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

R. A. Anvekar, J. J. Asciolla, E. Lopez-Rivera, K. V. Floros, S. Izadmehr, R. Elkholi, G. Belbin, A. G. Sikora, J. E. Chipuk

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Metastatic malignant melanoma is highly resistant to chemotherapy, and the average survival rate is under 1 year. The only FDAapproved 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.

Original languageEnglish
Article numbere420
JournalCell Death and Disease
Volume3
Issue number11
DOIs
StatePublished - Nov 2012

Keywords

  • ABT-737
  • Apoptosis
  • BCL-2 family
  • Chemotherapy
  • Melanoma

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