PI3K/Akt/mTOR pathway activation causes relapse and resistance after radiotherapy in breast cancer (BC). We aimed to radiosensitize BC cell lines to IR by PKI-402, a dual PI3K/mTOR inhibitor. We performed cytotoxicity, clonogenicity, hanging drop, apoptosis and DSB detection, and phosphorylation of 16 essential proteins involved in the PI3K/mTOR pathway. Our findings showed that PKI-402 has cytotoxic efficiency in all cell lines. Clonogenic assay results showed that PKI-402 plus IR inhibited the colony formation ability of MCF-7 and BCSC cell lines. Results showed that PKI-402 plus IR causes more apoptotic cell death than IR alone in the MCF-7 cells but did not cause significant changes in the MDA-MB-231. γ-H2AX levels were increased in MDA-MB-231 in PKI-402 plus IR groups, whereas we did not observe any apoptotic and γ-H2AX induction in BCSCs and MCF-10A cells in all treatment groups. Some pivotal phosphorylated proteins of the PI3K/AKT pathway decreased, several proteins increased and others did not change. In conclusion, if the combined use of PKI-402 with radiation is supported by in vivo studies, it can contribute to the treatment options and the course of the disease.

Background/Objectives: Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms may influence folate metabolism and DNA synthesis, potentially affecting disease characteristics and clinical outcomes in hematologic malignancies. This study investigated the associations of MTHFR C677T and A1298C polymorphisms with clinical features and survival outcomes in adult patients with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). Methods: A total of 92 adult patients with ALL or NHL treated with standard chemotherapy were retrospectively analyzed. MTHFR C677T and A1298C genotypes were determined using real-time polymerase chain reaction. Associations between genotypes and baseline clinical features, treatment response, toxicity, overall survival (OS), and progression-free survival (PFS) were examined. Results: The C677T heterozygous genotype was significantly associated with the presence of B symptoms (p = 0.027). No significant differences were observed across genotypes with respect to other baseline clinical features, treatment response, or treatment-related toxicity. In the overall cohort (ALL + NHL), OS and PFS did not differ significantly by C677T or A1298C genotypes. However, in the NHL cohort, carriers of the C677T variant demonstrated significantly shorter PFS (p = 0.048) and a non-significant trend toward lower OS. This association was also observed in the DLBCL subgroup for PFS (p = 0.043), with a similar non-significant trend observed for OS. Conclusions: Although MTHFR genotyping appears to have limited value for broad clinical stratification, the observed association between the C677T polymorphism and PFS in NHL—particularly in the DLBCL subgroup—suggests a potential subtype-specific relevance that warrants further validation in larger, disease-specific cohorts.

Objevtive: Breast cancer represents a significant clinical challenge due to tumor heterogeneity and the presence of therapy-resistant cancer stem cells (CSCs). The combination of epigenetic modulators and differentiation-inducing agents has emerged as a promising therapeutic strategy. In this study, we aimed to evaluate the anticancer effects of combining the methyltransferase inhibitor 3-Deazaneplanocin A (DZNep) and the MYC transcription inhibitor Stauprimide on breast cancer cell lines and breast cancer stem cells (BCSCs). Methods: Cytotoxicity was determined by real-time cell analysis (RTCA) to calculate IC₅₀ values and evaluate the synergistic potential of the combination using isobologram analyses. Apoptosis induction and cell cycle distribution were assessed via flow cytometry using Annexin V-FITC/PI staining and DNA content analysis, respectively. Cell migration was evaluated using wound-healing assays. Additionally, quantitative RT-PCR was performed to analyze expression changes in key apoptosis- and cell cycle-related genes following treatment. Results: The combination of DZNep and Stauprimide (1:1 ratio) demonstrated significant synergistic cytotoxicity in MCF-7 (luminal A) and MDA-MB-231 (triple-negative) breast cancer cells, substantially reducing effective doses of both agents (combination index values of 0.671 and 0.134, respectively). Treatment markedly induced apoptosis, triggered cell cycle arrest predominantly at G2/M and G0/G1 phases, increased polyploidy, and significantly inhibited migration. Notably, the combination selectively induced apoptosis and modulated gene expression (e.g., TP53 and p27 upregulation) in BCSCs, while exhibiting minimal toxicity towards the normal mammary epithelial cell line, MCF-10A. The combination of DZNep and Stauprimide exerts potent anticancer effects by selectively inducing apoptosis, cell cycle arrest, and suppressing migration in breast cancer cells, including CSC populations. Conclusion: These findings suggest translational potential for preventing recurrence and metastasis, positioning this therapeutic strategy as a promising candidate for further validation in preclinical and clinical studies.