Apoptosis sensitizers enhance cytotoxicity in hepatoblastoma cells

Lieber, Justus; Ellerkamp, Verena; Wenz, Julia; Kirchner, Bettina; Warmann, Steven W.; Fuchs, Joerg; Armeanu–Ebinger, Sorin

doi:10.1007/s00383-011-2988-z

Cited by 14 publications

(15 citation statements)

References 41 publications

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“…Western blot analysis was performed as previously described [24]. For detection of histone H3 phosphorylation rabbit anti-phospho-Histone H3 (Ser 10) antibody was used.…”

Section: Western Blot Analysismentioning

confidence: 99%

In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma

et al. 2012

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“…Western blot analysis was performed as previously described [24]. For detection of histone H3 phosphorylation rabbit anti-phospho-Histone H3 (Ser 10) antibody was used.…”

Section: Western Blot Analysismentioning

confidence: 99%

In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma

et al. 2012

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“…All three Bcl-2 SMIs currently in clinical trials have shown to potentiate and synergize with chemotherapy and radiation in vitro 22 , 64 - 72 . Interestingly, mitogen-activated protein kinase (MAPK) pathway inhibitors, such as the epidermal growth factor receptor (EGFR) inhibitor gefitinib and erlotinib or the MEK inhibitor UO126 synergize with Bcl-2 SMIs 73 - 76 .…”

Section: Clinical Relevance Of Bcl-2 Inhibitorsmentioning

confidence: 99%

Anti-cancer drug discovery and development

Liu

Wang

2012

Communicative & Integrative Biology

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Deregulated apoptosis is a hallmark of cancer, and the B-cell lymphoma-2 (Bcl-2) family of proteins is pivotal to mediating the intrinsic pathway of this process. Recent advances have yielded both pan-Bcl-2 small molecule inhibitors (SMIs) that inhibit both the Bcl-2 and the Mcl-1 arm of the Bcl-2 family anti-apoptotic proteins, as well as selective SMIs to differentially target the two arms. Of these SMIs, ABT-263 (navitoclax), AT-101 [(-)-gossypol], and obatoclax (GX15-070) are currently in clinical trials for multiple cancers. While pan-Bcl-2 inhibitors such as AT-101 and obatoclax can be more toxic for inhibiting all members of the anti-apoptotic Bcl-2 family of proteins, resistance can quickly develop for ABT-263, a selective Bcl-2 inhibitor. In this article, we discuss the current status of Bcl-2 family SMIs in preclinical and clinical development. As Mcl-1 upregulation is a major mechanism of ABT-263 resistance, Mcl-1-specific inhibitors are expected to be efficacious both in combination/sequential treatments and as a single agent against cancers resistant to ABT-263.

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“…The repertoire of BCL-2 family proteins appears to change in cells grown as spheroids, compared to the same cell line grown as a monolayer. Increases in the expression of BCL-2 and BCL-X L have been observed in spheroids [108-111], and decreases in the expression of MCL-1 has also been reported [108,109]. This implies a switch towards an ABT-737-sensitive phenotype in cells grown as spheroids.…”

Section: Factors That Complicate Measurement Of Sensitivity To Bh3 MImentioning

confidence: 99%

“…This implies a switch towards an ABT-737-sensitive phenotype in cells grown as spheroids. Thus, even though increased resistance to either cisplatin or the combination of bortezomib and TRAIL was observed when cells were grown as spheroids, this could be overcome by exposure to ABT-737 [108,109]. The expression of pro-apoptotic family members may also be changed, and the growth of melanoma cells in spheroids leads to reduced expression of NOXA [26] but increased expression of BIM confers sensitivity to ABT-737 [112].…”

Section: Factors That Complicate Measurement Of Sensitivity To Bh3 MImentioning

confidence: 99%

Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine

Stamelos¹,

Redman

Richardson

2012

JMS

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BH3 mimetics such as ABT-737 and navitoclax bind to the BCL-2 family of proteins and induce apoptosis through the intrinsic apoptosis pathway. There is considerable variability in the sensitivity of different cells to these drugs. Understanding the molecular basis of this variability will help to determine which patients will benefit from these drugs. Furthermore, this understanding aids in the design of rational strategies to increase the sensitivity of cells which are otherwise resistant to BH3 mimetics. We discuss how the expression of BCL-2 family proteins regulates the sensitivity to ABT-737. One of these, MCL-1, has been widely described as contributing to resistance to ABT-737 which might suggest a poor response in patients with cancers that express levels of MCL-1. In some cases, resistance to ABT-737 conferred by MCL-1 is overcome by the expression of pro-apoptotic proteins that bind to apoptosis inhibitors such as MCL-1. However, the distribution of the pro-apoptotic proteins amongst the various apoptosis inhibitors also influences sensitivity to ABT-737. Furthermore, the expression of both pro- and anti-apoptotic proteins can change dynamically in response to exposure to ABT-737. Thus, there is significant complexity associated with predicting response to ABT-737. This provides a paradigm for the multiplicity of intricate factors that determine drug sensitivity which must be considered for the full implementation of personalized medicine.

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Apoptosis sensitizers enhance cytotoxicity in hepatoblastoma cells

Abstract: The data provide evidence that ABT-737 and obatoclax might improve treatment results in children with HB.

Cited by 14 publications

References 41 publications

In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma

In vitro evaluation of the Aurora kinase inhibitor VX-680 for Hepatoblastoma

Anti-cancer drug discovery and development

Understanding sensitivity to BH3 mimetics: ABT-737 as a case study to foresee the complexities of personalized medicine

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