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: Hiu Yeung Lau, Pondy M Ramanujulu, Dianyan Guo, Tianming Yang, Melissa Wirawan, Patrick J Casey, Mei-Lin Go, Mei Wang
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 15 Issue 9 Pg. 1280-91 (Sep 2014) ISSN: 1555-8576 [Electronic] United States
• PMID: 24971579 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Lamin Type A
• Pyrimidines
• Quinazolines
• cysmethynil
• Protein Methyltransferases
• protein-S-isoprenylcysteine O-methyltransferase
• ErbB Receptors
• Oncogene Protein p21(ras)
• Gefitinib

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Drug Synergism
• ErbB Receptors (antagonists & inhibitors)
• Female
• Gefitinib
• Heterografts
• Humans
• Indoles (pharmacology, therapeutic use, toxicity)
• Lamin Type A (metabolism)
• Liver Neoplasms (drug therapy, pathology)
• Methylation
• Mice, SCID
• Oncogene Protein p21(ras) (metabolism)
• Protein Methyltransferases (antagonists & inhibitors, metabolism)
• Protein Prenylation
• Pyrimidines (pharmacology, therapeutic use, toxicity)
• Quinazolines (pharmacology)