Research Abstracts Online
January 2010 - March 2011
University of Minnesota Twin Cities
College of Pharmacy
of Medicinal Chemistry
PI: Changguo Xing
Drug Resistance in Acute Myeloid Leukemia
Development of drug resistance is one major barrier to the success of cancer therapy and there is an urgent need for new therapies to treat drug-resistant malignancies. Cancer cells can acquire drug resistance through multiple mechanisms, including over-expression of anti-apoptotic Bcl-2 protein family proteins, elevation of efflux proteins, and control of intracellular calcium homeostasis, some of which may regulate each other. The contributions of each process individually and their combinations to drug resistance are not well understood, slowing the development of effective therapies. The long-term goal of this research is to understand molecular mechanisms about how cancer cells acquire drug resistance and to rationally develop anticancer agent(s) that will effectively treat drug-resistant malignancies, thereby improving the clinical outcome of cancer patients.
During preliminary studies, this researcher has developed two structurally similar compounds as chemical probes, one being a positive lead (CXL017) and one being a negative control (CXL020), and four AML cell lines (one parental HL-60 cell line and three drug-resistant cell lines: HL-60/MX, HL-60/MX/CXL017, and HL-60/MX/CXL017/NT) as the cancer models for mechanistic investigation. The specific objective of this project is to identify the protein target(s) for CXL compounds and to determine the molecular pathways modulated by CXL compounds that account for their selective anticancer activity toward drug-resistant leukemias.