BH3 mimetics to improve cancer therapy; mechanisms and examples
Introduction
The majority of anticancer agents used in the clinic were empirically discovered through large-scale testing of synthetic chemicals and natural products in cancer cell lines and tumor models. These agents lack specificity and are often ineffective against common epithelial tumors. Recent advances in cancer biology revealed alterations in several key pathways underlying tumorigenesis, and provided molecular targets for developing new therapies (Hanahan and Weinberg, 2000, Vogelstein and Kinzler, 2004). For example, imatinib (Gleevec), which targets the Bcr-Abl fusion protein, is a very effective treatment for a subset of chronic myeloid leukemia (Sawyers, 2002). It is hoped that these so called “targeted drugs” will improve specificity while reducing side-effects, and move oncology practice toward individualized treatment based on the genetic composition of the tumors (Anderson et al., 2006).
Apoptosis is an evolutionally conserved process that is required for development and tissue homeostasis. It also serves as a barrier to oncogenic transformation. Resistance to apoptotic cell death is a hallmark of cancer and contributes to chemoresistance (Hanahan and Weinberg, 2000, Johnstone et al., 2002). Several key pathways controlling apoptosis are commonly altered in cancer (Vogelstein and Kinzler, 2004). For instance, more than half of human tumors contain mutations in the p53 tumor suppressor gene, virtually all of which abolish the ability of p53 to trigger apoptosis (Vogelstein et al., 2000). Overexpression of certain antiapoptotic proteins, such as Bcl-2, Bcl-XL, Akt, nuclear factor-kB (NF-kB), or inhibitor of apoptosis protein (IAP) family, is found in many types of human tumors (Reed, 2003). Defective apoptosis regulation drives neoplastic cells to gain additional tumorigenic features, including extended lifespan, further genetic mutations, growth under stress conditions, and tumor angiogenesis (Hanahan and Weinberg, 2000). Cancer cells become highly dependent on these genetic and epigenetic changes for survival, which seem to be ideal targets for development of novel anticancer drugs, as such drugs may selectively kill cancers cells while sparing normal cells whose survival does not rely on such changes (Demarchi and Brancolini, 2005).
The unfolding of the complex pathways involved in apoptosis signaling in the past decade has stimulated intensive efforts to restore apoptosis in cancer cells for therapeutic purposes (Mashima and Tsuruo, 2005, Yu, 2006, Mollinedo and Gajate, 2006). These efforts have led to several potential anticancer drugs, such as TNF-related apoptosis-inducing ligand (TRAIL), and inhibitors of the Bcl-2 protein family, IAPs and MDM2 (Reed and Pellecchia, 2005). One of the most promising approaches is to inhibit tumor cell survival using agents that mimic proapoptotic Bcl-2 homology 3 (BH3) domains, which play an essential role in apoptosis by neutralizing antiapoptotic Bcl-2 family proteins.
Section snippets
BH3 domains as critical inhibitors of the antiapoptotic Bcl-2 family members
Apoptosis in mammalian cells is regulated by two major pathways, one involving the mitochondria (intrinsic pathway) and the other involving the death receptors (extrinsic pathway). Apoptosis induced by anticancer agents is mainly regulated through the mitochondria by the Bcl-2 family of proteins, evolutionarily conserved apoptotic regulators that integrate a variety of inter- and intracellular signals (Danial and Korsmeyer, 2004). The Bcl-2 family, including 17 or more members, all contain
Rationale for targeting tumors with BH3 mimetics
Apoptosis deregulation in cancer cells appears to primarily affect the signaling pathways upstream of Bax/Bak and mitochondria, leaving the downstream core apoptotic machinery mostly intact (Danial and Korsmeyer, 2004, Reed, 2003). This presents a great opportunity for restoring apoptosis in cancer cells by manipulating the balance between the pro- and antiapoptotic Bcl-2 family members. In the last several years, a number of approaches have been used to identify Bcl-2 family inhibitors that
Peptide BH3 mimetics
In principle, peptides containing BH3 domain sequences should mimic the actions of BH3-only proteins and may be explored as pharmaceutical lead molecules (Shangary and Johnson, 2002). BH3 peptides longer than 14 amino acids can retain an α-helical structure and some biological activities (Shangary et al., 2004). In cell-free assays, these peptides bind to hydrophobic grooves of antiapoptotic proteins, and disrupt complexes formed between proapoptotic and antiapoptotic Bcl-2 family proteins (
Small-molecule Bcl-2 and Bcl-XL inhibitors
Compared to BH3 peptides, small-molecule BH3 mimetics appear to hold greater promise for targeting the Bcl-2 protein family. Targeting protein–protein interactions using small molecules are in general very difficult. However, the deep hydrophobic groove on the surface of Bcl-XL makes it feasible to develop highly specific inhibitors (Petros et al., 2000). This notion, coupled with the therapeutic relevance of Bcl-2 family proteins, has stimulated considerable interest in identifying small
Development and characterization of ABT-737
The most potent and specific Bcl-2/Bcl-XL inhibitor discovered to date is a synthetic small-molecule compound called ABT-737 (Table 1). It was developed by Abbott Laboratories using a combination of approaches, including NMR-based screening, parallel synthesis and structure-based design (Oltersdorf et al., 2005). The Bcl-XL hydrophobic binding groove was first divided into two smaller half-sites, each of which was individually targeted by a small molecule. The two lead compounds were then
Conclusions and future perspectives
Studies of BH3 mimetics, in particular ABT-737, provide strong proof-of-principle that it is feasible to target pro-survival Bcl-2 family members in tumors by inhibiting protein–protein interactions. Several issues will be encountered as the BH3 mimetics move forward into various stages of preclinical development and clinical testing, including compound stability and formulation, pharmacokinetics and metabolism, toxicity, and off-target effects. A key issue is their selectivity in normal versus
Acknowledgements
We thank Dr. Daniel E. Johnson at University of Pittsburgh and Dr. Dale Porter at Novartis for critical reading and comments. The authors’ research is supported by the National Institutes of Health grants CA106348 and CA121105, the American Cancer Society grant RSG-07-156-01-CNE, the American Lung Association (ALA)/Chest Foundation, the V Foundation for Cancer Research, the Outstanding Overseas Scholar Award from the Chinese Natural Science Foundation (L.Z.), the Flight Attendant Medical
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