HA14-1 - CAS 65673-63-4
Catalog number: 65673-63-4
Category: Inhibitor
Not Intended for Therapeutic Use. For research use only.
Molecular Formula:
Molecular Weight:
Bcl-2 Family
HA14-1 is a potent Bcl-2 inhibitor with potential anticancer activity. HA14-1 induces apoptosis in various human cancer cells. HA14-1 suppressed NF-kappaB activation through inhibition of phosphorylation and degradation of IkappaBalpha.
Canonical SMILES:
1.ITH4012 (ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8]naphthyridine-3-carboxylate), a novel acetylcholinesterase inhibitor with "calcium promotor" and neuroprotective properties.
Orozco C;de Los Rios C;Arias E;León R;García AG;Marco JL;Villarroya M;López MG J Pharmacol Exp Ther. 2004 Sep;310(3):987-94. Epub 2004 Apr 26.
Ethyl 5-amino-6,7,8,9-tetrahydro-2-methyl-4-phenylbenzol[1,8] naphthyridine-3-carboxylate (ITH4012) is a novel tacrine derivative that can reduce cell death induced by various compounds with different mechanisms of action, such as thapsigargin (reticular stress), H2O2 (free radicals), and veratridine (calcium overload), in bovine chromaffin cell. Cell viability, quantified as lactic dehydrogenase release, was significantly reduced by ITH4012 at concentrations ranging from 0.01 to 3 microM. In the human neuroblastoma cell line SH-SY5Y, ITH4012 also reduced amyloid beta25-35-induced apoptosis, determined by flow cytometry. ITH4012 caused a slight elevation in the cytosolic concentration of Ca2+ in fura 2-loaded bovine chromaffin cells, which could be related to the induction of protein synthesis relevant for cell survival. Blockade of protein synthesis by cycloheximide or blockade of Bcl-2's active site with HA14-1 (ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate) reversed the cytoprotective action of ITH4012. Furthermore, exposure of bovine chromaffin cells for 24 or 48 h to neuroprotective concentrations of this compound enhanced, nearly 3-fold, the expression of the antiapoptotic protein Bcl-2.
2.Bcl-2 inhibitors sensitize tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by uncoupling of mitochondrial respiration in human leukemic CEM cells.
Hao JH;Yu M;Liu FT;Newland AC;Jia L Cancer Res. 2004 May 15;64(10):3607-16.
Previous studies have shown that the lymphoblastic leukemia CEM cell line is resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis because of a low expression of caspase-8. Bcl-2 inhibitors, BH3I-2' and HA14-1, are small cell-permeable nonpeptide compounds, are able to induce apoptosis by mediating cytochrome c release, and also lead to dissipation of the mitochondrial membrane potential (DeltaPsim). This study aimed to use the Bcl-2 inhibitors to sensitize CEM cells to TRAIL-induced apoptosis by switching on the mitochondrial apoptotic pathway. We found that a low dose of BH3I-2' or HA14-1, which did not induce cytochrome c release, greatly sensitized CEM cells to TRAIL-induced apoptosis. In a similar manner to the classical uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP), both BH3I-2' and HA14-1 induced a reduction in DeltaPsim, a generation of reactive oxygen species (ROS), an increased mitochondrial respiration, and a decreased ATP synthesis. This uncoupling function of the Bcl-2 inhibitors was responsible for the synergy with TRAIL-induced apoptosis. CCCP per se did not induce apoptosis but again sensitized CEM cells to TRAIL-induced apoptosis by uncoupling mitochondrial respiration.
3.Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells.
Campàs C;Cosialls AM;Barragán M;Iglesias-Serret D;Santidrián AF;Coll-Mulet L;de Frias M;Domingo A;Pons G;Gil J Exp Hematol. 2006 Dec;34(12):1663-9.
OBJECTIVE: ;Antiapoptotic Bcl-2 is overexpressed in most cases of chronic lymphocytic leukemia (CLL). The inhibition of the antiapoptotic Bcl-2 proteins is an attractive strategy for either restoring normal apoptotic process in cancer cells or making these cells more susceptible to conventional chemotherapy. We studied the effect of Bcl-2 inhibitors on the viability of cells from CLL and other mature B-cell neoplasms.;MATERIALS AND METHODS: ;We studied the cytotoxic effects of four nonpeptidic cell-permeable Bcl-2 inhibitors (HA14-1, antimycin A, GX15-003, and GX15-070) on B cells from patients with CLL, mantle cell lymphoma (MCL), and splenic marginal zone lymphoma (SMZL). Moreover, we analyzed the effect of these inhibitors in combination with fludarabine or chlorambucil.;RESULTS: ;HA14-1 induced apoptosis with an EC50 lower than 50 microM in 26 of the 36 CLL samples analyzed. The mean EC50 for these sensitive patients was 23 +/- 2 microM. Antimycin A induced apoptosis in 13 of the 18 CLL samples analyzed. Both HA14-1 and antimycin A induced cytochrome c release from mitochondria and caspase-3 activation. Moreover, HA14-1 induced apoptosis in peripheral cells from MCL and SMZL. HA14-1 also induced apoptosis in CLL samples with alterations in p53 or ATM.
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CAS 65673-63-4 HA14-1

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