Novel Piperlongumine derivatives exert multimodal antitumor effects in prostate cancer via MAPK pathway activation, poly-mechanistic apoptosis induction, and DNMT3A-mediated DNA methylation reduction.

Phenotypic discovery of a pyrimidine derivative with dual anti-prostate cancer and cardioprotective potential via ROS modulation.

Cardiotoxicity remains a major limitation of current anticancer therapies, highlighting the need for agents that combine antitumor efficacy with intrinsic cardiac safety. Phenotypic screening of a pyrimidine-based compound library identified compound 9v as a potent anti-prostate cancer candidate with dual biological functions. Compound 9v inhibited PC-3 cell proliferation with an IC₅₀ of 3.96 ± 0.18 μM, outperforming 5-fluorouracil, and markedly suppressed colony formation and migration while inducing apoptosis. Mechanistic studies showed that 9v activated the mitochondrial apoptotic pathway by increasing Bax, cleaved caspase-9, and cleaved caspase-3 levels while reducing Bcl-2 expression. Remarkably, 9v exerted bidirectional regulation of ROS homeostasis, promoting ROS accumulation in PC-3 cells but suppressing oxidative stress in H9C2 cardiomyocytes under H₂O₂ challenge. In addition, 9v exhibited weak cytotoxicity toward normal prostate stromal cells, no obvious acute toxicity in mice, and no detectable cardiotoxicity in vitro. Moreover, it exhibited protective effects against oxidative injury in cardiomyocytes, as demonstrated by increased cell viability and decreased LDH and cTnT release. Taken together, these results identify 9v as a promising lead compound with both anti-prostate cancer activity and cardioprotective potential in an in vitro oxidative stress model, providing a basis for the development of multifunctional anticancer agents with improved cardiovascular safety.

2-Oxoindoline-based hydroxamic acids: novel HDAC inhibitors with promising anticancer activity

Histone deacetylase (HDAC) inhibitors are important epigenetic anticancer agents that regulate gene expression, induce cell cycle arrest, and promote apoptosis. In this study, a novel series of 2-oxoindoline-capped hydroxamic acids was designed, synthesized and evaluated for their capacity to inhibit histone deacetylases and suppress cancer cell proliferation. The screening panel incorporated multiple cancer models spanning different organ systems, including colorectal adenocarcinoma (SW620, HCT116), triple-negative breast cancer (MDA-MB-231), non-small cell lung carcinoma (A549), and prostate cancer (PC-3). Comparative assessment against non-transformed fibroblasts (MRC-5) enabled evaluation of selectivity and tolerability profiles. Several derivatives exhibited potent HDAC inhibition at submicromolar concentrations, with compounds 7c, 10b, and 10c showing stronger activity than the reference inhibitor SAHA. Among them, compound 10c demonstrated broad antiproliferative effects while maintaining relatively low toxicity toward normal cells. Mechanistic investigations revealed that 10c induced S-phase cell cycle arrest and promoted apoptosis in SW620 colorectal cancer cells. Molecular docking studies against multiple HDAC isoforms supported the experimental findings by revealing favorable zinc coordination and key interactions within the catalytic pocket. To further elucidate the binding behavior and dynamic features of the most active derivatives, molecular dynamics simulations were performed for HDAC complexes with 7c, 10b, and 10c. The simulations revealed stable protein–ligand interactions without perturbation of the overall protein structure, while highlighting distinct binding dynamics among the compounds, with 10c exhibiting the highest binding persistence, followed by 7c and 10b. In addition, in silico ADME and toxicity predictions were carried out for compound 10c as a representative highly active derivative, indicating acceptable drug-like properties and a favorable safety profile. Overall, 2-oxoindoline-based hydroxamic acids, particularly those bearing extended alkyl linkers, represent promising scaffolds for further development of HDAC-targeted anticancer agents.

Thymoquinone Potentiates Docetaxel-Induced Antitumor Activity with the Involvement of ROS and PI3K/AKT Pathway Modulation in Triple-Negative Breast Cancer Cells

Background: Drug resistance and treatment-associated toxicity remain major limitations of conventional chemotherapy for triple-negative breast cancer (TNBC). Thymoquinone (TQ), a bioactive phytochemical derived from Nigella sativa, has demonstrated anticancer properties and may enhance the therapeutic efficacy of docetaxel (DTX) through complementary molecular mechanisms. Objective: To investigate whether TQ potentiates the antitumor activity of DTX in MDA-MB-231 TNBC cells by affecting apoptosis, oxidative stress, wound closure, and PI3K/AKT pathway-related gene expression. Methods: MDA-MB-231 TNBC cells and HaCaT keratinocytes were treated with TQ, DTX, or their combination. Cell viability was determined using the MTT assay, and drug interactions were evaluated by the Chou–Talalay combination index (CI) method. Apoptosis, intracellular reactive oxygen species (ROS) production, ROS rescue experiments using N-acetyl-L-cysteine (NAC), caspase-9 expression, wound closure, and gene-expression changes were assessed using Annexin V/PI flow cytometry, DCFH-DA-based flow cytometric and fluorescence analyses, immunocytochemistry, wound-healing assay, and quantitative real-time PCR (qRT-PCR), respectively. Bioinformatic analyses were performed to identify signaling pathways associated with the observed molecular alterations. Results: The TQ + DTX combination demonstrated synergistic cytotoxicity and significantly increased apoptotic cell death compared with either monotherapy. Combination treatment markedly enhanced intracellular ROS accumulation, whereas NAC pretreatment significantly attenuated ROS generation and partially reversed the cytotoxic and pro-apoptotic effects, suggesting the involvement of ROS in the observed antitumor effects. Caspase-9 immunoreactivity was markedly increased following combination treatment, suggesting the involvement of the intrinsic apoptotic pathway. Furthermore, the combination significantly suppressed wound closure and downregulated BCL2, PIK3CA, and AKT1 while upregulating BAX, CASP9, and PTEN. Bioinformatic analyses identified apoptosis, p53, PI3K/AKT, mTOR, and MAPK signaling as the principal pathways potentially associated with the observed gene expression changes. Conclusions: TQ potentiates the antitumor activity of DTX, with the involvement of oxidative stress, apoptotic signaling, suppression of wound closure, and regulation of PI3K/AKT pathway-related gene expression in TNBC cells. These findings provide evidence supporting further preclinical investigation of the TQ + DTX combination as a promising therapeutic strategy for triple-negative breast cancer.

Quinoxaline-based cyanoacrylate hybrids as multi-target anti-proliferative and anti-inflammatory agents with potent activity against hepatocellular carcinoma: induction of apoptosis and modulation of oxidative stress signaling

Findings identify compound 9 as a promising multi-target quinoxaline-based agent with dual antiproliferative and anti-inflammatory activities, mediated through induction of mitochondrial apoptosis and modulation of oxidative stress and cytokine signaling pathways.

Nutraceutical Iridoid Glycoside Monotropein Induces Apoptosis and Suppresses PI3K/Akt/mTOR Signaling in Breast Cancer Cells: An In Vitro Evaluation

The rising global burden of breast cancer, marked by increasing incidence and mortality rates, has intensified the pursuit of anti-cancer agents that are both effective and mechanistically targeted while minimizing systemic toxicity. In this context, nutraceuticals are being explored for their therapeutic potential due to their capacity to influence multiple oncogenic and survival pathways, their favorable safety profiles, and their potential to complement or enhance conventional chemotherapeutic approaches. Monotropein, a plant-derived iridoid glycoside, has garnered considerable interest owing to its diverse pharmacological activities, including anti-inflammatory, antioxidant, and cytoprotective effects. Despite these documented bioactivities, the specific anti-cancer mechanisms of monotropein, particularly in the context of breast carcinoma, remain inadequately explored. The present study aims to elucidate the anti-cancer potential of monotropein in a breast adenocarcinoma cell line. The anti-cancer potential of monotropein was assessed using an in vitro breast cancer model. Cytotoxicity was assessed in MCF-7 breast adenocarcinoma cells and normal Vero epithelial cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the IC50 value of monotropein was determined. Nuclear morphological alterations induced by monotropein were examined through DAPI (4´,6-diamidino-2-phenylindole) staining. Apoptosis was further validated by quantifying caspase activation and the expression of key apoptotic regulators in monotropein-treated MCF-7 cells. In addition, phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling proteins were measured to elucidate the compound’s mechanistic effects. Our findings demonstrated that monotropein exhibited selective anti-cancer activity against breast cancer cells. Increased caspase activity and elevated Bax levels, accompanied by a decline in the anti-apoptotic protein B-cell lymphoma 2 (Bcl-2), were observed in the MCF-7 cells treated with monotropein. Furthermore, monotropein treatment significantly downregulated PI3K, Akt, and mTOR protein expression. Collectively, these findings demonstrate that monotropein exerted an anti-cancer effect in the breast adenocarcinoma cell line through the activation of the apoptotic cascade and suppression of PI3K/Akt/mTOR signaling. These findings highlight monotropein’s potential as a nutraceutical-based therapeutic candidate, although further investigations are required to validate its efficacy and underlying mechanisms in advanced pre-clinical models.

Enhanced in vitro anticancer activity of a platinum-Mesalazine complex against colorectal cancer cells apoptotic modulation and evidence of non-intercalative DNA binding.