Pro-apoptotic Activity of BH3-only Proteins and BH3 Mimetics: from Theory to Potential Cancer Therapy
ABSTRACT The evasion of cancer cells from the induction of cell death pathways results in the resistance of tumor to current treatment modalities. Therefore, the resistance to cell death, one of the hallmarks of cancer, is a major target in the development of new approaches to selectively affect cancer cells. The complex interplay between individual members of Bcl-2 family regulates both cell survival and the mitochondrial pathway of apoptosis by maintaining mitochondrial membrane integrity (anti-apoptotic Bcl-2 subfamily) and by triggering its disruption in response to stress stimuli (Bax-like subfamily). BH3-only proteins, another Bcl-2 subfamily, act either by direct stimulation of pro-apoptotic proteins of the Bax subfamily or by interfering with anti-apoptotic proteins of the Bcl-2 subfamily. Thus, pro-apoptotic BH3 mimetics, thought to function as BH3-only proteins, are expected to improve the effectiveness of cancer treatment. BH3 mimetics could be either natural or synthetic, peptidic or only based on a helical peptide-like scaffold. Experimental and clinical evidence indicates that BH3 mimetics may not be sufficient to cure cancer patients when used as a single agent. BH3 profiling of cancer cells was introduced to better predict the in vivo responsiveness of tumor to BH3 mimetics combined with conventional therapies. In summary, targeting the Bcl-2 proteins is a promising tool with potential to generate new treatment modalities and to complement existing anti-cancer therapies. This review presents the current knowledge on BH3-only proteins and the spectrum of strategies employing BH3 mimetics in preclinical and clinical studies that aim at tumor targeting.
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ABSTRACT: Apoptosis plays a pivotal role in sustaining proper tissue development and homeostasis. Evading apoptosis by cancer cells is a part of their adaption to microenvironment and therapies. Cellular integrity is predominantly maintained by pro-survival members of Bcl-2 family and IAPs. Melanoma cells are characterized by a labile and stage-dependent phenotype. Pro-survival molecules can protect melanoma cells from apoptosis and mediate other processes, thus enhancing aggressive phenotype. The essential role of Bcl-2, Mcl-1, Bcl-X(L), livin, survivin and XIAP was implicated for melanoma, often in a tumor stage-dependent fashion. In this review, the current knowledge of pro-survival machinery in melanoma is discussed.Cancer letters 01/2013; 331(1). DOI:10.1016/j.canlet.2013.01.010 · 5.62 Impact Factor
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ABSTRACT: Biomimetic pro-apoptotic agents (e.g., BH3 mimetics) have been shown to activate the intrinsic death pathway (Type 2 apoptosis) selectively in cancer cells, a mechanism that can be key to developing successful anti-cancer therapy. This work reports mathematical modeling and computer simulations to explore the mechanisms for cancer cell apoptosis. The results indicate that a combination of low probability Bid-Bax type reaction along with overexpressed reactant molecules allows specific killing of cancer cells. Low-probability activation of Bax also emerges as a basis for inherent cell-to-cell variability in apoptotic activation. Variations in Bcl-2 to Bax ratio within a cancer cell population can further affect intrinsic fluctuations generated due to the stochastic Bid-Bax reaction. Such heterogeneity in apoptosis resistance can also provide a mechanism for the origin of cells with higher tumorigenic potential (cancer stem-like cells). The implications of our results for cancer therapy, such as in minimizing stochastic fluctuations in cancer cell death, are discussed.Journal of Healthcare Engineering 03/2013; 4(1):47-66. DOI:10.1260/2040-2222.214.171.124 · 0.75 Impact Factor
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ABSTRACT: Intracellular eukaryotic parasites and their host cells constitute complex, coevolved cellular interaction systems that frequently cause disease. Among them, Plasmodium parasites cause a significant health burden in humans, killing up to one million people annually. To succeed in the mammalian host after transmission by mosquitoes, Plasmodium parasites must complete intracellular replication within hepatocytes and then release new infectious forms into the blood. Using Plasmodium yoelii rodent malaria parasites, we show that some liver stage (LS)-infected hepatocytes undergo apoptosis without external triggers, but the majority of infected cells do not, and can also resist Fas-mediated apoptosis. In contrast, apoptosis is dramatically increased in hepatocytes infected with attenuated parasites. Furthermore, we find that blocking total or mitochondria-initiated host cell apoptosis increases LS parasite burden in mice, suggesting that an anti-apoptotic host environment fosters parasite survival. Strikingly, although LS infection confers strong resistance to extrinsic host hepatocyte apoptosis, infected hepatocytes lose their ability to resist apoptosis when anti-apoptotic mitochondrial proteins are inhibited. This is demonstrated by our finding that B-cell lymphoma 2 family inhibitors preferentially induce apoptosis in LS-infected hepatocytes and significantly reduce LS parasite burden in mice. Thus, targeting critical points of susceptibility in the LS-infected host cell might provide new avenues for malaria prophylaxis.Cell Death & Disease 08/2013; 4(8):e762. DOI:10.1038/cddis.2013.286 · 5.01 Impact Factor