ABSTRACT
A large number of hormones and local agonists activating guanine-binding protein-coupled receptors (GPCR) play a major role in cancer progression. Here, we characterize the new imidazo-pyrazine derivative BIM-46174, which acts as a selective inhibitor of heterotrimeric G-protein complex. BIM-46174 prevents the heterotrimeric G-protein signaling linked to several GPCRs mediating (a) cyclic AMP generation (Galphas), (b) calcium release (Galphaq), and (c) cancer cell invasion by Wnt-2 frizzled receptors and high-affinity neurotensin receptors (Galphao/i and Galphaq). BIM-46174 inhibits the growth of a large panel of human cancer cell lines, including anticancer drug-resistant cells. Exposure of cancer cells to BIM-46174 leads to caspase-3-dependent apoptosis and poly(ADP-ribose) polymerase cleavage. National Cancer Institute COMPARE analysis for BIM-46174 supports its novel pharmacologic profile compared with 12,000 anticancer agents. The growth rate of human tumor xenografts in athymic mice is significantly reduced after administration of BIM-46174 combined with either cisplatin, farnesyltransferase inhibitor, or topoisomerase inhibitors. Our data validate the feasibility of targeting heterotrimeric G-protein functions downstream the GPCRs to improve anticancer chemotherapy.
Subject(s)
Cysteine/analogs & derivatives , Heterotrimeric GTP-Binding Proteins/antagonists & inhibitors , Imidazoles/pharmacology , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Growth Processes/drug effects , Cell Line, Tumor , Cysteine/pharmacology , Drug Screening Assays, Antitumor , Female , GTP-Binding Protein alpha Subunits/antagonists & inhibitors , GTP-Binding Protein alpha Subunits/metabolism , GTP-Binding Protein beta Subunits/antagonists & inhibitors , GTP-Binding Protein beta Subunits/metabolism , GTP-Binding Protein gamma Subunits/antagonists & inhibitors , GTP-Binding Protein gamma Subunits/metabolism , HL-60 Cells , Heterotrimeric GTP-Binding Proteins/metabolism , Humans , Mice , Neoplasm Invasiveness , Xenograft Model Antitumor AssaysABSTRACT
BN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered beta-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G(0)-G(1) synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC(50) values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927.
