A Preclinical Evaluation of Minnelide as a Therapeutic Agent Against Pancreatic Cancer

Abstract

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 (KRasG12D; Trp53R172H; 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.

Triptolide-induced Cell Death in Pancreatic Cancer Is Mediated by O-GlcNAc Modification of Transcription Factor Sp1

“…However, for most cancer cells, the LD 50 for triptolide has been found to be 100 nmol/liter (37), at which XPB remains unaffected. The use of a water-soluble derivative of triptolide (Minnelide) in an animal model for over 300 days without any adverse effect on the normal physiology of the animals further indicates that this compound does not result in a global transcriptional shutdown and that an alternative mechanism of action exists for this compound at physiological doses (28). Triptolide is known to affect a number of prosurvival pathways in a cancer cell.…”

“…Our laboratory has previously shown that triptolide induces tumor cell death by down-regulating HSPs (22,28,32). This down-regulation of HSP70 is mediated at the transcriptional level, and expression at both the mRNA and protein levels is reduced upon treatment with this compound.…”

“…Although triptolide is an effective anticancer compound in vitro, its use in animals has been restricted because of its limited solubility in water. Recently, a water-soluble prodrug of triptolide (Minnelide), synthesized by the University of Minnesota, has overcome this concern and shown considerable promise in preclinical studies (25,28). Despite considerable research on triptolide, its exact mechanism of action has not been defined thus far.…”

Activator protein 1 promotes gemcitabine-induced apoptosis in pancreatic cancer by upregulating its downstream target Bim

“…At present, ~40% of patients have metastatic disease, and these patients are primarily treated with palliative therapy (26). The current chemotherapeutic agent of choice for pancreatic cancer is gemcitabine, which was approved by the FDA in 1996.…”

Pharmacokinetics and tissue distribution study in mice of triptolide-loaded lipid emulsion and accumulation effect on pancreas

“…Some reports indicated that TP can not only inhibit the proliferation of many different types of cancer cells in vitro, but also inhibit the growth and metastasis of solid tumors in vivo, including prostatic cancer, lung cancer, breast cancer, colon cancer and pancreatic cancer. Moreover, it can enhance the anti-tumor effects of cytotoxic agents and chemotherapeutic agents (Lee et al, 1999;Chang et al, 2000;Chan et al, 2001;Yang et al, 2003;Wang et al, 2009;Liu, 2011;Chugh et al, 2012).…”