Abstract
Abstract Multidrug resistance (MDR) is a major hurdle in the treatment of cancer and there is a pressing need for new therapies. We have recently developed a small molecule, CXL017, with selective cytotoxicity towards MDR cancer cells. In this study, we offer new mechanistic insights about multidrug resistance in acute myeloid leukemias and present evidence for the selective therapeutic potential of CXL017 in the treatment of MDR AMLs. CXL017 significantly and selectively suppresses the growth of tumors derived from the MDR AML cells. In addition, drug resistant AML cells failed to develop stable resistance to CXL017 upon prolonged exposure. Remarkably, instead of acquiring cross-resistance, drug resistant AML cells exposed to CXL017 were re-sensitized to standard therapies (10 to 100-fold). Through gene profiling, protein characterization, and genetic up/down-regulation, we have identified several key signaling processes both at the transcription, such as Topo IIβ, and post-transcription levels, such as Mcl-1, that contribute to the multidrug resistance. Some of these changes also contribute to the selective sensitivity of multidrug resistant AMLs to CXL017. These results overall demonstrate the possibility of developing small-molecule therapies selective against multidrug resistance in cancer therapy upon gaining the mechanistic insights of drug resistance.
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