title: Sensitization to the mitochondrial pathway of apoptosis augments melanoma tumor cell responses to conventional chemotherapeutic regimens.
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.
authors.affiliation: Mount Sinai School of Medicine, Department of Oncological Sciences, New York, NY 100129, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Anvekar
authors.forename: J J
authors.initials: JJ
authors.lastname: Asciolla
authors.forename: E
authors.initials: E
authors.lastname: Lopez-Rivera
authors.forename: K V
authors.initials: KV
authors.lastname: Floros
authors.forename: S
authors.initials: S
authors.lastname: Izadmehr
authors.forename: R
authors.initials: R
authors.lastname: Elkholi
authors.forename: G
authors.initials: G
authors.lastname: Belbin
authors.forename: A G
authors.initials: AG
authors.lastname: Sikora
authors.forename: J E
authors.initials: JE
authors.lastname: Chipuk
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D002945:Cisplatin