The efficacy of novel small molecule inhibitors of GSTP1 in pancreatic cancer
Date
2023-11
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of 11% and a median survival of only months. PDAC currently ranks as the fourth leading cause of cancer death in the US and is anticipated to ascend to the second position by 2030. The disease is predominantly propelled by oncogenic KRAS mutations. Strategies for targeting KRAS directly have not worked; therefore, the focus is on targeting the downstream effector proteins, such as Glutathione S-Transferase Pi 1 (GSTP1), which is an enzyme crucial for chemotherapy resistance and cell signaling. A collaborator synthesized the 15 innovative GSTP1 inhibitors. We assessed all 15 and selected the three that exhibited substantial efficacy, showing potent IC50 values in the sub-micromolar range, as corroborated by the WST-1 assay. Additionally, they were observed to induce apoptosis, as indicated by the Cleaved PARP western blots. Furthermore, our studies spotlighted that GSTP1 inhibition profoundly affects the ERK and JNK signaling pathways. As preparations are ongoing for the siRNA-mediated knockdown of GSTP1, in vivo studies are also on the horizon. Five million PDAC cells will be subcutaneously implanted in 6–8-week-old immune-compromised female mice, which will subsequently be treated with either the primary GSTP1 inhibitor or a vehicle control. Tumor progression will be consistently measured, and upon study conclusion, tumors will be extracted for comprehensive analysis. This research may pave the way in new treatment in PDAC treatment methodologies.
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Keywords
Pancreatic Cancer, GSTP1