NDLI: Sensitization to the mitochondrial pathway of apoptosis augments melanoma tumor cell responses to conventional chemotherapeutic regimens.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Anvekar, R. A. Asciolla, J. J. Lopez-Rivera, E. Floros, K. V. Izadmehr, S. Elkholi, R. Belbin, G. Sikora, A. G. Chipuk, J. E.
Description	Country affiliation: United States Author Affiliation: Anvekar RA ( Mount Sinai School of Medicine, Department of Oncological Sciences, New York, NY 100129, USA.)
Abstract	Metastatic malignant melanoma is highly resistant to chemotherapy, and the average survival rate is under 1 year. The only FDA-approved conventional chemotherapy (i.e., dacarbazine) targets melanoma tumor cells by inducing a form of cell death referred to as apoptosis. However, dacarbazine exhibits a response rate of ~5%, and combination chemotherapies consisting of cisplatin, vinblastine, and dacarbazine often offer little clinical advantage over dacarbazine alone. Apoptosis is governed by the BCL-2 family of proteins, which is comprised of anti-apoptotic and pro-apoptotic members. To determine if the anti-apoptotic BCL-2 repertoire established the cell death threshold and chemoresistance in melanoma, a novel treatment strategy was designed to inhibit the anti-apoptotic BCL-2 members with ABT-737. Using various melanoma model systems, we determined the affects of ABT-737 on sensitivity to dacarbazine-based regimens. Strikingly, ABT-737 re-sensitized melanoma cell lines to common chemotherapeutics leading to marked BIM-mediated apoptosis. Cellular features of the ABT-737 combination treatments were loss of proliferation, mitochondrial fragmentation, nuclear condensation, phosphatidylserine exposure, and decreased clonogenic survival. We also observed significant anti-tumor activity in an in vivo melanoma model system. Our data indicate that ABT-737 may be a beneficial adjuvant therapy to improve melanoma response rates when conventional chemotherapy is the only option.
File Format	HTM / HTML
e-ISSN	20414889
DOI	10.1038/cddis.2012.161
Journal	Cell Death and Disease
Volume Number	3
Language	English
Publisher	Nature Publishing Group
Publisher Date	2012-11-15
Publisher Place	Great Britain (UK)
Access Restriction	Open
Subject Keyword	Research Support, N.i.h., Extramural Research Support, Non-u.s. Gov't Piperazines Cell Survival Melanoma Drug Therapy Antineoplastic Agents Pharmacology Biphenyl Compounds Metabolism Drug Effects Cisplatin Antagonists & Inhibitors Physiopathology Discipline Cell Biology Mitochondria Sulfonamides Cell Line, Tumor Genetics Nitrophenols Proto-oncogene Proteins C-bcl-2 Apoptosis
Content Type	Text
Resource Type	Article

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