GDC-0326 Enhances the Effects of 5-Fu in Colorectal Cancer Cells by Inducing Necroptotic Death

• DOI: 10.2147/ott.s302334
• Publication Date: 2021-04-12T22:53:49Z
• Authors: Zizhen Zhang; Fangyu Ju; Fei Chen; Haoyue Wu; Jingyu Chen; Jing Zhong; Liming Shao; Sheng Zheng; Liangjing Wang; Meng Xue
• Keywords: 0303 health sciences; 03 medical and health sciences; OncoTargets and Therapy; Original Research; 3. Good health

Chemoresistance to 5-fluorouracil (5-Fu) is common in colorectal cancer (CRC). Programmed necrosis (necroptosis) is an alternative form of programmed cell death regulated by receptor-interacting protein kinase (RIPK) 1 and 3, assumed as a novel target of cancer therapy. In this study, we aimed to explore whether a novel small molecular agent GDC-0326 could facilitate the effect of 5-Fu through necroptosis.Cell Counting Kit-8 (CCK-8) assay and colony formation were performed to confirm the function of GDC-0326 in CRC cells. Western blot and immunofluorescence were conducted to measure the altered expressions of RIPK1/RIPK3 induced by GDC-0326. Subcutaneous tumor models were used to evaluate the chemotherapeutic effects and concomitant side effects of GDC-0326 in vivo.We found that GDC-0326 effectively suppressed the growth of CRC cells in a dose-dependent manner. The induction of necroptosis by GDC-0326 was correlated with the modulation of RIPK1 and RIPK3. Necrostatin-1 and GSK-872, inhibitors of RIPK1 and RIPK3, respectively, could rescue the cell death induced by GDC-0326. In addition, in vitro and in vivo studies showed that 5-Fu plus GDC-0326 evinced a better antitumor efficacy by suppressing tumor growth and increasing tumor necrosis with no increased toxicity.This study demonstrates that GDC-0326 plus 5-Fu has augmented antitumor efficacy and acceptable safety, which might be a promising therapeutic strategy for CRC patients in the future.