ex-527 and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

The effectiveness of Hsp90 inhibitors as anticancer agents was limited in multidrug-resistant (MDR) human cancer cells due to induction of heat shock proteins (Hsps) such as Hsp70/Hsp27 and P-glycoprotein (P-gp)-mediated efflux. In the present study, we showed that resistance to Hsp90 inhibitors of MDR human cancer cells could be overcome with SIRT1 inhibition. SIRT1 knock-down or SIRT1 inhibitors (amurensin G and EX527) effectively suppressed the resistance to Hsp90 inhibitors (17-AAG and AUY922) in several MDR variants of human lymphoblastic leukemia and human breast cancer cell lines. SIRT1 inhibition down-regulated the expression of heat shock factor 1 (HSF1) and subsequently Hsps and facilitated Hsp90 multichaperone complex disruption via hyperacetylation of Hsp90/Hsp70. These findings were followed by acceleration of ubiquitin ligase CHIP-mediated mutant p53 (mut p53) degradation and subsequent down-regulation of P-gp in 17-AAG-treated MDR cancer cells expressing P-gp and mut p53 after inhibition of SIRT1. Therefore, combined treatment with Hsp90 inhibitor and SIRT1 inhibitor could be a more effective therapeutic approach for Hsp90 inhibitor-resistant MDR cells via down-regulation of HSF1/Hsps, mut p53 and P-gp.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzoquinones; Breast Neoplasms; Carbazoles; Cell Line, Tumor; Dibenzocycloheptenes; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Gene Knockdown Techniques; HSP70 Heat-Shock Proteins; HSP90 Heat-Shock Proteins; Humans; Isoxazoles; Lactams, Macrocyclic; MCF-7 Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Resorcinols; Sirtuin 1