Bcl-2 Family Proteins as Therapeutic Targets

The Walter and Eliza Hall Institute for Medical Research, 1G Royal Parade, Parkville, Victoria, Australia.
Current pharmaceutical design (Impact Factor: 3.45). 09/2010; 16(28):3132-48. DOI: 10.2174/138161210793292429
Source: PubMed


The mitochondrion provides the stage for the interplay of molecular interactions that regulate apoptosis via the intrinsic pathway. The release of apoptogenic factors from this compartment constitutes a critical juncture in this apoptotic pathway. Regulation of the integrity of the outer mitochondrial membrane (OMM) is the task of the Bcl-2 family of proteins. A network of interactions between the various subgroups of the family decides the apoptotic fate of a cell and, as such, an imbalance within this network can lead to a variety of disease states. In particular, over-expression of pro-survival Bcl-2 family proteins is a hallmark of many cancers. Here we discuss recent advances in targeting the Bcl-2 family with both peptides and small molecules.

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    • "Therapeutic targeting of the BCL-2 family proteins the disclosure of ABT-737 (Figure 3D), a potent inhibitor of BCL-2, BCL-XL and BCL-W (Oltersdorf et al., 2005), which has become a widely utilized chemical biology probe. The development of ABT-737 and of its orally available analogue ABT- 263 (navitoclax, Figure 3E) has been reviewed extensively elsewhere (Lessene et al., 2008; Czabotar and Lessene, 2010; Juin et al., 2013). Notably, the mechanism of action of this class of compounds has been thoroughly studied and there is now little doubt that their potent cell-killing ability is mediated by direct interaction with pro-survival BCL-2 proteins (Konopleva et al., 2006; van Delft et al., 2006; Del Gaizo Moore et al., 2007; Tse et al., 2008). "
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    ABSTRACT: The BCL-2 protein family determines the commitment of cells to apoptosis, an ancient cell suicide programme that is essential for development, tissue homeostasis and immunity. Too little apoptosis can promote cancer and autoimmune diseases; too much apoptosis can augment ischaemic conditions and drive neurodegeneration. We discuss the biochemical, structural and genetic studies that have clarified how the interplay between members of the BCL-2 family on mitochondria sets the apoptotic threshold. These mechanistic insights into the functions of the BCL-2 family are illuminating the physiological control of apoptosis, the pathological consequences of its dysregulation and the promising search for novel cancer therapies that target the BCL-2 family.
    Nature Reviews Molecular Cell Biology 12/2013; 15(1):49-63. DOI:10.1038/nrm3722 · 37.81 Impact Factor
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    • "Early studies showed that p53 can bind the Bax gene promoter region and regulate Bax gene transcription [12,13]. The Bcl-2 protein family plays a critical role in the regulation of apoptosis [14]. Because we observed apoptotic changes in CRC cells, we analyzed the levels of P53, Bax and Bcl-2 in cells treated with pEGFP-N1-GADD45B and Si-GADD45B, respectively. "
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    ABSTRACT: Background GADD45B is a member of the growth arrest DNA damage-inducible gene family associated with cell growth control, apoptosis, and DNA damage repair response. The aim of this study is to detect the role of GADD45B in colorectal carcinoma (CRC); the area not studied in depth to date. Methods The mRNA and protein levels of GADD45B were examined by Real-Time quantitative PCR (RT-qPCR) and immunohistochemistry (IHC) in CRC tissues and adjacent noncancerous tissues (ANCT). Over-expression plasmids and SiRNA were used to regulate GADD45B expression in CRC cell lines in vitro and flow cytometry and Western blotting were used to detect apoptotic changes. Results The mRNA and protein levels of GADD45B were significantly higher in CRC tissues than those in ANCT (P<0.05). Up-regulation of GADD45B was also correlated with relapse and death of CRC patients (P<0.05). The Kaplan-Meier survival curves indicated that disease-free survival (DFS) was significantly worse in CRC patients who showed GADD45B overexpression. A Cox multivariate analysis revealed that GADD45B overexpression and TNM stage were significant factors affecting patients’ survival. On the other hand, as a tumor suppressor gene, GADD45B amplified from normal colorectal tissues could induce apoptosis in CRC cell lines and may be associated with the p53-mediated apoptotic pathways. Conclusion GADD45B, a tumor suppressor gene potentially through the p53-mediated apoptotic pathways, is paradoxically overexpressed in CRC and as such may play an unappreciated role in tumorigenesis. The exact mechanism of GADD45B inactivation and overexpression requires further investigation. GADD45B could be a potential therapeutic target for CRC treatment in future.
    Journal of Translational Medicine 10/2012; 10(1):215. DOI:10.1186/1479-5876-10-215 · 3.93 Impact Factor
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    • "An ‘apoptosome’ is formed by the interaction of cytochrome c, Apaf-1, d-ATP/ ATP and procaspase-9 with subsequent initiation of the caspase cascade [26]. Overexpression of BCL-2 and associated anti-apoptotic proteins Bcl-xL, Mcl-1, and BCL-W occurs in substantial subsets of common cancer types that include pancreatic, ovarian, lymphoma, multiple myeloma, lung adenocarcinoma, prostate adenocarcinoma, etc [27,28]. These Bcl-2 proteins can essentially make cancer cells resistant to a variety of chemotherapeutic agents and therefore these proteins are currently important targets for the development of new anti-cancer agents [29]. "
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    ABSTRACT: Pancreatic cancer (PC) has a complex etiology and displays a wide range of cellular escape pathways that allow it to resist different treatment modalities. Crucial signaling molecules that function downstream of the survival pathways, particularly at points where several of these pathways crosstalk, provide valuable targets for the development of novel anti-cancer drugs. Bcl-2 family member proteins are anti-apoptotic molecules that are known to be overexpressed in most cancers including PC. The anti-apoptotic machinery has been linked to the observed resistance developed to chemotherapy and radiation and therefore is important from the targeted drug development point of view. Over the past ten years, our group has extensively studied a series of small molecule inhibitors of Bcl-2 against PC and provide solid preclinical platform for testing such novel drugs in the clinic. This review examines the efficacy, potency, and function of several small molecule inhibitor drugs targeted to the Bcl-2 family of proteins and their preclinical progress against PC. This article further focuses on compounds that have been studied the most and also discusses the anti-cancer potential of newer class of Bcl-2 drugs.
    Cancers 06/2011; 3(2):1527-1549. DOI:10.3390/cancers3021527
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