Minnelide Overcomes Oxaliplatin Resistance by Downregulating the DNA Repair Pathway in Pancreatic Cancer.
BACKGROUND
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.
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA.
Shrey
S
Modi
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA.
Devika
D
Kir
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA.
Bhuwan
B
Giri
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA.
Kaustav
K
Majumder
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA.
Nivedita
N
Arora
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA.
Vikas
V
Dudeja
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA.
Sulagna
S
Banerjee
Division of Basic and Translational Research, Department of Surgery, University of Minnesota, 420 Delaware Street SE, MMC195, Minneapolis, MN, 55455, USA. asaluja@umn.edu.
Ashok K
AK
Saluja
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004224:Diterpenes / Q000494:pharmacology* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D004852:Epoxy Compounds / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D010755:Organophosphates / Q000494:pharmacology* / Q000627:therapeutic use; D009944:Organoplatinum Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010616:Phenanthrenes / Q000494:pharmacology* / Q000627:therapeutic use; D011897:Random Allocation
D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; D010755:Organophosphates; D009944:Organoplatinum Compounds; D010616:Phenanthrenes; D000077150:Oxaliplatin; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt
DNA damage pancreatic cancer; Minnelide; NER; Oxaliplatin; Triptolide