OncoTargets and Therapy (Apr 2021)

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

  • Zhang Z,
  • Ju F,
  • Chen F,
  • Wu H,
  • Chen J,
  • Zhong J,
  • Shao L,
  • Zheng S,
  • Wang L,
  • Xue M

Journal volume & issue
Vol. Volume 14
pp. 2519 – 2530

Abstract

Read online

Zizhen Zhang,1– 3,* Fangyu Ju,1– 3,* Fei Chen,1– 3 Haoyue Wu,4 Jingyu Chen,1– 3 Jing Zhong,1– 3 Liming Shao,1– 3 Sheng Zheng,1– 3 Liangjing Wang,1– 3 Meng Xue1– 3 1Department of Gastroenterology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, 310020, People’s Republic of China; 2Institution of Gastroenterology, Zhejiang University, Hangzhou, 310000, People’s Republic of China; 3Zhejiang University Cancer Center, Hangzhou, 310000, People’s Republic of China; 4Institute of Genetics and Department of Genetics, Zhejiang University School of Medicine, Hangzhou, 310012, People’s Republic of China*These authors contributed equally to this workCorrespondence: Meng Xue; Liangjing Wang Email [email protected]; [email protected]: 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.Main Methods: 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.Key Findings: 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.Significance: 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.Keywords: GDC-0326, 5-fluorouracil, colorectal cancer, combination therapy

Keywords