent anti-cancer agent against a variety of cancers carrying dismal outcomes, including glioblastoma, non-small cell lung cancer, and non-Hodgkin’s lymphoma. It is particularly effective in animal studies of brain cancer both primary, such as glioblastoma, metastatic tumors to the brain, such as melanoma and non-small cell lung cancer. Its isolation from plants has generally been accompanied with variable success as it depends on the plant species, their location and the time of plant collection. In this study, an optimized procedure for the extraction of narciclasine yielding 300 mg/kg of dried plant material. This represents a crucial step towards the development of optimized narciclasine derivatives, as the price of narciclasine from commercial sources ranges from $100-$500 per milligram. Additionally, clinical advancement of narciclasine and its derivatives has been severely thwarted, potentially owing to its sparing water-solubility. Insolubility in water makes administration at therapeutic dosages difficult and can lead to unfavorable pharmacokinetic and pharmacodynamic characteristics. To this effort, the synthesis of five prodrug esters of narciclasine is presented, with the target of a water-soluble narciclasine prodrug. Citation Format: Alexander Kornienko, Ryan Rutledge. Novel efficient isolation and water-soluble prodrug preparation of anti-cancer natural product narciclasine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1818.

Abstract 2033: Rigosertib promotes anti-tumor activity of cancer cells via CETSA revealed novel targets and activates NLRP3-dependent inflammatory responses

Abstract Background: Rigosertib (ON 01910.Na) is considered a promising anticancer agent due to its ability to inhibit multiple disease signaling pathways, including RAS-MAPK signaling. Rigosertib is in a Phase 2 program in advanced squamous cell carcinoma complicating recessive dystrophic epidermolysis bullosa (RDEB-associated SCC) (NCT03786237, NCT04177498), and a Phase 2 trial in combination with pembrolizumab in patients with metastatic melanoma (NCT05764395). The aim of our study was to further elucidate the mechanism of action and to identify potential novel targets engaged by rigosertib. Methods: A variety of biochemical, molecular and cell biological assays were performed to characterize the binding of rigosertib to previously proposed targets and its effect on RAS-MAPK signaling and tumor cell survival. A mass spectrometry-based Cellular Thermal Shift Assay (CETSA-MS) was conducted to identify potential new protein targets of rigosertib. Time-lapse microscopy was used for detection of ROS levels and tubulin polymerization in rigosertib treated lung cancer cells. Bone Marrow Derived Macrophages (BMDM) collected from C57/BL6 mice and human lung cancer organoids were treated with rigosertib and the cell death was determined by flow cytometry. Results: Comparative CETSA profiling of rigosertib and colchicine, a classical tubulin depolymerizing agent, reveals unique targets of rigosertib in multiple tumor cell types. We identify two ROS-related proteins, ERO1A and NQO2 that potentially contribute to the induction of ROS-dependent JNK activation. Fluorescence live-cell imaging confirms the effect of ERO1A and NQO2 on rigosertib induced ROS generation. NEK7, a relevant protein for microtubule organization, is another potential target for rigosertib. NEK7 knock-down reveals reduced microtubule depolymerization in rigosertib treated lung cancer cells. While we confirm that rigosertib might affect microtubules at higher concentrations, the main cellular target(s) responsible for the induction of stress and JNK-mediated inhibition of RAS-RAF-MEK signaling needs to be further characterized. Rigosertib affects the tumor immune environment by activating NLRP3-dependent inflammatory responses and Caspase-1 to trigger IL-1β and IL-18 secretion in THP1 cells, as well as in human cancer organoids, and in wild-type, Casp1/11−/−, Asc−/− and Nlrp3−/− BMDMs. Conclusion: These findings indicate that rigosertib may represent an effective compound for inhibition of RAS-MAPK signaling through ROS-mediated JNK activation. The rigosertib-dependent mechanism for NLRP3 activation suggests a reprogramming of the tumor immune environment which may contribute to the synergistic effect seen with immune checkpoint inhibitors pre-clinically and clinically. Clinical trials in several difficult-to-treat cancers continue. Citation Format: Petros Kechagioglou, Camille Dupont, Hajime Yurugi, Alexey Chernobrovkin, Rossana Romero, Rebecca Tweedell, Thirumala-Devi Kanneganti, Stephen Cosenza, Steven M. Fruchtman, Krishnaraj Rajalingam. Rigosertib promotes anti-tumor activity of cancer cells via CETSA revealed novel targets and activates NLRP3-dependent inflammatory responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2033.

Unveiling the Chemical Composition, Bioactive Profile and Antioxidant Capacity of Dried Egyptian Jew's Mallow Stems as a Promising Anticancer Agent.

Phytochemicals from waste materials generated by agricultural and industrial processes have become globally significant due to their accessibility and potential effectiveness with few side effects. These compounds have essential implications in both medicine and the economy. Therefore, a quantitative analysis of the phytochemical profile, sugar types, and water-soluble vitamins of dried Corchorus olitorius L."DJMS" extract (dried Jew's mallow stem) was carried out with HPLC. In addition, the chemical composition, TPC, chlorophyll a and b, beta-carotene, and antioxidant effect using DPPH were investigated. Furthermore, the anticancer activity of the DJMS was evaluated by SRB assay using Huh-7 and MDA-MB-231 cell lines. In the quantitative study, DJMS extract showed a high antioxidant potential (67%) due to its content of bioactive compounds such as TPC (276.37 mg 100 g-1) and chlorophyll a and b (20.31, 12.02 mg 100 g-1, respectively), as well as some vitamins and minerals such as B-complex (B12; 146.8 mg 100 g-1 and vitamin C 6.49 mg 100 g-1) and selenium (<0.2 μg kg-1). Moreover, the main sugar types found were sucrose and stachyose, which recorded 9.23 and 6.25 mg 100 g-1, respectively. Identifying phenolic and flavonoids showed that the major components were ellagic acid (4905.26 μg kg-1), ferulic acid (3628.29 μg kg-1), chlorogenic acid (3757.08 μg kg-1), luteolin-7-O-glucoside (4314.48 μg kg-1), naringin (4296.94 μg kg-1) and apigenin-6-rhamnose-8 glucoside (3078.87 μg kg-1). The dried stem extract showed significant MDA-MB-231 inhibition activity and reached 80% at a concentration of 1000 µg/mL of DJMS extract, related to the content of phytochemical components such as isoflavones like genistein (34.96 μg kg-1), which had a tremendous anticancer effect. Hence, the stem of Jew's mallow (which is edible and characterized by its viability and low production cost) possesses the capacity to serve as a pharmaceutical agent for combating cancer owing to its abundance of bioactive components.

Novel pyrano[2,3-c]pyrazolopyrimidines as promising anticancer agents: Design, synthesis, and cell cycle arrest of HepG2 cells at S phase

The poor selectivity, significant toxicity, high cost, and emergence of resistance of conventional chemotherapies are driving motive for the ongoing search for novel anticancer agents. New pyrano[2,3-c]pyrazolopyrimidines were synthesized and examined as antiproliferative agents, and the possible molecular mechanism(s) of action were explored. The mass and elemental analyses, alongside the IR,1H, and 13C NMR spectra, confirmed the proposed structures of the obtained compounds. Derivatives 4 and 7 demonstrated the best antiproliferative profile against HepG2 cancer cells at 4 µM, with a high selectivity index of ∼7–9 folds. They increased the S phase cell population by 51% and 40% and caused a 5- and 11-fold increase in the p21 protein. Compound 7 was superior in inhibiting HepG2 cell migration and delayed wound healing, reducing migration rates by 55% and 90%, respectively. Future studies on the pharmacokinetics, pharmacodynamics, antimetastatic, and antitumor activities in animal models would be a robust advance.

Flavokawain C inhibits proliferation and migration of liver cancer cells through FAK/PI3K/AKT signaling pathway

PurposeThis study investigated the potential applicability and the underlying mechanisms of flavokawain C, a natural compound derived from kava extracts, in liver cancer treatment.MethodsDrug distribution experiment used to demonstrate the preferential tissues enrichment of flavokawain C. Cell proliferation, apoptosis and migration effect of flavokawain C were determined by MTT, colony formation, EdU staining, cell adhesion, transwell, flow cytometry and western blot assay. The mechanism was explored by comet assay, immunofluorescence assay, RNA-seq-based Kyoto encyclopedia of genes and genomes analysis, molecular dynamics, bioinformatics analysis and western blot assay. The anticancer effect of flavokawain C was further confirmed by xenograft tumor model.ResultsThe studies first demonstrated the preferential enrichment of flavokawain C within liver tissues in vivo. The findings demonstrated that flavokawain C significantly inhibited proliferation and migration of liver cancer cells, induced cellular apoptosis, and triggered intense DNA damage along with strong DNA damage response. The findings from RNA-seq-based KEGG analysis, molecular dynamics, bioinformatics analysis, and western blot assay mechanistically indicated that treatment with flavokawain C notably suppressed the FAK/PI3K/AKT signaling pathway in liver cancer cells. This effect was attributed to the induction of gene changes and the binding of flavokawain C to the ATP sites of FAK and PI3K, resulting in the inhibition of their phosphorylation. Additionally, flavokawain C also displayed the strong capacity to inhibit Huh-7-derived xenograft tumor growth in mice with minimal adverse effects.ConclusionsThese findings identified that flavokawain C is a promising anticancer agent for liver cancer treatment.

Multiple Treatment of Triple-Negative Breast Cancer Through Gambogic Acid-Loaded Mesoporous Polydopamine.

Triple-negative breast cancer (TNBC) is a highly heterogeneous subtype of breast cancer, characterized by aggressiveness and high recurrence rate. As monotherapy provides limited benefit to TNBC patients, combination therapy emerges as a promising treatment approach. Gambogic acid (GA) is an exceedingly promising anticancer agent. Nonetheless, its application potential is hampered by low drug loading efficiency and associated toxic side effects. To overcome these limitations, using mesoporous polydopamine (MPDA) endowed with photothermal conversion capabilities is considered as a delivery vehicle for GA. Meanwhile, GA can inhibit the activity of heat shock protein 90 (HSP90) to enhance the photothermal effect. Herein, GA-loaded MPDA nanoparticles (GA@MPDA NPs) are developed with a high drug loading rate of 75.96% and remarkable photothermal conversion performance. GA@MPDA NPs combined with photothermal treatment (PTT) significantly inhibit the tumor growth, and effectively trigger the immunogenic cell death (ICD), which thereby increase the number of activated effector T cells (CD8+ T cells and CD4+ T cells) in the tumor, and hoist the level of immune-inflammatory cytokines (IFN-γ, IL-6, and TNF-α). The above results suggest that the combination of GA@MPDA NPs with PTT expected to activate the antitumor immune response, thus potentially enhancing the clinical therapeutic effect on TNBC.

A decade'soverview of 2-aminothiophenes and their fused analogs as promising anticancer agents.

Over the past decades, cancer has been a challenging domain for medicinal chemists as it is an international health concern. In association, small molecules such as 2-aminothiophenes and their derivatives showed significant antitumor activity through variable modes of action. Therefore, this article aims to review the advances regarding these core scaffolds over the past 10 years, where 2-aminothiophenes and their fused analogs are classified and discussed according to their biological activity and mode of action, in the interest of boosting new design pathways for medicinal chemists to develop targeted antitumor candidates.

Promising Dual Anticancer and Antimetastatic Action by a Cu(II) Complex Derived from Acylhydrazone on Human Osteosarcoma Models.

Osteosarcoma cancers are becoming more common in children and young adults, and existing treatments have low efficacy and a very high mortality rate, making it pressing to search for new chemotherapies with high efficacy and high selectivity index. Copper complexes have shown promise in the treatment of osteosarcoma. Here, we report the synthesis, characterization, and anticancer activity of [Cu(N-N-Fur)(NO3)(H2O)] complex where N-N-Fur is (E)-N'-(2-hydroxy-3-methoxybenzylidene)furan-2-carbohydrazide. The [Cu(N-N-Fur)(NO3)(H2O)] complex was characterized via X-ray diffraction and electron spin resonance (ESR), displaying a copper center in a nearly squared pyramid environment with the nitrate ligand acting as a fifth ligand in the coordination sphere. We observed that [Cu(N-N-Fur)(NO3)(H2O)] binds to DNA in an intercalative manner. Anticancer activity on the MG-63 cell line was evaluated in osteosarcoma monolayer (IC50 2D: 1.1 ± 0.1 μM) and spheroids (IC50 3D: 16.3 ± 3.1 μM). Selectivity assays using nontumoral fibroblast (L929 cell line) showed that [Cu(N-N-Fur)(NO3)(H2O)] has selectivity index value of 2.3 compared to cis-diamminedichloroplatinum(II) (CDDP) (SI = 0.3). Additionally, flow cytometry studies demonstrated that [Cu(N-N-Fur)(NO3)(H2O)] inhibits cell proliferation and conveys cells to apoptosis. Cell viability studies of MG-63 spheroids (IC50 = 16.3 ± 3.1 μM) showed that its IC50 value is 4 times lower than for CDDP (IC50 = 65 ± 6 μM). Besides, we found that cell death events mainly occurred in the center region of the spheroids, indicating efficient transport to the microtumor. Lastly, the complex showed dose-dependent reductions in spheroid cell migration from 7.5 to 20 μM, indicating both anticancer and antimetastatic effects.

Aspongopus chinensis ach-miR-276a-3p induces breast cancer cell cycle arrest by targeting APPL2 to regulate the CDK2-Rb-E2F1 signaling pathway

Breast cancer, the most common cancer, presents a significant challenge to the health and longevity of women. Aspongopus chinensis Dallas is an insect with known anti-breast cancer properties. However, the anti-breast cancer effects and underlying mechanisms have not been elucidated. Exogenous microRNAs (miRNAs), which are derived from plants and animals, have been revealed to have notable capacities for controlling the proliferation of cancerous cells. To elucidate the inhibitory effects of miRNAs derived from A. chinensis and the regulatory mechanism involved in the growth of breast cancer cells, miRNA sequencing was initially employed to screen for miRNAs both in A. chinensis hemolymph and decoction and in mouse serum and tumor tissue after decoction gavage. Subsequently, the experiments were performed to assess the suppressive effect of ach-miR-276a-3p, the miRNA screened out from a previous study, on the proliferation of MDA-MB-231 and MDA-MB-468 breast cancer cell lines in vitro and in vivo. Finally, the regulatory mechanism of ach-miR-276a-3p in MDA-MB-231 and MDA-MB-468 breast cancer cells was elucidated. The results demonstrated that ach-miR-276a-3p notably inhibited breast cancer cell proliferation, migration, colony formation, and invasion and induced cell cycle arrest at the G0/G1 phase. Moreover, the ach-miR-276a-3p mimics significantly reduced the tumor volume and weight in xenograft tumor mice. Furthermore, ach-miR-276a-3p could induce cell cycle arrest by targeting APPL2 and regulating the CDK2-Rb-E2F1 signaling pathway. In summary, ach-miR-276a-3p, derived from A. chinensis, has anti-breast cancer activity by targeting APPL2 and regulating the CDK2-Rb-E2F1 signaling pathway and can serve as a promising candidate anticancer agent.

Effectiveness of Rhenium(I)-diselenoether Low Doses in a Triple-negative Breast Cancer Chicken Embryo Model.

Rhenium(I)-diselenoether (Re-diSe) is a promising anticancer agent composed of one rhenium and two selenium atoms. Its effectiveness was established in inhibiting cancer cells while maintaining low toxicity toward normal cells at a 5 μM dose for 120 hours in MDA-MB-231 cells. In MDA-MB-231 breast tumor-bearing mice, anti-tumor and anti-metastatic effects were observed at a 10 mg/kg dose. However, contradictory results were observed in the 4T1 breast cancer model, where a dose of 60 mg/kg had a pro-tumor effect. To address these discrepancies, the efficacy of Re-diSe at the effective 10 mg/kg dose was validated in a transplanted MDA-MB-231 breast tumor model using the chicken chorioallantoic membrane assay. MDA-MB-231 cancer cells were xenografted onto the chicken chorioallantoic membrane (CAM), and daily drug administration was carried out for nine days at doses of 0.1, 1, and 10 mg/kg. At the study's conclusion, a standard histological analysis was conducted. The low dose of 0.1 mg/kg showed a significant reduction in tumor weights compared to controls. The 1 mg/kg dose resulted in an increased inflammation score but did not induce a significant difference in tumor weights compared to the 0.1 mg/kg dose. Notably, at the 10 mg/kg dose, six out of 11 treated embryos displayed no visible signs of tumors. These tumors exhibited extensive tumor necrosis and significant infiltration by inflammatory cells. In this particular model, the anticancer efficacy of Re-diSe was achieved at the low dose of 0.1 mg/kg. The higher dose of 10 mg/kg, while eliminating visible tumors, might have immune-mediated effects, as indicated by substantial tumor necrosis and infiltration by inflammatory cells. Overall, this study successfully demonstrated the effectiveness of Re-diSe as an anticancer agent.

Chalcones: Effective Agents for Fighting Cancer Across Multiple Cell Lines

AbstractThis review article explores the mushrooming research on chalcone hybrid molecules as promising anticancer agents. Chalcones, featuring a unique chemical structure, exhibit diverse biological activities, including potent anticancer properties. Various synthetic chalcones and their derivatives have demonstrated remarkable efficacy against different cancer cell lines, offering advantages such as reduced mutagenicity. The article summarizes recent advancements in chalcone hybrid research, highlighting their potential in cancer treatment and paving the way for novel, safer, and more effective chemotherapeutic agents.

Molecular modeling of novel 2-aminopyridine derivatives as potential JAK2 inhibitors: a rational strategy for promising anticancer agents

Janus kinase 2(JAK2) is a potential target for anticancer drugs in the treatment of numerous myeloproliferative diseases due to its central role in the JAK/STAT signaling cascade. In this study, the binding behavior of 2 amino-pyridine derivatives as JAK2 inhibitors was investigated by using multifaceted strategies including 3D-QSAR, molecular docking, Fingerprint analysis, MD simulations, and MM-PBSA calculations. A credible COMFA (q 2 = 0.606 and r 2 = 0.919) and COMSIA (q 2 = 0.641 and r 2 = 0.992) model was developed, where the internal and external validation revealed that the obtained 3D-QSAR models could be capable of predicting bioactivities of JAK2 inhibitors. The structural criteria provided by the contour maps of model were used to computationally develop more potent 100 new JAK2 inhibitors. Docking studies were conducted on the model data set and newly developed compounds (in-house library) to demonstrate their binding mechanism and highlight the key interacting residues within JAK2 active site. The selected docked complexes underwent MD simulation (100 ns), which contributed in the further study of the binding interactions. Binding free energy analyses (MMGB/PBSA) revealed that key residues such as Glu930, Leu932 (hinge region), Asp939 (solvent accessible region), Arg980, Asn981and Asp994 (catalytic site) have a significantly facilitate ligand-protein interactions through H-bonding and van der Waals interactions. The preliminary in-silico ADMET evaluation revealed encouraging results for all the modeled and in-house library compounds. The findings of this research have the potential to offer valuable recommendations for the advancement of novel, potent, and efficacious JAK2 inhibitors. Overall, this work has successfully employed a wide range of computer-based methodologies to understand the interaction dynamics between 2-amino-pyridine derivatives and the JAK2 enzyme, which is a crucial target in myeloproliferative disorders. Communicated by Ramaswamy H. Sarma

Calocedrus formosana Essential Oils Induce ROS-Mediated Autophagy and Apoptosis by Targeting SIRT1 in Colon Cancer Cells.

Colorectal cancer is the most common cancer that affects both sexes and has a poor prognosis due to aggressiveness and chemoresistance. Essential oils isolated from Calocedrus formosana (CF-EOs) have been shown to demonstrate anti-termite, antifungal, anti-mosquito, and anti-microbial activities. However, the anticancer effects of CF-EOs are not yet fully understood. Therefore, the present study aimed to explore the molecular mechanism underlying CF-EOs-mediated anti-proliferative activity in colon cancer cells. Here, cell impedance measurements showed that CF-EOs inhibit proliferation in colon cancer cells with wild-type or mutant p53. Flow cytometry revealed that CF-EOs at 20, 50 µg/mL significantly induced ROS generation and autophagy in both HCT116 p53-wt and HCT116 p53-null cell lines, whereas pretreatment with the ROS scavenger N-acetyl cysteine (NAC) markedly attenuated these changes. CF-EOs also induced apoptosis at 50 µg/mL in both lines, as determined by flow cytometry. Protein analysis showed that CF-EOs markedly induced apoptosis markers, including Trail, cleaved caspase-3, cleaved caspase-9, and cleaved PARP, as well as autophagy markers, such as the levels of ULK1, Atg5, Atg6, Atg7, and the conversion of LC3-I to LC3-II. CF-EOs were further found to inhibit the activity and expression of the NAD+-dependent deacetylase SIRT1 to increase the levels of acetylated p53 (Ac-p53) in p53-wt cells and acetylated c-Myc (Ac-c-Myc) in p53-null cells, ultimately inducing apoptosis in both lines. Interestingly, suppression of SIRT1 by CF-EOs enhanced the acetylation of ULK1, which in turn prompted ROS-dependent autophagy in colon cancer cells. The induction of apoptosis and autophagy by CF-EOs suggests that they may have potential as a promising new approach for treating cancer. Collectively, our results suggest that essential oils isolated from Calocedrus formosana act as a promising anticancer agent against colon cancer cells by targeting SIRT1 to induce ROS-mediated autophagy and apoptosis.

Structure, Spectroscopy, and Theoretical insights on Co-crystals of 2,4-Diamino-6-Methyl-1,3,5-Triazine Bis(4-Aminobenzoic acid) Monohydrate as a promising anti-cancer agent

Co-crystals of 2,4-diamino-6-methyl-1,3,5-triazine bis (4-aminobenzoic acid) monohydrate (hereafter named DMTAB) have been grown from a slow solvent method at room temperature. Single crystal XRD reveals the centrosymmetric nature of the grown crystal with the P21/n space group. Hirshfeld Surface analysis has been performed to visualize and analyse the spatial distribution of intermolecular interactions in a molecular system. The presence of functional groups has been analysed with Fourier Transform Infrared and Raman studies. By employing NBO analysis, valuable insights into the nature of chemical bonds, electron delocalization, and the overall stability of molecular systems have been examined. Theoretical UV–Vis spectrum studies using Time-Dependent - Density Functional Theory (TD-DFT) in different solvents provide a valuable computational tool to predict and understand the electronic transitions of molecules. HOMO-LUMO analysis and density of states spectrum in different solvents further shed light on the electronic structure and reactivity of molecules in their surroundings. First-order hyperpolarizability calculations have been used to analyse the nonlinear optical response of a grown material. Molecular docking studies were conducted to anticipate the binding conformation of the DMTAB ligand with the relevant target proteins, specifically the ovarian cancer target (Rad6 ubiquitin-conjugated enzyme [PDB ID: 2YB6]) and breast cancer target (protein kinase CK2 [PDB ID: 6HNY].

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

Preparation, characterization and in vitro evaluation of the antimicrobial and antitumor activity of MnOx nanoparticles

Manganese oxide containing nanoparticles (MnOx NPs) have emerged as promising antimicrobial and anticancer agents due to their unique properties. However, the different initial materials and synthesis techniques often yield nanoparticles with highly different properties which limit their applications especially in the biomedical field. Thus, we aimed to explore the suitability of pyrolusite as a new and sustainable manganese mineral source for MnOx production. Moreover, we examined the effect of various synthesis methods on the physicochemical characteristics and biological activity of MnOx NPs to explore their therapeutic utilization potential against microbes and in cancer treatment. We produced MnOx NPs from a naturally occurring mineral via mechanochemical, chemical, and electrochemical processes, characterized them thoroughly, and assessed their cytotoxicity against bacteria, fungi, and human cancerous and non-cancerous cells. We verified that the synthesis method utilized to obtain MnOx NPs impacted significantly nanoparticle properties leading to distinct structural, morphological, and biological characteristics. Although none of the particles was effective against the tested bacterial strains, electrochemically produced NPs demonstrated significant antifungal activity. These nanoparticles were also the most potent anticancer agents, exhibiting cancer-selective toxicity attributed to apoptosis induction rather than altered cell proliferation or direct necrotic effects. These results are relevant for the development of effective and safe nanotherapeutics and highlight the potential of MnOx nanoparticles - obtained through carefully selected initial mineral source and adequate synthetic approach - in antimicrobial and anticancer therapy.