Journal
ONCOTARGETS AND THERAPY
Volume 14, Issue -, Pages 2519-2530Publisher
DOVE MEDICAL PRESS LTD
DOI: 10.2147/OTT.S302334
Keywords
GDC-0326; 5-fluorouracil; colorectal cancer; combination therapy
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Funding
- National Natural Science Foundation of China [81802348]
- Zhejiang Provincial Natural Science Foundation [LY18H160009, LY16H160031]
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This study demonstrates that GDC-0326 can effectively suppress CRC cell growth through inducing necroptosis and modulating RIPK1 and RIPK3. The combination of 5-Fu with GDC-0326 shows enhanced antitumor efficacy with minimal toxicity in vitro and in vivo studies.
Aim: 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.
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