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News, Calendars, and Events » Calendars » Master Calendar » Biochemistry and Molecular & Cellular Biology, Department of
Seminar Series: Dr. David Boothman
Schedule information
Event Seminar Series: Dr. David Boothman
When Tuesday, December 3, 2013 from 12:00pm to 1:00pm
Where Basic Science Building 341 (Library)
Event details
Details 'Exploiting a tumor-selective 'kiss of death' therapy for NQO1+ solid cancers'

David A. Boothman, Ph.D.
Robert B. and Virginia Payne Endowed Scholar in Oncology
Associate Director for Translational Research
Professor of Pharmacology and Radiation Oncology
University of Texas Southwestern Medical Center at Dallas

Abstract: A neglected strategy for the treatment of cancer is to exploit an enzyme over-expressed in cancer vs normal tissue, whereby the administered drug is ‘bioactivated’ and kills in a manner dependent on expression of this target enzyme. Our lab has developed a unique class of NQO1 ‘bioactivatable drugs’ (i.e., ß-lapachone, deoxynyboquinone and their derivatives) that exploit the two-electron Phase II detoxifying enzyme, NAD(P)H:Quinone oxidoreductase 1 (NQO1). We discovered that NQO1 is over-expressed in most solid cancers, while Catalase expression is low compared to normal tissue. As a result, the NQO1/Catalase ratios in tumor vs normal tissue create a very favorable therapeutic window for the treatment of solid cancers, such as recalcitrant nonsmall cell lung and pancreatic cancers. Out of thousands of quinones, this unique class of drugs are unique in that they undergo an NQO1-dependent futile redox cycle in which massive levels of superoxide and hydrogen peroxide (H2O2) are created, stored endoplasmic reticulum Ca+2 is released and there is a dramatic loss of NAD(P)H energy equivalence with concomitant build-up of NAD(P)+. Accumulation of long-lived H2O2 ultimately leads to DNA base and single strand breaks and the hyperactivation of poly(ADP-ribose) polymerase I (PARP1), which leads to dramatic loss of NAD+ and ATP. Recently, we discovered that there were major and specific inhibitory effects on glycolytic and KREBs cycles. Metabolomic studies are needed. Knowledge of the mechanism of action of these compounds have lead to strategies to (a) radiosensitize human NQO1+ cancers; (b) inhibit DNA base and single strand break repair; (c) prevent cell recovery processes by inhibiting NAD+ synthesis and glycolytic as well as KREBs cycle pathways. Strategies for increased efficacy of these compounds will be discussed as an initial first-in-man clinical trial is currently underway at UT Southwestern.
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Contact Juanita Chipani Biochemistry and Molecular & Cellular Biology office, x71512
Sponsors Department of Biochemistry and Molecular & Cellular Biology
Calendar Biochemistry and Molecular & Cellular Biology, Department of
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