Modulation of Apoptosis and ER Stress Markers in Hepatocellular Carcinoma Cells by Irinotecan, Hesperidin, and Piperine

Aim: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, and there is a pressing need to explore novel therapeutic strategies that enhance the efficacy of existing treatments. This study aims to investigate the effects of irinotecan (IRT), hesperidin (HSP), and piperine (PIP) on HCC (HepG2), focusing on their modulation of apoptosis-related genes and endoplasmic reticulum (ER) stress markers. Methods: This study is an in vitro experimental study. IC50 values for IRT, HSP, and PIP were determined using MTT cell viability assays. Researchers performed total RNA extraction and quantitative PCR to assess mRNA levels of Bad, Bax, and p53 (apoptosis-related genes) and ATF4, CHOP, and GRP78 (ER stress markers). Results: Irinotecan significantly upregulated the expression of Bad, Bax, and p53 genes, as well as ER stress markers such as ATF4, CHOP, and GRP78. Hesperidin-enhanced apoptotic gene expression and exacerbated ER stress. Piperine attenuated IRT-induced apoptosis and suppressed ER stress markers. Conclusion: Combining IRT with HSP enhanced apoptosis and ER stress in HepG2 cells, suggesting synergistic potential against HCC. Conversely, IRT combined with PIP reduced apoptotic response and ER stress markers, possibly compromising IRT's efficacy. These findings highlight complex interactions between chemotherapeutic agents and natural compounds, warranting further exploration in combination therapies.