Melittinin sisplatin duyarlı ve dirençli MDA-MB-231 meme kanseri hücrelerinde antikanser etkileri ile BRMS1/CTR1 gen ekspresyonunun değerlendirilmesi

Abstract

Breast cancer, particularly the triple-negative subtype, is among the malignancies that are difficult to treat due to its high metastatic potential and tendency to develop resistance to chemotherapy. Although platinum-based chemotherapeutic agents such as cisplatin are effective, resistance mechanisms that develop over time limit treatment success. Therefore, there is a need for more effective and less toxic alternative or complementary therapeutic approaches. In this context, melittin, the main component of honeybee (Apis mellifera) venom and a biologically active peptide, has attracted attention due to its anticancer potential. In this study, the anticancer effects of melittin on cisplatin-sensitive and cisplatin-resistant MDA-MB-231 breast cancer cell lines, as well as its effects on BRMS1 and CTR1 gene expression, were investigated. These genes were selected because of the metastasis-suppressing role of BRMS1 and the critical regulatory function of CTR1 in intracellular cisplatin transport. Cell viability was evaluated using the XTT assay; cell migration was assessed by the wound healing assay, and invasion capacity was analyzed by the invasion assay. Gene expression levels were determined using the qRT-PCR method. The obtained results showed that melittin exerted a pronounced dose-dependent cytotoxic effect in both cell lines. In addition, melittin treatment significantly reduced cell migration and invasion capacities in both cisplatin-sensitive and resistant cells (p<0.05). These findings indicate that melittin has a suppressive effect on metastatic processes. When gene expression analyses were evaluated, melittin treatment was observed to significantly increase BRMS1 gene expression, particularly in cisplatin-sensitive cells (p<0.05), whereas variable responses were observed in cisplatin-resistant cells depending on dose and treatment conditions (in some groups, p>0.05). In terms of CTR1 gene expression, melittin treatment led to a marked and statistically significant increase, especially at higher doses in cisplatin-sensitive cells (p<0.05). In contrast, the expression response in resistant cells was heterogeneous, and in most conditions did not reach statistical significance (p>0.05). In conclusion, melittin was shown not only to exert cytotoxic effects but also to significantly suppress cell migration and invasion, thereby demonstrating anti-metastatic potential, and to exert molecular-level effects through BRMS1/CTR1 gene expression. This suggests that melittin may play a regulatory role in intracellular drug transport and, consequently, in the chemotherapeutic response. These findings indicate that melittin may be considered a potential adjunct agent in the development of new therapeutic strategies aimed at overcoming cisplatin resistance.