Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma

Trudel, Suzanne; Li, Zhi Hua; Rauw, Jennifer; Tiedemann, Rodger E.; Wen, Xiaoru; Stewart, A. Keith

doi:10.1182/blood-2006-10-047951

Cited by 202 publications

(191 citation statements)

References 37 publications

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“…14 In addition, it failed to exhibit efficacy in tumour xeno-transplant models in vivo. 15 To date, the most studied and promising synthetic small molecule BH3-mimetic is ABT-737. 16 It exhibits apoptotic efficacy against several cell tumor cell lines and ex-vivo tumor cells, [16][17][18] potentiates the activity of some commonly used therapeutic agents 19,20 and counteracts human tumor growth in mouse xenograft models.…”

Section: Introductionmentioning

confidence: 99%

A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

Ponassi

Biasotti²,

Tomati³

et al. 2008

Cell Cycle

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Section: Introductionmentioning

confidence: 99%

A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

Ponassi

Biasotti²,

Tomati³

et al. 2008

Cell Cycle

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“…Gossypol induces the generation of reactive oxygen species, which may be responsible for the induction of cell death. 44 In vivo gossypol is known to cause male infertility, whereas obatoclax had been reported to induce both neurological symptoms in early clinical trials of patients with CLL as well as neuronal toxicity in mice, 25,45 which might be because of targets outside the BCL2 family. In this regard a recent study showed that obatoclax exerted growth inhibitory effects at lower concentrations than induction of apoptosis and suggested that obatoclax targeted other proteins in addition to BCL2 family members.…”

Section: Discussionmentioning

confidence: 99%

Different forms of cell death induced by putative BCL2 inhibitors

et al. 2009

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Several inhibitors of BCL2 proteins have been identified that induce apoptosis in a variety of tumor cells, indicating their potential in cancer therapy. We investigated the specificity of six putative BCL2 inhibitors (obatoclax, gossypol, apogossypol, EM20-25, chelerythrine and ABT-737). Using cells deficient either for Bax/Bak or caspase-9, we found that only ABT-737 specifically targeted BCL2 proteins and induced apoptosis by activation of caspase-9, as only ABT-737 induced apoptosis was completely inhibited in cells deficient for Bax/Bak or caspase-9. Our data show that only ABT-737 is a specific BCL2 inhibitor and all other compounds investigated were not specific for BCL2 proteins. Furthermore, investigations of the effects of these compounds in primary chronic lymphocytic leukemic cells showed that all compounds induced certain biochemical hallmarks of apoptosis, such as release of cytochrome c and caspase cleavage. However, they all caused strikingly different ultrastructural changes. ABT-737 induced all the characteristic ultrastructural changes of apoptosis together with early rupture of the outer mitochondrial membrane, whereas obatoclax, chlelerythrine and gossypol induced pronounced mitochondrial swelling with formation of phospholipid inclusions. Therefore, we conclude that biochemical measurements used earlier to define apoptosis like mitochondrial release of cytochrome c and caspase cleavage, are insufficient to distinguish between classic apoptosis and other forms of cell death.

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“…These results show that GX15-070 can be used as a drug in treatment of AML. In addition, preclinical studies with GX15-070 on multiple myeloma cells show that GX15-070 is very effective in treatment of multiple myeloma (Trudel et al 2007). GX15-070 inhibited binding of Bak to Mcl-1, elevating the levels of Bim.…”

Section: Potentiation Of Apoptosis In Cancer Therapymentioning

confidence: 99%

“…GX15-070 inhibited binding of Bak to Mcl-1, elevating the levels of Bim. It also promoted the release of cytochrome c from mitochondria and activated caspase-3 in various human myeloma cells (Trudel et al 2007). In some of the cancer cells Mcl-I conferred resistance to apoptotic cell death induced by either ABT-737 (A small molecule that targets Bcl2) or bortezomib (Proteosome inhibitor).…”

Section: Potentiation Of Apoptosis In Cancer Therapymentioning

confidence: 99%

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

Chaabane

User

El-Gazzah

et al. 2012

Arch. Immunol. Ther. Exp.

252

149

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Preclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma

Cited by 202 publications

References 37 publications

A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

Different forms of cell death induced by putative BCL2 inhibitors

Autophagy, Apoptosis, Mitoptosis and Necrosis: Interdependence Between Those Pathways and Effects on Cancer

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