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XingC

Research Abstracts Online
January - December 2011

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University of Minnesota Twin Cities
College of Pharmacy
Department of Medicinal Chemistry

PI: Chengguo Xing

Mechanisms of Anticancer Agents Against Drug-Resistant Leukemia

Drug resistance is a significant problem in cancer therapy, because it is a general phenomenon among all malignancies and there is no effective solution. Therefore there is an unmet clinical need for new therapies to be developed targeting drug-resistant malignancies, which is challenging, due to the limited knowledge about drug resistance mechanisms and the lack of appropriate cancer models and research tools. The long-term goal of this group is to elucidate the mechanisms whereby cancer cells acquire resistance to treatment, and to rationally develop antitumor agents that will effectively treat drug-resistant malignancies. Drug-resistant leukemias over-express anti-apoptotic Bcl-2 family proteins and/or p-glycoprotein. Some also have elevated levels of Sarco/- Endoplasmic Reticulum Ca2+-ATPase (SERCA), which has been reported to interact with the Bcl-2 protein. CXLs induce ER Ca2+ release and ER stress, inhibit SERCA and p-glycoprotein. These researchers have recently identified a set of small molecules, termed CXLs and derived from HA 14-1 (a putative Bcl-2 inhibitor), that demonstrate preferential anticancer activity toward drug-resistant leukemias, despite the fact that such cancers reveal cross resistance to standard therapies. Leukemia cells also fail to develop resistance to CXLs. In fact, CXLs greatly re-sensitize drug-resistant leukemias to standard therapies (30-400 fold). The objective of this project is to identify the protein target(s) for CXL positive lead and to determine the molecular pathways modulated by CXLs, which account for CXL's selective anticancer activity towards drug-resistant leukemias. MSI resources will be used to help data analysis and molecular modeling.

Group Members

Flora Danhua Fan, Research Associate
David Hermanson, Graduate Student
Tae Hyun Hwang, Graduate Student
Kevin A.T. Silverstein, Faculty Collaborator