title: Combining a BCL2 inhibitor with the retinoid derivative fenretinide targets melanoma cells including melanoma initiating cells.
abstract: Investigations from multiple laboratories support the existence of melanoma initiating cells (MICs) that potentially contribute to melanoma's drug resistance. ABT-737, a small molecule BCL-2/BCL-XL/BCL-W inhibitor, is promising in cancer treatments, but not very effective against melanoma, with the antiapoptotic protein MCL-1 as the main contributor to resistance. The synthetic retinoid fenretinide N-(4-hydroxyphenyl)retinamide (4-HPR) has shown promise for treating breast cancers. Here, we tested whether the combination of ABT-737 with 4-HPR is effective in killing both the bulk of melanoma cells and MICs. The combination synergistically decreased cell viability and caused cell death in multiple melanoma cells lines (carrying either BRAF or NRAS mutations) but not in normal melanocytes. The combination increased the NOXA expression and caspase-dependent MCL-1 degradation. Knocking down NOXA protected cells from combination-induced apoptosis, implicating the role of NOXA in the drug synergy. The combination treatment also disrupted primary spheres (a functional assay for MICs) and decreased the percentage of aldehyde dehydrogenase (high) cells (a marker of MICs) in melanoma cell lines. Moreover, the combination inhibited the self-renewal capacity of MICs, measured by secondary sphere-forming assays. In vivo, the combination inhibited tumor growth. Thus, this combination is a promising treatment strategy for melanoma, regardless of mutation status of BRAF or NRAS.
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Mukherjee
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Reuland
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: Yuchun
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: Karoline
authors.initials: K
authors.lastname: Lambert
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Fujita
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Robinson
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Robinson
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA; Department of Veterans Affairs Medical Center, Dermatology Section, Denver, Colorado, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Norris
authors.affiliation: Department of Dermatology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, Colorado, USA. Electronic address: Yiqun.Shellman@ucdenver.edu.
authors.forename: Yiqun G
authors.initials: YG
authors.lastname: Shellman
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D017313:Fenretinide / Q000494:pharmacology*; D006801:Humans; D008545:Melanoma / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012176:Retinoids; D012878:Skin Neoplasms / Q000473:pathology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D012176:Retinoids; D013449:Sulfonamides; D017313:Fenretinide; D000444:Aldehyde Dehydrogenase