Study on the mechanism of the new anti-glioma chemotherapy drug ACT001

Platinum drugs such as cisplatin are chemotherapy drugs for glioblastoma (GBM), often used in combination with tamoxamine, carmostine, etc., but their resistance and side effects limit clinical applicationAccendatech Co., Ltddeveloped by Ltdthe glycerides and semi-terpene (ACT001), a micheliolide derivative targeted at STAT3 and NF-BThe FDA has approved GBM treatment as an "undeveloped synthetic drug"ACT001 has shown good efficacy in clinical Phase I trials, and is currently in the United States and the European Union in phase II anti-tumor clinical trialsHowever, the anti-tumor mechanism of ACT001 is not clearPrevious studies have found that ACT001 inhibits tumor metabolism by selectively combining PKM2 at cysteine residue 424Xiaonan Xi of Nankai University School of Pharmacy in Tianjin, China, and other research on the effect of ACT001 on glioma proliferation and its mechanism, found that filisolyse progenitor inhibitor-1 (PAI-1) is the direct target of ACT0001The findings were published online October 2019 in Cell Death Disresearch methods
PAI-1 is a protease inhibitor that regulates angiogenesis, affects tumor growth, and involves tumor cell migration, invasion and adhesion, which is closely related to poor clinical prognosis in tumor patients; Studies have confirmed that GBM high expression PAI-1ACT001 is a compound in the form of uxineste-rich marite, which can be converted to utigraterine in physiological conditionsThe researchers verified the interaction between ACT001 and PAI-1 using cell thermal displacement determination, Biacore analysis, thermal stability analysis, and ACT001 probe analysisThrough proteomic analysis, it is found that ACT0001 can inhibit the PI3K/AKT pathway by directly binding to PAI-1, affecting the proliferation, invasion and migration of glioma cellsIn vitro cell experiments and in vivo experiments with U118 mouse subcutaneous tumor models have confirmed that ACT001 and cisplatin are co-effects of inhibitive gliomaconclusions the study clarifies the mechanism of ACT001 anti-glioma, PAI-1 is the target of ACT001, and ACT001 and PAI-1 combine to inhibit the PI3K/AKT pathway ACT001 and cisplatin work together to combat glioma, providing new ideas for clinical GBM chemotherapy.