Buse Birinci

Background/Objectives: Non-small-cell lung carcinoma (NSCLC) accounts for approximately 85% of lung cancers and remains a leading cause of cancer-related mortality. Although cisplatin is a cornerstone chemotherapeutic agent, its clinical effectiveness is limited by drug resistance and systemic toxicity. Capsaicin (CAP), a bioactive phytochemical derived from chili peppers, has demonstrated anticancer activity in several tumor types and has been investigated as a potential adjunct to conventional chemotherapy. Methods: An experimental study was conducted using A549 NSCLC cells and a xenograft mouse model. Cells were treated with CAP (50–300 µM), cisplatin (1 µg/mL), or their combination. Cell proliferation and apoptosis were evaluated using sulforhodamine B (SRB) assay, immunocytochemistry, and Western blot analysis. In vivo, tumor growth inhibition, histopathological alterations, and immunohistochemical expression of Ki-67 and cleaved caspase-3 were assessed. Results: Low CAP concentrations (50–100 µM) slightly increased proliferation, whereas concentrations ≥ 150 µM significantly reduced cell viability and induced apoptosis. Cisplatin monotherapy markedly suppressed proliferation and activated apoptosis. Bliss independence analysis demonstrated concentration-dependent synergy between CAP and cisplatin, with maximal synergy scores reaching 28.1 at 100 µM CAP. Combination treatment at CAP concentrations ≥ 150 µM produced the strongest antiproliferative effect in vitro and the highest tumor growth inhibition in vivo (88%). CAP did not further enhance cisplatin-induced apoptosis but significantly reinforced proliferation suppression with reduced Ki-67 expression. Conclusions: CAP exhibits biphasic dose-dependent effects in NSCLC and enhances cisplatin antitumor efficacy predominantly through proliferation suppression, supporting its further evaluation as an adjunctive phytochemical in cisplatin-based NSCLC therapy.