Cisplatin is a potent chemotherapeutic drug for ovarian cancer (OC) treatment. However, its efficacy is significantly limited due to the development of cisplatin resistance. Although the acquisition of cisplatin resistance is a complex process involving various molecular alterations within cancer cells, the increased reliance of cisplatin-resistant cells on glycolysis has gained increasing attention. Isoalantolactone, a sesquiterpene lactone isolated from Inula helenium L., possesses various pharmacological properties, including anticancer activity. In this study, isoalantolactone was investigated as a potential glycolysis inhibitor to overcome cisplatin resistance in OC. Isoalantolactone effectively targeted key glycolytic enzymes (e.g., lactate dehydrogenase A, phosphofructokinase liver type, and hexokinase 2), reducing glucose consumption and lactate production in cisplatin-resistant OC cells (specifically A2780 and SNU-8). Importantly, it also sensitized these cells to cisplatin-induced apoptosis. Isoalantolactone-cisplatin treatment regulated mitogen-activated protein kinase and AKT pathways more effectively in cisplatin-resistant cells than individual treatments. In vivo studies using cisplatin-sensitive and resistant OC xenograft models revealed that isoalantolactone, either alone or in combination with cisplatin, significantly suppressed tumor growth in cisplatin-resistant tumors. These findings highlight the potential of isoalantolactone as a novel glycolysis inhibitor for treating cisplatin-resistant OC. By targeting the dysregulated glycolytic pathway, isoalantolactone offers a promising approach to overcoming drug resistance and enhancing the efficacy of cisplatin-based therapies.
Keywords: cancer metabolism; cisplatin resistance; combination therapy; glycolysis; isoalantolactone; ovarian cancer.