Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group

Bedikian, Agop Y.; Millward, Michael; Pehamberger, Hubert; Conry, Robert M.; Gore, Martin; Trefzer, Uwe; Pavlick, Anna C.; DeConti, Ronald C.; Hersh, Evan M.; Hersey, Peter; Kirkwood, John M.; Haluska, Frank G.

doi:10.1200/jco.2006.06.0483

Cited by 552 publications

(353 citation statements)

References 18 publications

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“…Although no difference in treatment-related mortality was observed between patients receiving dacarbazine alone or in combination with oblimersen, patients undergoing combination therapy reported a higher incidence of adverse events, including neutropenia, thrombocytopenia, and nausea (39). We have shown that mebendazole, like oblimersen, also acts through Bcl-2 to induce apoptosis in melanoma cells.…”

Section: Discussionmentioning

confidence: 78%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

126

114

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Most metastatic melanoma patients fail to respond to available therapy, underscoring the need for novel approaches to identify new effective treatments. In this study, we screened 2,000 compounds from the Spectrum Library at a concentration of 1 Mmol/L using two chemoresistant melanoma cell lines ) and a spontaneously immortalized, nontumorigenic melanocyte cell line (melan-a). We identified 10 compounds that inhibited the growth of the melanoma cells yet were largely nontoxic to melanocytes. Strikingly, 4 of the 10 compounds (mebendazole, albendazole, fenbendazole, and oxybendazole) are benzimidazoles, a class of structurally related, tubulin-disrupting drugs. Mebendazole was prioritized to further characterize its mechanism of melanoma growth inhibition based on its favorable pharmacokinetic profile. Our data reveal that mebendazole inhibits melanoma growth with an average IC 50 of 0.32 Mmol/L and preferentially induces apoptosis in melanoma cells compared with melanocytes. The intrinsic apoptotic response is mediated through phosphorylation of Bcl-2, which occurs rapidly after treatment with mebendazole in melanoma cells but not in melanocytes. Phosphorylation of Bcl-2 in melanoma cells prevents its interaction with proapoptotic Bax, thereby promoting apoptosis. We further show that mebendazole-resistant melanocytes can be sensitized through reduction of Bcl-2 protein levels, showing the essential role of Bcl-2 in the cellular response to mebendazole-mediated tubulin disruption. Our results suggest that this screening approach is useful for identifying agents that show promise in the treatment of even chemoresistant melanoma and identifies mebendazole as a potent, melanoma-specific cytotoxic agent. (Mol Cancer Res 2008;6(8):1308 -15)

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Section: Discussionmentioning

confidence: 78%

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Doudican¹,

Rodriguez²,

Osman

et al. 2008

Molecular Cancer Research

126

114

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“…BPTF mediated its proproliferative and pro-oncogenic effects by regulating the expression of prosurvival genes, such as BCL2, BCL-XL, and CCND2. The antiapoptotic BCL2 protein plays important roles in promoting melanocytic survival and as a potential therapeutic target (12,13). The BCL2 gene is a direct target of the MITF protein, because an E-box motif on the BCL2 promoter has been shown to be a principal mechanism by which MITF activates BCL2 (14).…”

Section: Discussionmentioning

confidence: 99%

BPTF transduces MITF-driven prosurvival signals in melanoma cells

Dar

Majid

Bezrookove

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Microphthalmia-associated transcription factor (MITF) plays a critical and complex role in melanocyte transformation. Although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are incompletely understood. Recent studies identified an oncogenic role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression, in part through activation of BCL2, a canonical target of MITF signaling. Analysis of the BPTF promoter identified a putative MITF-binding site, suggesting that MITF may regulate BPTF expression. Overexpression of MITF resulted in up-regulation of BPTF in a panel of melanoma and melanocyte cell lines. shRNA-mediated down-regulation of MITF in melanoma cells was accompanied by down-regulation of BPTF and BPTF-regulated genes (including BCL2) and resulted in reduced proliferative capacity of melanoma cells. The suppression of cell growth mediated by MITF silencing was rescued by overexpression of BPTF cDNA. Binding of MITF to the BPTF promoter was demonstrated using ChIP analysis. MITF overexpression resulted in direct transcriptional activation of BPTF, as evidenced by increased luciferase activity driven by the BPTF promoter. These results indicate that BPTF transduces key prosurvival signals driven by MITF, further supporting its important role in promoting melanoma cell survival and progression. melanoma | signaling cascade | oncogenes M icrophthalmia-associated transcription factor (MITF) is known to play a key role in melanocyte biology and progression. MITF performs these functions by activating transcription of many genes through interaction with the consensus DNA-binding sequence (CACGTG, termed E box) present on the promoters of target genes. MITF controls expression of several proteins required for melanin synthesis, including tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and dopachrome tautomerose (DCT) (1-3). In addition, MITF plays a critical role in melanocyte survival and serves as a lineagespecific oncogene in melanoma, as evidenced by its amplification in a subset of melanomas (4-6). MITF expression is regulated by several factors, including SOX-10, CREB, PAX3, LEF1, and ATF2 (7,8). MITF in turn regulates a plethora of genes, with its complex role in melanoma biology, as its overexpression has been shown to result in both proproliferative and antiproliferative stimuli (4, 5, 9, 10). Accordingly, verified targets of MITF include both genes that promote cell survival and block apoptosis, (e.g., CDK2, BCL2, DIAPH1, and TBX2), and genes that block cell cycle progression (e.g., CDKN2A and p21Cip1). Thus, although several downstream targets of MITF action have been identified, the precise mechanisms by which MITF promotes melanocytic tumor progression are still poorly understood.Recently, we identified a role for the bromodomain plant homeodomain finger transcription factor (BPTF) gene in melanoma progression (11). BPTF is the largest subunit of the nucleoso...

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“…The alkylating agent dacarbazine (DTIC-Dome, Bayer, West Haven, CT) has been approved by the Food and Drug Administration (FDA) in the 1970s and is considered to be the reference single agent for advanced disease. DTIC has been reported to induce objective clinical responses in about 15 to 20% of patients in older trials, but with response rates of below 10% in recent multicenter trials 16,17 . Although complete clinical responses have been reported, most responses are partial and last for around 5-7 months 16, 17 .…”

Section: Conventional Therapeuticsmentioning

confidence: 99%

Growth Factors and Oncogenes as Targets in Melanoma: Lost in Translation?

Kwong

Chin

Wagner³

2007

Advances in Dermatology

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If untreated at early stages, melanoma becomes a highly aggressive cancer with rapid metastasis to distant sites. Although cell biologic analyses have uncovered a multitude of signaling pathways involved in melanoma genesis and progression -including the MAPK, PI3K, and FAK pathwaysefficacious therapies that target these cellular components have remained elusive. Genome-wide technologies such as microarray chips and array comparative genomic hybridization have generated genetic information that can identify cellular mechanisms critical for the induction and maintainence of the malignant phenotype. Thus, such data can guide the choice of a biologically relevant drug. However, these techniques have also identified melanoma as a genetically and biologically highly heterogeneous disease that likely requires individually tailored therapies based on the patient¹s individual genetic and biologic alterations. In addition, these techniques have generated a large body of data on candidate melanoma genes that await extensive functional validation to separate so called "driver" from "passenger" events. In this review, we cover several advances in melanoma therapeutics and their current limitations as well as emerging genomic, proteomic, and epigenetic strategies for the identification of critical cellular dependencies that may be tractable to therapeutic targeting. Keywords melanoma; growth factors; oncogenes; therapy; melanoma genome THE DISEASEMelanoma arises from melanocytes, specialized pigmented cells that reside in the skin, at the choroidal layer of the eye, the gastrointestinal and genitourethral mucosal surfaces and the meninges. Melanocytes produce melanins, the pigments responsible for skin and hair color. InCorresponding author for proof and reprints: Stephan N. Wagner, MD, Division of Immunology, Allergy and Infectious Diseases, Department of Dermatology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, AUSTRIA, ++43-1-40400-7915, ++43-1-40400-7574 (fax), stephan.wagner@meduniwien.ac.at (e-mail). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptAdv Dermatol. Author manuscript; available in PMC 2008 December 17. Published in final edited form as:Adv Dermatol. 2007 ; 23: 99-129. doi:10.1016/j.yadr.2007.07.015. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript the skin, melanocytes reside between keratinocytes in the basal layer of the epidermis and in the hair follicles and produce melanin to a variety of direct and indirect stimuli such as ultraviolet (UV) radiation. Thereby, melanocytes...

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Bcl-2 Antisense (oblimersen sodium) Plus Dacarbazine in Patients With Advanced Melanoma: The Oblimersen Melanoma Study Group

Abstract: The addition of oblimersen to dacarbazine significantly improved multiple clinical outcomes in patients with advanced melanoma and increased overall survival in patients without an elevated baseline serum LDH.

Cited by 552 publications

References 18 publications

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

Mebendazole Induces Apoptosis via Bcl-2 Inactivation in Chemoresistant Melanoma Cells

BPTF transduces MITF-driven prosurvival signals in melanoma cells

Growth Factors and Oncogenes as Targets in Melanoma: Lost in Translation?

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