Omeprazole Enhances Olaparib-Associated Cytotoxicity in Gastric Cancer Cells: Metabolic and Transcriptional Responses

• Negar Taghavi Pourianazar

  Medical Laboratory Techniques, Vocational School of Health Services, Istanbul Aydin University, Istanbul, Turkey

Gastric cancer remains a major therapeutic challenge, and the clinical activity of poly(ADP-ribose) polymerase inhibitors such as olaparib may be limited in tumors without established DNA-repair vulnerabilities. This study investigated the effects of combining olaparib with the proton-pump inhibitor omeprazole in AGS and MKN45 gastric cancer cells. Cell viability and cytotoxicity were evaluated using MTS and LDH assays. Oxidative DNA-damage-associated signal, gene expression, lactate production, intracellular ATP, glucose uptake, and Caspase-3 activity were assessed using ELISA-based, quantitative PCR, and colorimetric methods. Under the tested in-vitro conditions, omeprazole enhanced the olaparib-associated reduction in MTS signal and increased LDH release. Combination-index analysis indicated concentration- and cell-line-dependent interactions: all tested AGS combinations had CI values below 1, although the lowest AGS combination was close to additivity, whereas the lowest tested MKN45 combination was antagonistic and the remaining tested MKN45 combinations had CI values below 1. Combination treatment was associated with an increased 8-OHdG signal, reduced lactate production, decreased intracellular ATP levels and glucose uptake, and altered expression of BRCA1, RAD51, GLUT1/SLC2A1, HK2, LDHA, MCT4/SLC16A3, p21/CDKN1A, and p16/CDKN2A. Increased Caspase-3 activity was consistent with enhanced apoptosis-associated signaling. The observed changes in BRCA1 and RAD51 transcript levels suggest a potential modulation of DNA-repair-related responses, although their functional significance remains to be established. Overall, these findings support further investigation of the olaparib–omeprazole combination as a hypothesis-generating strategy in gastric cancer models, with future studies required to clarify its molecular basis and translational relevance.

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