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Questions And Answer

• description

  ABT-737 is a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with potential pro-apoptotic and antineoplastic activities,  with an affinity two to three orders of magnitude more potent than previously reported compounds but no affinity towards less homologous proteins, such as BCL-B, MCL-1, and A1. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumors, and produces cures in a high percentage of the mice. ABT-737 binds to Bcl-2, Bcl-xL and Bcl-w with very high affinities (Ki <1 nM) and also shows a very high specificity over Mcl-1 and A1.
  ABT-737 induces apoptosis in MM cells, including those resistant to conventional therapy. Importantly, ABT-737 decreases the viability of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage.
  ABT-737 has shown single-agent activity against lymphoma and small-cell lung cancer as well as substantial antimyeloma activity both in vitro and in vivo. In recent studies, acute myeloid leukemia blast, origenitor, and stem cells are effectively killed by ABT-737 with normal hematopoietic cells intact. The disruption of the BCL-2/BAX complex and BAK-dependent but BIM-independent activation of the intrinsic apoptotic pathway could also be induced by ABT-737.;

• ABT-737 and ABT-263

  Both are small molecules designed to bind to the key p2 and p4 hotspots of Bcl-2 and Bcl-XL. ABT-737 as single agent exhibits effective antitumor activity in vitro against lymphoma and small-cell carcinoma cells, and also in mouse xenograft models with high expression of Bcl-2 or Bcl-XL. However, ABT-737 has low solubility and oral bioavail- ability in contrast to ABT-263, which is a second-generation ABT-737 with the same mechanism of action. Phase-I and phase-II c linical trials showed that both ABT-263 and ABT-737 were effective in CLL and small-cell lung cancer (SCLC) as a single agent. While they are useful as a single agent, ABT-737 and ABT-263 have significant synergistic effects in inducing apoptosis when combined with other antitumor drugs. ABT-263 has been shown to enhance the therapeutic effect of radiation therapy and chemotherapy for SCLC, follicular lymphoma, CLL, so on, while ABT-737 sensitized cancer cells for flavopiridol, arsenic trioxide, or fenretinide. Additional studies showed that ABT- 263 sensitized conventional agents, such as fludarabine, cyclophosphamide, and rituximab, in treating many solid tumors. However, both ABT-737 and ABT-263 can reduce platelet for targeting Bcl-Xl, which is required in maintaining the lifespan of circulating platelet, requesting the development of selective Bcl-2 inhibitors.
  Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy, Volume 4 1st Edition;

• Biological activity

  ABT-737 is a kind of BH3 mimic inhibitor, acting on Bcl-xL, Bcl-2 and Bcl-w, with the EC50 being 78.7 nM, 30.3 nM and 197.8 nM in cell-free assays; However, it has no inhibitory effect on Mcl-1, Bcl-B and Bfl-1.
  ABT737 up-regulates the expression of apoptosis-related gene Bim through JNK/c-Jun signaling pathway, and induce the apoptosis of Hela cells.
  Use MTT assay to measure the inhibitory effect of ABT-737 on the growth of human cervical cancer Hela cells; apoptosis rate was detected by flow cytometry; the expression of JNK, phospho-JNK, c-Jun and phospho-c-Jun were detected by Western blot; the mRNA expression of Bim protein was detected by RT-PCR. The activity of JNK and c-Jun was inhibited by transiently transfect of the JNK-specific inhibitor SP600125 and siRNA.
  ABT-737 can inhibit the growth of HeLa cells and induce HeLa cells to encounter apoptosis. ABT737 can activate the JNK kinase activity as well as its downstream target molecule c-Jun, further up-regulating the mRNA expression and protein expression of apoptosis-related gene Bim. ABT737-induced up-regulation of Bim and apoptosis were also blocked through inhibiting the activity or the expression of JNK or c-Jun by JNK-specific inhibitor SP600125 and siRNA targeting JNK and c-Jun.
  This information is compiled and edited by Xiao Nan from Chemicalbook.;

• In vitro

  ABT-737 shows low activity to Bcl-B and no effects to Mcl-1 and BFL-1. ABT-737 is sensitive to HL60, KG1 and NB4 cells with IC50 of 50 nM, 80 nM and 80 nM, respectively. ABT-737 induces apoptosis in HL60 cells, which due to decreased Bcl-2/Bax heterodimerization and has no effect on cell cycle distribution. ABT-737 also induces cytochrome c release from purified mitochondria and promotes conformational changes in Bax that are associated with apoptosis.Resistant cells (Hela and MCF-7) can be sensitized to ABT-737 by approaches that down-regulate, destabilize, or inactivate Mcl-1. ABT-737 also causes Bax/BAK-dependent cytochrome c release only when Mcl-1 has been neutralized.ABT-737 displaces Bim from Bcl2's BH3-binding pocket, allowing Bim to activate Bax, induce mitochondrial permeabilization, and rapidly commit the primary chronic lymphocytic leukemia (CLL) cells to death.  Knockdown of Mcl-1 with siRNA sensitizes two resistant SCLC cell lines H196 and DMS114 to ABT-737 by enhancing the induction of apoptosis. Likewise, up-regulation of Noxa sensitizes H196 cells to ABT-737. ABT-737 inhibits proliferation and induces apoptosis in many SCLC cell lines including NCI-H889, NCI-H1963, NCI-H1417, NCI-H146 and etc. Bcl-2 and Noxa may contribute mechanistically to the cellular response to ABT-737 in NCI-H146 cells. A recent study shows that ABT-737 significantly induces apoptosis in HTLV-1 infected T-cell lines as well as in fresh ATLL cells. ;

• In vivo

  In aggressive leukemia model, ABT-737 suppresses the leukemia burden by 53% at the 30 mg/kg, with significantly extended survival of mice. ABT-737 does not induce significantly abnormalities in blood cell counts or serum chemistries.  ABT-737 prolongs the survival of recipient mice transplanted with Bcl-2-transduced tumors. ABT-737 shows great antitumor activity in an ATLL mouse model at a dose of 100 mg/kg. ;

• Feature

  ABT-737 is the first-generation small molecule inhibitors of the anti-apoptotic BCL-2 family protein.;

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