The Combination of BH3-Mimetic ABT-737 with the Alkylating Agent Temozolomide Induces Strong Synergistic Killing of Melanoma Cells Independent of p53

Reuland, Steven N.; Goldstein, Nathaniel B.; Partyka, Katie; Cooper, David A.; Fujita, Mayumi; Norris, David A.; Shellman, Yiqun G.

doi:10.1371/journal.pone.0024294

Cited by 33 publications

(42 citation statements)

References 28 publications

(36 reference statements)

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“…Hence, our treatment combination significantly enhanced efficacy compared to treatment with either agent alone, confirming positive data reported with the BH3-mimetic ABT-737 and various chemotherapies such as fotemustine [31], temozolomide [31], [32], melphalan [33], cytosine arabinoside [34], gemcitabine [35], actinomycine D [36], carboplatin [37], and others, or with Bcl-2 antisense and cyclophosphamide [38] or chlorambucil [39]. In the MM66 xenograft, this observation could be explained by the fact that fotemustine highly increased Bcl-2 expression that could be therefore more efficiently inhibited.…”

Section: Discussionsupporting

confidence: 83%

Targeting Bcl-2/Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts

et al. 2014

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PurposeUveal melanoma (UM) is associated with a high risk of metastases and lack of efficient therapies. Reduced capacity for apoptosis induction by chemotherapies is one obstacle to efficient treatments. Human UM is characterized by high expression of the anti-apoptotic protein Bcl-2. Consequently, regulators of apoptosis such as Bcl-2 family inhibitors may constitute an attractive approach to UM therapeutics. In this aim, we have investigated the efficacy of the Bcl-2/Bcl-XL inhibitor S44563 on 4 UM Patient-Derived Xenografts (PDXs) and derived-cell lines.Experimental DesignFour well characterized UM PDXs were used for in vivo experiments. S44563 was administered alone or combined with fotemustine either concomitantly or after the alkylating agent. Bcl-2, Bcl-XL, and Mcl-1 expressions after S44563 administration were evaluated by immunohistochemistry (IHC).ResultsS44563 administered alone by at 50 and 100 mg/kg i.p. induced a significant tumour growth inhibition in only one xenograft model with a clear dose effect. However, when S44563 was concomitantly administered with fotemustine, we observed a synergistic activity in 3 out of the 4 tested models. In addition, S44563 administered after fotemustine induced a tumour growth delay in 2 out of 3 tested xenografts. Finally, IHC analyses showed that Bcl-2, Bcl-XL, and Mcl-1 expression were not modified after S44563 administration.ConclusionThe novel anti-apoptotic experimental compound S44563, despite a relative low efficacy when administered alone, increased the efficacy of fotemustine in either concomitant or sequential combinations or indeed subsequent to fotemustine. These data support further exploration of potential therapeutic effect of Bcl-2/Bcl-xl inhibition in human UM.

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Section: Discussionsupporting

confidence: 83%

Targeting Bcl-2/Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts

et al. 2014

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“…However, primary human SCLC xenografts were less responsive, as were other SCLC lines in vitro (16). Recent studies have reported synergy between ABT-737 or its relative ABT-263 and cytotoxic drugs in a variety of tumor xenograft models (47,(49)(50)(51), including melanomas (52,53). The IC 50 values we observed for ABT-737 on NOXAoverexpressing melanoma cells in flat culture were comparable with those reported for ABT-737-sensitive SCLC and lymphoid malignancies (13).…”

Section: Discussionsupporting

confidence: 82%

“…If so, it does not represent an obstacle in principle. The MM200 cells tested may not be representative melanoma xenografts, as suggested by the responsiveness of A375 xenografts to ABT-737 plus temozolomide (52). In any case, development of more diffusible BH3 mimetics (56), which have improved oral bioavailability, charge balance, and metabolism properties, will likely obviate such problems.…”

Section: Discussionmentioning

confidence: 99%

Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737

Lucas

Mohana-Kumaran

Lau

et al. 2012

Clinical Cancer Research

107

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Purpose: Drug resistance in melanoma is commonly attributed to ineffective apoptotic pathways. Inhibiting antiapoptotic BCL-2 and its relatives is an attractive strategy for sensitizing lymphoid malignancies to drugs but it has been largely unsuccessful for melanoma and other solid tumors. ABT-737, a smallmolecule BH3-mimetic, selectively inhibits BCL-2, BCL-XL, and BCL-w and shows promise for treating leukemia, lymphoma, and small-cell lung cancer. Melanoma cells are insensitive to ABT-737, but MCL-1 inhibition reportedly increases the sensitivity of other tumors to the compound.Experimental Design: The efficacy of MCL-1 and BFL-1 inhibition for sensitizing melanoma cells to ABT-737 was investigated by short hairpin RNA-mediated knockdown or overexpression of their antagonist NOXA in two-dimensional cell culture, a three-dimensional organotypic spheroid model, and an in vivo model.Results: MCL-1 downregulation or NOXA overexpression strongly sensitized melanoma cells to ABT-737 in vitro. NOXA-inducing cytotoxic drugs also strongly sensitized melanomas to ABT-737 but, surprisingly, not vice versa. The drugs most suitable are not necessarily those normally used to treat melanoma. Resistance to ABT-737 occurred quickly in three-dimensional melanoma spheroids through reduced NOXA expression, although experiments with both xenografts and three-dimensional spheroids suggest that penetration of ABT-737 into tumor masses may be the principal limitation, which may be obviated through use of more diffusible BH3-mimetics.Conclusion: Sensitization of tumors to BH3-mimetics by cytotoxic drugs that induce NOXA is a therapeutic strategy worth exploring for the treatment of melanoma and other solid cancers. Clin Cancer Res; 18(3); 783-95. Ó2011 AACR.

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“…42,43 Recent studies indicated that BH3-mimetics can be used to treat nonlymphoid cancers but mostly in combination with oestrogen antagonists, proteasome inhibitors, specific PI3K-mTOR inhibitors or chemotherapy. 24,[44][45][46][47][48][49] As previous findings from our laboratory demonstrated that E-cadherin-negative lobular breast cancer depends on p120-catenin-mediated activation of RhoA, Rock and subsequent actomyosin contraction, 26 we anticipate that dual inhibition of these pathways might be successful in E-cadherin-negative cancers that are not driven by oncogenic activation of GFR pathways. Although we do not yet know whether RhoA-Rock signals converge onto the GFR-AKT-FOXO axis in the regulation of anoikis resistance, the fact that FOXO expression had no effect on survival of B-RAF/KRAS-mutated MDA-MB-231 cells seems to be in line with this assumption.…”

Section: Discussionmentioning

confidence: 86%

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

et al. 2016

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Loss of cellular adhesion leads to the progression of breast cancer through acquisition of anchorage independence, also known as resistance to anoikis. Although inactivation of E-cadherin is essential for acquisition of anoikis resistance, it has remained unclear how metastatic breast cancer cells counterbalance the induction of apoptosis without E-cadherin-dependent cellular adhesion. We report here that E-cadherin inactivation in breast cancer cells induces PI3K/AKT-dependent FOXO3 inhibition and identify FOXO3 as a novel and direct transcriptional activator of the pro-apoptotic protein BMF. As a result, E-cadherin-negative breast fail to upregulate BMF upon transfer to anchorage independence, leading to anoikis resistance. Conversely, expression of BMF in E-cadherin-negative metastatic breast cancer cells is sufficient to inhibit tumour growth and dissemination in mice. In conclusion, we have identified repression of BMF as a major cue that underpins anoikis resistance and tumour dissemination in E-cadherin-deficient metastatic breast cancer.

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The Combination of BH3-Mimetic ABT-737 with the Alkylating Agent Temozolomide Induces Strong Synergistic Killing of Melanoma Cells Independent of p53

Cited by 33 publications

References 28 publications

Targeting Bcl-2/Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts

Targeting Bcl-2/Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts

Modulation of NOXA and MCL-1 as a Strategy for Sensitizing Melanoma Cells to the BH3-Mimetic ABT-737

Restraining FOXO3-dependent transcriptional BMF activation underpins tumour growth and metastasis of E-cadherin-negative breast cancer

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