Work

Sodium bicarbonate potentiates the antitumor effects of Olaparib in ovarian cancer via cGMP/PKG-mediated ROS scavenging and M1 macrophage transformation

Year: 2024

Type: article

Abstract: The high metabolic requirements of cancer cells result in excess accumulation of H + in the tumor microenvironment. Therefore, the extracellular pH of solid tumors is acidic, whereas the pH of normal tissues is more alkaline. The acidic tumor environment is correlated with tumor metastasis, immune escape, and chemoresistance, but the underlying mechanisms remain elusive. Herein, we demonstrate that sodium bicarbonate, a weakly alkaline compound, induces cytotoxicity in ovarian cancer cells and hinders cancer migration and invasion in vitro . The anti-cancer efficacy of Olaparib can be significantly augmented when combined with sodium bicarbonate. In vivo experiments suggest that the combinatorial treatment of sodium bicarbonate and Olaparib is biocompatible and more effective at inhibiting ovarian cancer growth than either treatment alone. Additionally, RNA-sequencing results reveal that the differentially expressed genes are enriched in pathways related to reactive oxygen species (ROS) generation, such as the cGMP/PKG pathway. The combined treatment increases M1 macrophage composition in tumors and reduces the accumulation of excessive ROS. These findings strongly suggest that sodium bicarbonate holds great potential as an adjuvant treatment by scavenging ROS accumulation and promoting M1 macrophage composition, thereby enhancing Olaparib’s anti-cancer activity. Combination treatment of sodium bicarbonate and Olaparib exerts synergistic cytotoxicity on ovarian cancer cells, promoting apoptosis and hindering migration and invasion in vitro . RNA-sequencing analysis reveals that enrichment of differentially expressed genes in the cGMP/PKG pathway, linked to ROS generation. This combinatorial also approach promotes M1 macrophage polarization in tumors, enhancing the antitumor response. • Combination treatment of sodium bicarbonate and Olaparib exerts synergistic cytotoxicity in ovarian cancer cells in vitro . • Compared to single treatment, the combinatorial treatment shows good biosafety and inhibits ovarian cancer growth in mice models. • RNA-sequencing analysis reveals that differentially expressed genes are enriched in the cGMP/PKG pathway, which is correlated with ROS generation. • The combinatorial approach increases in M1 macrophage in tumors, enhancing the antitumor response.

Source: Biomedicine & Pharmacotherapy

DOI: 10.1016/j.biopha.2024.117509