Control of apoptosis by using small molecule regulators of Bcl-2 family proteins

Mitochondria in hematopoiesis and hematological diseases

“…This activation of caspases is in apparent contrast with Epo-mediated upregulation of the antiapoptotic protein Bcl-X L through activation of the transcription factor GATA-1 during terminal erythroid differentiation (Gregory et al, 1999;Motoyama et al, 1999). The main function of Bcl-X L in this differentiation pathway is supposed to be the prevention of apoptosis during erythroid development (Wang et al, 2000), for example by limiting differentiation-related caspase activation. Analysis of an erythroleukemia cell model of erythroid differentiation suggested that Bcl-X L was also required for heme synthesis in the mitochondria, independently of its antiapoptotic function (HafidMedheb et al, 2003).…”

“…Small peptide molecules that mimic the BH3 domain, a B16 amino-acid amphipathic a-helix that inserts into a hydrophobic crevice on the surface of antiapoptotic proteins, can suppress human myeloid leukemia growth in severe combined immunodeficient mice (Wang et al, 2000;Letai, 2005). Small, nonpeptidic organic compounds that interact with the surface pocket of Bcl-2 (also called BH3 mimetics) have been identified through various strategies, for example ABT-737 was rationally designed (Oltersdorf et al, 2005) whereas GXO1 was selected by functional screening.…”

Bcl-2 family proteins as targets for anticancer drug design

“…Using a di erent transporter based on fatty acids, Wang et al (2000b) designed another class of cell permeable Bcl-2 binding peptides by chemically attaching the N-terminus of synthetic BH3 peptides Figure 1 The resistance of tumor cells to conventional chemotherapy or radiation therapy mediated by high expression of Bcl-2 Non-peptidic small molecules that inhibit the function of Bcl-2 or Bcl-x L Two natural products have been suggested to antagonize the anti-apoptotic function of Bcl-2 or Bcl-x L . Nakashima et al (2000) reported that a natural product Tetrocarcin A inhibited mitochondrial functions of Bcl-2 and suppressed its anti-apoptotic activity ( Figure 3a).…”

Solution structure of the antiapoptotic protein bcl-2

“…Bcl-2 has been implicated also in the resistance of many cancers to treatment with radiation and chemotherapeutic agents (10,13). Therefore, Bcl-2 represents a target for the treatment of cancers, especially those in which Bcl-2 is overexpressed and for which traditional therapy has failed (15)(16)(17)(18)(19).…”