Oxidative cytotoxic agent withaferin A resensitizes temozolomide-resistant glioblastomas via MGMT depletion and induces apoptosis through Akt/mTOR pathway inhibitory modulation

摘要: Temozolomide (TMZ) has remained the chemotherapy of choice in patients with glioblastoma multiforme (GBM) primarily due to lack more effective drugs. Tumors, however, quickly develop resistance this line treatment creating a critical need for alternative approaches and strategies resensitize cells. Withaferin A (WA), steroidal lactone derived from several genera Solanaceae plant family previously demonstrated potent anti-cancer activity multiple tumor models. Here, we examine effects WA against TMZ-resistant GBM cells as monotherapy combination TMZ. prevented cell proliferation by dose-dependent G2/M cycle arrest death through both intrinsic extrinsic apoptotic pathways. This effect correlated depletion principle proteins Akt/mTOR MAPK survival pathways diminished phosphorylation Akt, mTOR, p70 S6K but compensatory activation ERK1/2. Depletion tyrosine kinase surface receptors c-Met, EGFR, Her2 was also observed. induction N-acetyl-L-cysteine-repressible oxidative stress measured directly subsequent heat shock response HSP32 HSP70 upregulation decreased HSF1. Finally, pretreatment associated O6-methylguanine-DNA methyltransferase (MGMT) which potentiated TMZ-mediated MGMT degradation. Combination TMZ resulted resensitization MGMT-mediated TMZ-resistance not mismatch repair mutations. These studies suggest great clinical potential utilization resensitizer standard chemotherapeutic agent