Summary
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.
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Acknowledgements
We thank Drs. T. Abe and K. Miyanishi (department of medical oncology, Sapporo medical university school of medicine) for various valuable suggestions for experimental details and technical advice for GSTP1 staining, respectively.
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Data curation: KT, YS, RS, WK, and YT, Formal analysis: KT, Supervision: YN, and YS, Investigation: KT, Writing-original draft: YN, and YS, Writing-review and editing: YN, and YS.
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All experiments were undertaken in accordance with criteria outlined in a license granted under the Animals (Scientific Procedures) Act 1986 and approved by the Animal Ethics Committees of the Sapporo Medical University.
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YT is an employee of GlaxoSmithKline K.K. This work was conducted independently of, and was not funded by GlaxoSmithKline K.K.
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Kogawa, T., Sato, Y., Shimoyama, R. et al. Chemoprevention of pancreatic cancer by inhibition of glutathione-S transferase P1. Invest New Drugs 39, 1484–1492 (2021). https://doi.org/10.1007/s10637-021-01129-y
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DOI: https://doi.org/10.1007/s10637-021-01129-y