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METHOD:PUBLISH
BEGIN:VEVENT
UID:http://sitemason.vanderbilt.edu/element/bzrandu/id/52211
SUMMARY:Chemistry Colloquium Series\, "Can we selectively target ER-specific Bcl-2 proteins?"
DESCRIPTION:Speaker\: Dr. Chengguo Xing\, Department of Medicinal Chemistry\, University  of Minnesota\nAbstract\:\n\n Drug resistance is a major challenge to the success of cancer chemotherapy. One mechanism by which tumor acquires resistance is through elevation of the level of anti-apoptotic Bcl-2 family proteins. Antagonizing these apoptotic inhibitory proteins is therefore a promising approach to overcoming drug resistance in cancer therapy. sHA 14-1 - a stable analog of HA 14-1 was recently synthesized in this laboratory as a putative antagonist against anti-apoptotic Bcl-2 family proteins\, which effectively induces apoptosis in tumor cells.\n\n In the current presentation\, we demonstrated that sHA 14-1 can selectively target various drug-resistant leukemia cells\, which have elevated levels of anti-apoptotic Bcl-2 proteins\, such as Bcl-2\, Bcl-XL\, and Mcl-1. As a putative Bcl-2 antagonist\, sHA 14-1 also synergized the activities of chemotherapeutic agents with distinct mechanisms of action. Moreover\, sHA 14-1 revealed selective toxicity against human leukemic cells while exhibiting minimal toxicity toward normal human lymphoial cells. Mechanistically\, sHA 14-1 induced endoplasmic reticulum (ER) calcium release in vitro within seconds upon treatment\, which was demonstrated to be critical for the cytoxicity of sHA 14-1. ER stress in vitro was detected within one hour after sHA 14-1 treatment while loss of mitochondrial membrane potential was not detected until 6 hours after sHA 14-1 treatment\, indicating that ER is the upper stream organelle compared to mitochondria for sHA 14-1 to induce cell death. We also demonstrated that sHA 14-1 induced ER calcium release through directly interacting with cellular targets on ER\, instead of indirect signal transduction.\n\n Furthermore\, the drug-resistant leukemic cells had elevated levels of ER calcium\, and sHA 14-1 treatment at the same concentrations resulted in more ER calcium release from drug-resistant cells than that from parent leukemic cells. The differential potency of sHA 14-1 to induce [Ca2+]ER release explained the selective toxicity of sHA 14-1 against drug resistant cancer.\n\n Given the fact that ER-localized anti-apoptotic Bcl-2 proteins induce drug resistance through regulating calcium homeostasis\, we propose that sHA 14-1 antagonizes ER-specific anti-apoptotic Bcl-2 proteins to induce [Ca2+]ER release\, which serves as the up-stream signals for its anticancer activity\, independent of mitochondrial apoptotic pathway.
URL;VALUE=URI:http://www.vanderbilt.edu/AnS/Chemistry/colloquia/index.php?ID=89
LOCATION:Stevenson Science Center\, Room 5211
CATEGORIES:academics,colloquiumslecturesmeetingssymposiums,myvu,as
CLASS:PUBLIC
SEQUENCE:1
DTSTAMP:20080820T033751
CREATED:20080312T101016
LAST-MODIFIED:20080312T102014
ORGANIZER;CN=Amy Allen:MAILTO:amy.l.allen@vanderbilt.edu
DTSTART:20080324T161500
DTEND:20080324T173000
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