The Interventional Effects and Mechanisms of Lonidamine in Combination with Apigenin on Colorectal Cancer

Colorectal cancer (CRC) is the second most prevalent cancer globally and remains a significant cause of cancer-related mortality. The limited efficacy and toxicities of conventional therapies underscore the urgent need for novel treatments. Lonidamine (LND), a synthetic indazole-3-carboxylic acid derivative, possesses anticancer properties, yet its clinical use is limited by toxic side effects. Apigenin (AP), a naturally occurring flavonoid present in a variety of fruits and vegetables, has been observed to enhance the efficacy of conventional chemotherapy regimens while mitigating associated side effects. In this study, we explored the potential synergistic anticancer effects and mechanisms of combining LND with AP in colon cancer cell lines MC38 and CT26. The results showed that LND and AP in combination synergistically inhibited the growth of colon cancer cells. In vitro, the combination therapy inhibited cell migration, induced cell cycle arrest in the G2/M phase, and promoted apoptosis by downregulating Bcl-2 and upregulating Bax expression. It disrupted glycolysis by reducing HK2 and GLUT1 expression, resulting in decreased glucose consumption and lactate production. Additionally, our findings suggested that the co-administration led to nucleotide depletion and disrupted NAD⁺ metabolism. The synergistic anticancer effect of LND combined with AP was also validated in MC38 tumor-bearing mice. These findings provide preliminary evidence that the combination of LND and AP may exert beneficial effects against CRC.