A novel SERCA inhibitor demonstrates synergy with classic SERCA inhibitors and targets multidrug-resistant AML.

ABSTRACT: Drug resistance exists as a major obstacle in the treatment of cancer, and drug molecules that retain effectiveness against resistant cancers are a high clinical priority. Ethyl 2-amino-6-(3,5-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (CXL017) was recently identified as a promising lead for the treatment of multidrug-resistant leukemia, which elicits its cytotoxic effect, in part, through inhibition of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA). Herein initial experiments with SERCA1a and CXL017 demonstrated no significant effect on calcium affinity, competed with ATP, and induced a dose-dependent decrease in ATPase activity. Among all CXLs tested, (-)-CXL017 exhibited the greatest SERCA inhibition with an IC50 = 13.5 ± 0.5 μM. Inhibitor combination stud

SUBMITTER: Bleeker NP 

PROVIDER: S-EPMC3946399 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature