ABSTRACT
Multinuclear platinum complexes are characterized by a peculiar DNA binding mode and higher cytotoxic potency than the mononuclear complexes, and efficacy against a wide range of preclinical tumor models. To reduce the high irreversible plasma protein binding and improve the chemical and metabolic drug stability, novel bis-platinum complexes were designed starting from the parent compound CT-3610. The novel second-generation bis-platinum complexes utilize alkylcarboxylate as leaving groups to improve their pharmacokinetic and pharmacodynamic profiles, thus overcoming the limitations of the previously developed multinuclear compounds. The selected compounds [CT-47518 and CT-47463, respectively (bis-capronate) platinum and (bis-butyrate) platinum], have similar in vitro degradation kinetics in human and murine plasma and, above all, an increased stability when compared to CT-3610, particularly in human plasma. In addition, both compounds exhibited a marked cytotoxic potency as compared with cisplatin and oxaliplatin. Interestingly, they were capable of overcoming resistance mediated by DNA mismatch repair defects in different cellular models. The complexes showed marked antitumor efficacy in Pt-refractory tumor xenografts, with remarkable activity in terms of tumor growth inhibition and tumor growth delay. The improved stability profile in human plasma compared to early bis- and triplatinum complexes together with the marked activity in cellular systems as well as in in vivo models, make CT-47518 and CT-47463 attractive candidates for further development.
Subject(s)
Antineoplastic Agents/pharmacology , Organoplatinum Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cisplatin/pharmacology , DNA Adducts/metabolism , DNA Mismatch Repair , Drug Design , Drug Resistance, Neoplasm , Drug Stability , Female , Humans , Mice , Mice, Nude , Organoplatinum Compounds/chemistry , Organoplatinum Compounds/pharmacokinetics , Oxaliplatin , Xenograft Model Antitumor AssaysABSTRACT
Modulating protein ubiquitination via proteasome inhibition represents a promising target for cancer therapy, because of the higher sensitivity of cancer cells to the cytotoxic effects of proteasome inhibition. Here we show that CEP-18770 is a novel orally-active inhibitor of the chymotrypsin-like activity of the proteasome that down-modulates the nuclear factor-kappaB (NF-kappaB) activity and the expression of several NF-kappaB downstream effectors. CEP-18770 induces apoptotic cell death in multiple myeloma (MM) cell lines and in primary purified CD138-positive explant cultures from untreated and bortezomib-treated MM patients. In vitro, CEP-18770 has a strong antiangiogenic activity and potently represses RANKL-induced osteoclastogenesis. Importantly, CEP-18770 exhibits a favorable cytotoxicity profile toward normal human epithelial cells, bone marrow progenitors, and bone marrow-derived stromal cells. Intravenous and oral administration of CEP-18770 resulted in a more sustained pharmacodynamic inhibition of proteasome activity in tumors relative to normal tissues, complete tumor regression of MM xenografts and improved overall median survival in a systemic model of human MM. Collectively, these findings provide evidence for the utility of CEP-18770 as a novel orally active proteasome inhibitor with a favorable tumor selectivity profile for the treatment of MM and other malignancies responsive to proteasome inhibition.
Subject(s)
Antineoplastic Agents/pharmacology , Boronic Acids/pharmacology , Enzyme Inhibitors/pharmacology , Neoplasms/drug therapy , Proteasome Inhibitors , Pyrazines/pharmacology , Threonine/analogs & derivatives , Administration, Oral , Animals , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Boronic Acids/administration & dosage , Boronic Acids/chemistry , Boronic Acids/therapeutic use , Bortezomib , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Endothelial Cells/drug effects , Endothelial Cells/pathology , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Macrophage Colony-Stimulating Factor/pharmacology , Mice , Mice, Nude , Multiple Myeloma/pathology , NF-kappa B/antagonists & inhibitors , Neoplasms/pathology , Osteogenesis/drug effects , Pyrazines/administration & dosage , Pyrazines/therapeutic use , RANK Ligand/pharmacology , Threonine/administration & dosage , Threonine/chemistry , Threonine/pharmacology , Threonine/therapeutic use , Treatment Outcome , Ubiquitin/antagonists & inhibitors , Xenograft Model Antitumor AssaysABSTRACT
Lysophosphatidic acid, the substrate for lysophosphatidic acid acyltransferase beta (LPAAT-beta), is a well-studied autocrine/paracrine signaling molecule that is secreted by ovarian cancer cells and is found at elevated levels in the blood and ascites fluid of women with ovarian cancer. LPAAT-beta converts lysophosphatidic acid to phosphatidic acid, which functions as a cofactor in Akt/mTOR and Ras/Raf/Erk pathways. We report that elevated expression of LPAAT-beta was associated with reduced survival in ovarian cancer and earlier progression of disease in ovarian and endometrial cancer. Inhibition of LPAAT-beta using small interfering RNA or selective inhibitors, CT32521 and CT32228, two small-molecule noncompetitive antagonists representing two different classes of chemical structures, induces apoptosis in human ovarian and endometrial cancer cell lines in vitro at pharmacologically tenable nanomolar concentrations. Inhibition of LPAAT-beta also enhanced the survival of mice bearing ovarian tumor xenografts. Cytotoxicity was modulated by diacylglycerol effectors including protein kinase C and CalDAG-GEF1. LPAAT-beta was localized to the endoplasmic reticulum and overexpression was associated with redistribution of protein kinase C-alpha. These findings identify LPAAT-beta as a potential prognostic and therapeutic target in ovarian and endometrial cancer.
