A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer.
Pancreatic cancer is one of the most lethal human malignancies with an all-stage 5-year survival frequency of <5%, which highlights the urgent need for more effective therapeutic strategies. We have previously shown that triptolide, a diterpenoid, is effective against pancreatic cancer cells in vitro as well as in vivo. However, triptolide is poorly soluble in water, limiting its clinical use. We therefore synthesized a water-soluble analog of triptolide, named Minnelide. The efficacy of Minnelide was tested both in vitro and in multiple independent yet complementary in vivo models of pancreatic cancer: an orthotopic model of pancreatic cancer using human pancreatic cancer cell lines in athymic nude mice, a xenograft model where human pancreatic tumors were transplanted into severe combined immunodeficient mice, and a spontaneous pancreatic cancer mouse model (KRas(G12D); Trp53(R172H); Pdx-1Cre). In these multiple complementary models of pancreatic cancer, Minnelide was highly effective in reducing pancreatic tumor growth and spread, and improving survival. Together, our results suggest that Minnelide shows promise as a potent chemotherapeutic agent against pancreatic cancer, and support the evaluation of Minnelide in clinical trials against this deadly disease.
Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
Rohit
R
Chugh
Veena
V
Sangwan
Satish P
SP
Patil
Vikas
V
Dudeja
Rajinder K
RK
Dawra
Sulagna
S
Banerjee
Robert J
RJ
Schumacher
Bruce R
BR
Blazar
Gunda I
GI
Georg
Selwyn M
SM
Vickers
Ashok K
AK
Saluja
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival; D004224:Diterpenes / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D004852:Epoxy Compounds / Q000494:pharmacology; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D010755:Organophosphates / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010616:Phenanthrenes / Q000494:pharmacology*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism
D018906:Antineoplastic Agents, Alkylating; D004224:Diterpenes; D004852:Epoxy Compounds; D010755:Organophosphates; D010616:Phenanthrenes; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt; D010744:Phosphoric Monoester Hydrolases