Introduction: Oxaliplatin is part of pancreatic cancer therapy in the FOLFIRINOX or GEMOX/XELOX regimen. DNA damage repair is one of the factors responsible for oxaliplatin resistance that eventually develops in this cancer. Triptolide/Minnelide has been shown to be effective against pancreatic cancer in preclinical trials. In this study, we evaluated the efficacy of combination of triptolide and oxaliplatin against pancreatic cancer. Methods: Highly aggressive pancreatic cancer cells (MIA PaCa-2 and PANC-1) were treated with oxaliplatin (0–10 μM), low-dose triptolide (50 nM), or a combination of both for 24–48 h. Cell viability, apoptosis, and DNA damage were evaluated by appropriate methods. Nucleotide excision repair pathway components were quantitated using qPCR and Western blot. Combination of low doses of Minnelide and oxaliplatin was tested in an orthotopic murine model of pancreatic cancer. Results: Proliferation of pancreatic cancer cells was markedly inhibited by combination treatment. Triptolide potentiated apoptotic cell death induced by oxaliplatin and sensitized cancer cells towards oxaliplatin-induced DNA damage by suppressing the oxaliplatin-induced DNA damage repair pathway. Combination of low doses of Minnelide and oxaliplatin inhibited tumor progression by inducing significant apoptotic cell death in these tumors. Conclusions: Combination of low doses of Minnelide and oxaliplatin has immense potential to emerge as a novel therapeutic strategy against pancreatic cancer.
Bibliographical noteFunding Information:
This study was funded by NIH grants R01-CA170946 and CA124723 (to AKS); NIH grant R01-CA184274 (to SB); UAB/UMN SPORE in Pancreatic Cancer-P50 CA101955 (to SM); Katherine and Robert Goodale foundation support (to AKS); and Minneamrita Therapeutics LLC (to AKS).
- DNA damage pancreatic cancer