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

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 speci c 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 ve cohorts. In the treated group I, which was treated neither with HGBPE nor vehicle, sequential appearance of precancerous lesions, ductal complexes, and adenocarcinoma was con rmed as previously reported. We also con rmed 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 signi cantly lower than those in groups III and V. These data clearly suggest the e cacy of HGBP as a potential chemopreventive agent for pancreatic cancer.

Implications of glutathione-S transferase P1 in MAPK signaling as a CRAF chaperone: In memory of Dr. Irving Listowsky

“…5 ), 9 ) indicating that without GSTP1 expression, mKRAS-dependent colon carcinogenesis may be significantly impaired and, therefore, chemoprevention approaches using anti-GSTP1 agents should be highly efficacious for mKRAS colon cancer. Taking this into account, we examined the effect of a GSTP1 inhibitor, which we synthesized, HGBPE, on carcinogenesis in the pancreas in a murine model induced by 7,12-dimethyl-benzanthracene (DMBA) and confirmed significant suppression of both precancerous lesions, ductal complexes, and adenocarcinoma, 57 ) proving a concept of chemoprevention of mKRAS cancer by inhibitor of GSTP1.…”

Rutin Inhibits Hepatic and Pancreatic Cancer Cell Proliferation by Inhibiting CYP3A4 and GST

“…[44][45][46][47] Overexpression of GST (glutathione S-transferases) and efflux pumps in tumor cells may impair chemotherapy drugs' anticancer efficacy. [48][49][50] Recently, it has become evident that glutathione-Stransferases are also involved in the control of apoptosis through involvement of the JNK signaling pathway. 51 Here, we reported that rutin was able to inhibit GST in a dose-dependent manner indicating a rational for its combination-based therapies and that rutin could prevent resistance to chemotherapy in combination therapies.…”

“…Rutin inhibited growth of cell lines in a concentration dependent manner (Table 1). The most affected cell line was the human liver cancer cells (HepG-2) (IC 50 13.95±1.41) while the least affected cancer cell line was the pancreatic suit-2 cells (30.50 ± 4.63). Cellular sensitivity to rutin were in the following descending order: HepG-2 > Huh-7 > MiaPaca-2 > BxPc-3 > Suit-2.…”

Targeting GSTP1-dependent ferroptosis in lung cancer radiotherapy: Existing evidence and future directions

“…GSTs are found in cells mainly in the cytoplasm, mitochondria and microsomes, mainly divide into α (GSTA), π (GSTP), μ (GSTM), σ (GSTS), θ (GSTT), ζ (GSTZ), and ω (GSTO) seven isoforms. Among them, GSTP1 is the most widely studied member of the GST family (Chatterjee and Gupta, 2018;Kogawa et al, 2021). The gene encoding GSTP1 is localized on chromosome 11q13 and is approximately 3.2 kb long, which contains 9 exons and 6 introns.…”