Chemoprevention of pancreatic cancer by inhibition of glutathione-S transferase P1.

Takahiro Kogawa,Yasuyuki Tashiro,Wataru Kurata,Yasushi Sato,Yoshiro Niitsu,Rai Shimoyama

doi:10.1007/s10637-021-01129-y

Abstract

Pancreatic cancer is among the most refractory malignancies with poor prognosis. Thus, preventive approaches, in addition to the development of novel therapeutic strategies are essential for this type of cancer. KRAS mutations occur very early in the development of pancreatic cancers and could be targeted for its prevention, yet specific inhibitors for mutated KRAS are lacking. Accordingly, Glutathione-S Transferase p1 (GSTP1), which we recently found to be an autocrine stimulator of mutated KRAS signaling, is predicted to be an alternative target for chemoprevention of pancreatic cancer. In this study, chemopreventive effects of O-Hexadecyl-γ-glutamyl-S-benzyl-cysteinyl-D-phenyl glycine-Ethylester (HGBPE), which we previously synthesized to inhibit GSTP1 activity, was analyzed for its effect on the prevention of a rat pancreatic carcinogenesis model induced by 7,12-dimethyl-benzanthracene (DMBA). Rats administered with DMBA were grouped into five cohorts. In the treated group I, which was treated neither with HGBPE nor vehicle, sequential appearance of precancerous lesions, ductal complexes, and adenocarcinoma was confirmed as previously reported. We also confirmed in this group that mutations of KRAS and expression of GSTP1 simultaneously occurred in the ductal complex. To rats of groups II and IV, HGBPE was administered, and vehicle to those of group III and V. In groups of II and IV, the incidence of both ductal complex and adenocarcinoma were significantly lower than those in groups III and V. These data clearly suggest the efficacy of HGBP as a potential chemopreventive agent for pancreatic cancer.

Highlights

Pancreatic cancer is often asymptomatic and usually diagnosed at very advanced stages, engendering low survival rates [1]
Glutathione-S Transferase p1 (GSTP1), which we recently found to be an autocrine stimulator of mutated KRAS signaling, is predicted to be an alternative target for chemoprevention of pancreatic cancer
Chemopreventive effects of O-Hexadecyl-γ-glutamyl-S-benzyl-cysteinyl-D-phenyl glycine-Ethylester (HGBPE), which we previously synthesized to inhibit GSTP1 activity, was analyzed for its effect on the prevention of a rat pancreatic carcinogenesis model induced by 7,12-dimethyl-benzanthracene (DMBA)

Summary

Introduction

Pancreatic cancer is often asymptomatic and usually diagnosed at very advanced stages, engendering low survival rates [1]. Preventive measures for pancreatic cancer may include passive prophylaxis; avoidance of risk factors such as tobacco smoke, obesity, type II diabetes, chronic inflammation of the pancreas, high dietary intake of fried food and red meat [3] or active prophylaxis; surgical resection of precancerous legions, IPMN [4], proactive intake of foods containing chemopreventive compounds such as curcumin, vitamins such as vitamins D and E, capsaicin, genistein, isothiocyanates [3] and administration of synthetic chemopreventive agents such as NSAIDs, angiotensin-I-converting enzyme inhibitors, aspirin, Ibuprofen, Metformin, Statins, Farnesyl transferase inhibitors [3]. The use of chemopreventive agents is a most promising and preferable approach because of its noninvasive nature and availability of efficacy monitoring of cancer at early stages or precancerous lesions during the treatment period. The pathogenesis of pancreatic cancer at initial stages often primarily involves KRAS mutations [5] to which direct inhibitory agents are currently unavailable. In GSTp1 null mice, which exhibited no apparent physical abnormalities, mKRAS relevant colon carcinogenesis evoked by administering azoxymethane was significantly impaired [6], suggesting the potential efficacy of interfering with GSTP1 can be effective chemopreventive agents for mKRAS cancers

Methods

Results

Conclusion