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An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo.

Publication ,  Journal Article
Lau, HY; Ramanujulu, PM; Guo, D; Yang, T; Wirawan, M; Casey, PJ; Go, M-L; Wang, M
Published in: Cancer Biol Ther
September 2014

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.

Duke Scholars

Published In

Cancer Biol Ther

DOI

EISSN

1555-8576

Publication Date

September 2014

Volume

15

Issue

9

Start / End Page

1280 / 1291

Location

United States

Related Subject Headings

  • Quinazolines
  • Pyrimidines
  • Protein Prenylation
  • Protein Methyltransferases
  • Oncology & Carcinogenesis
  • Oncogene Protein p21(ras)
  • Mice, SCID
  • Methylation
  • Liver Neoplasms
  • Lamin Type A
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lau, H. Y., Ramanujulu, P. M., Guo, D., Yang, T., Wirawan, M., Casey, P. J., … Wang, M. (2014). An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol Ther, 15(9), 1280–1291. https://doi.org/10.4161/cbt.29692
Lau, Hiu Yeung, Pondy M. Ramanujulu, Dianyan Guo, Tianming Yang, Melissa Wirawan, Patrick J. Casey, Mei-Lin Go, and Mei Wang. “An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo.Cancer Biol Ther 15, no. 9 (September 2014): 1280–91. https://doi.org/10.4161/cbt.29692.
Lau HY, Ramanujulu PM, Guo D, Yang T, Wirawan M, Casey PJ, et al. An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol Ther. 2014 Sep;15(9):1280–91.
Lau, Hiu Yeung, et al. “An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo.Cancer Biol Ther, vol. 15, no. 9, Sept. 2014, pp. 1280–91. Pubmed, doi:10.4161/cbt.29692.
Lau HY, Ramanujulu PM, Guo D, Yang T, Wirawan M, Casey PJ, Go M-L, Wang M. An improved isoprenylcysteine carboxylmethyltransferase inhibitor induces cancer cell death and attenuates tumor growth in vivo. Cancer Biol Ther. 2014 Sep;15(9):1280–1291.

Published In

Cancer Biol Ther

DOI

EISSN

1555-8576

Publication Date

September 2014

Volume

15

Issue

9

Start / End Page

1280 / 1291

Location

United States

Related Subject Headings

  • Quinazolines
  • Pyrimidines
  • Protein Prenylation
  • Protein Methyltransferases
  • Oncology & Carcinogenesis
  • Oncogene Protein p21(ras)
  • Mice, SCID
  • Methylation
  • Liver Neoplasms
  • Lamin Type A