RT Journal Article
SR Electronic
T1 Over-Expression of Mcl-1 Confers Multi-Drug Resistance While Topo IIβ Down-Regulation Introduces Mitoxantrone-Specific Drug Resistance in Acute Myeloid Leukemia
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.113.086140
DO 10.1124/mol.113.086140
A1 David Hermanson
A1 Sonia Das
A1 Yunfang Li
A1 Chengguo Xing
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/05/21/mol.113.086140.abstract
AB Drug resistance is a serious challenge in cancer treatment and can be acquired through multiple mechanisms. These molecular changes may introduce varied extents of resistance to different therapies and need to be characterized for optimal therapy choice. A recently discovered small molecule, CXL017, reveals selective cytotoxicity towards drug resistant leukemia. A drug resistant AML cell line, HL60/MX2, also failed to acquire resistance to CXL017 upon chronic exposure and regained sensitivity towards standard therapies. In this study, we investigated the mechanisms responsible for HL60/MX2 cells' drug resistance and the molecular basis for its re-sensitization. Results show that the HL60/MX2 cell line has an elevated level of Mcl-1 protein relative to the parental cell line, HL60, and its re-sensitized cell line, HL60/MX2/CXL017, while it has a reduced level of topoisomerase IIβ. Mcl-1 over-expression in HL60/MX2 cells is mainly regulated through phospho-ERK1/2 mediated Mcl-1 stabilization while the reduction of topoisomerase IIβ in HL60/MX2 cells is controlled through genetic down-regulation. Up-regulating Mcl-1 introduces multi-drug resistance to standard therapies while its down-regulation results in significant cell death. Down-regulating topoisomerase IIβ confers resistance specifically to mitoxantrone, not to other topoisomerase II inhibitors. Overall, these data suggest that Mcl-1 over-expression is a critical determinant for cross-resistance to standard therapies while topoisomerase IIβ down-regulation is specific to mitoxantrone resistance.