Isoegomaketone improves radiotherapy efficacy and intestinal injury by regulating apoptosis, autophagy and PI3K/AKT/mTOR signaling in a colon cancer model.

Abstract

The current study aimed to investigate the effect of isoegomaketone (IK) as a radiosensitizer for colon cancer and its effect on intestinal injury, and to verify its potential mechanism. A total of 40 BALB/c nude mice were selected to construct a HT‑29 tumor‑bearing mice model with T lymphocyte deficiency. Tumor size was measured every other day, and the survival of mice was counted. Intestinal and tumor tissues of mice were harvested when the experiment ended. The levels of inflammatory factors and markers of oxidative stress in intestinal tissues of different groups of mice were analyzed by ELISA. Western blotting was used to examine the expression of apoptosis‑ and autophagy‑related proteins, and the phosphorylation levels of the PI3K/AKT/mTOR signaling pathway in HT‑29 cells and tumor tissues. Radiotherapy (RT) combined with IK significantly reduced the viability of HT‑29 cells. The optimal dose proportion of RT combined with IK was 8 Gy and 100 µg/ml, and the combination index was <1, suggesting a strong combination effect. In addition, IK could further promote radiation DNA damage in HT‑29 cells by inhibiting the PI3K/AKT/hypoxia inducible factor 1α (HIF‑1α) signaling pathway, while upregulating the expression of proapoptotic and autophagy‑related proteins in HT‑29 cells. In HT‑29 tumor‑bearing mice, RT in combination with IK significantly inhibited the growth of xenografts and improved mouse survival. In addition, the combination of RT and IK significantly upregulated BAX and Beclin‑1 expression, downregulated BCL‑2 expression, and promoted the conversion of LC3 I to LC3 II. Radiation induced an increase in inflammatory cytokine levels as well as oxidative stress marker levels in intestinal tissue. Western blot analysis showed that the combination of RT and IK significantly inhibited the phosphorylation level of the PI3K/AKT/mTOR signaling pathway compared with the control and monotherapy groups. IK could significantly enhance the efficacy of RT by regulating the apoptosis and autophagy of colon cancer tumors, and alleviate inflammation and oxidative stress by regulating the PI3K/AKT/mTOR signaling pathway to alleviate intestinal injury. The present findings suggest that IK can be used as a promising sensitizer and has the potential to enhance the efficacy and safety of RT for colon cancer.