title: An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo.
abstract: Inhibitors of isoprenylcysteine carboxylmethyltransferase (Icmt) are promising anti-cancer agents, as modification by Icmt is an essential component of the protein prenylation pathway for a group of proteins that includes Ras GTPases. Cysmethynil, a prototypical indole-based inhibitor of Icmt, effectively inhibits tumor cell growth. However, the physical properties of cysmethynil, such as its low aqueous solubility, make it a poor candidate for clinical development. A novel amino-derivative of cysmethynil with superior physical properties and marked improvement in efficacy, termed compound 8.12, has recently been reported. We report here that Icmt (-/-) mouse embryonic fibroblasts (MEFs) are much more resistant to compound 8.12-induced cell death than their wild-type counterparts, providing evidence that the anti-proliferative effects of this compound are mediated through an Icmt specific mechanism. Treatment of PC3 prostate and HepG2 liver cancer cells with compound 8.12 resulted in pre-lamin A accumulation and Ras delocalization from the plasma membrane, both expected outcomes from inhibition of the Icmt-catalyzed carboxylmethylation. Treatment with compound 8.12 induced cell cycle arrest, autophagy and cell death, and abolished anchorage-independent colony formation. Consistent with its greater in vitro efficacy, compound 8.12 inhibited tumor growth with greater potency than cysmethynil in a xenograft mouse model. Further, a drug combination study identified synergistic antitumor efficacy of compound 8.12 and the epithelial growth factor receptor (EGFR)-inhibitor gefitinib, possibly through enhancement of autophagy. This study establishes compound 8.12 as a pharmacological inhibitor of Icmt that is an attractive candidate for further preclinical and clinical development.
authors: Program of Cancer and Stem Cell Biology; Duke-NUS Graduate Medical School; Singapore.
authors: Hiu Yeung
authors: HY
authors: Lau
authors: Department of Pharmacy; Faculty of Science; National University of Singapore; Singapore.
authors: Pondy M
authors: PM
authors: Ramanujulu
authors: Program of Cancer and Stem Cell Biology; Duke-NUS Graduate Medical School; Singapore.
authors: Dianyan
authors: D
authors: Guo
authors: Department of Pharmacy; Faculty of Science; National University of Singapore; Singapore.
authors: Tianming
authors: T
authors: Yang
authors: Program of Cancer and Stem Cell Biology; Duke-NUS Graduate Medical School; Singapore.
authors: Melissa
authors: M
authors: Wirawan
authors: Program of Cancer and Stem Cell Biology; Duke-NUS Graduate Medical School; Singapore.
authors: Patrick J
authors: PJ
authors: Casey
authors: Department of Pharmacy; Faculty of Science; National University of Singapore; Singapore.
authors: Mei-Lin
authors: ML
authors: Go
authors: Program of Cancer and Stem Cell Biology; Duke-NUS Graduate Medical School; Singapore.
authors: Mei
authors: M
authors: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D000077156:Gefitinib; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D034904:Lamin Type A / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008745:Methylation; D016513:Mice, SCID; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017368:Protein Prenylation; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011799:Quinazolines / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D034904:Lamin Type A; D011743:Pyrimidines; D011799:Quinazolines; C530692:cysmethynil; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D066246:ErbB Receptors; D015689:Oncogene Protein p21(ras); D000077156:Gefitinib
keywords: Icmt; Ras; anti-proliferation; autophagy; compound 8.12; cysmethynil; gefitinib; synergy