A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras

Naveen A. Mallangada, Joselin M. Vargas, Swaroopa Thomas, Matthew G. DiGiovanni, Brandon M. Vaeth, Matthew D. Nemesure, Ruixue Wang, Joseph F. LaComb, Jennie L. Williams, Lorne M. Golub, Francis Johnson, Gerardo Mackenzie

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Pancreatic Cancer (PC) is a deadly disease in need of new therapeutic options. We recently developed a novel tricarbonylmethane agent (CMC2.24) as a therapeutic agent for PC, and evaluated its efficacy in preclinical models of PC. CMC2.24 inhibited the growth of various human PC cell lines in a concentration and time-dependent manner. Normal human pancreatic epithelial cells were resistant to CMC2.24, indicating selectivity. CMC2.24 reduced the growth of subcutaneous and orthotopic PC xenografts in mice by up to 65% (P < 0.02), and the growth of a human patient-derived tumor xenograft by 47.5% (P < 0.03 vs vehicle control). Mechanistically, CMC2.24 inhibited the Ras-RAF-MEK-ERK pathway. Based on Ras Pull-Down Assays, CMC2.24 inhibited Ras-GTP, the active form of Ras, in MIA PaCa-2 cells and in pancreatic acinar explants isolated from Kras mutant mice, by 90.3% and 89.1%, respectively (P < 0.01, for both). The inhibition of active Ras led to an inhibition of c-RAF, MEK, and ERK phosphorylation by 93%, 91%, and 87%, respectively (P < 0.02, for all) in PC xenografts. Furthermore, c-RAF overexpression partially rescued MIA PaCa-2 cells from the cell growth inhibition by CMC2.24. In addition, downstream of ERK, CMC2.24 inhibited STAT3 phosphorylation levels at the serine 727 residue, enhanced the levels of superoxide anion in mitochondria, and induced intrinsic apoptosis as shown by the release of cytochrome c from the mitochondria to the cytosol and the further cleavage of caspase 9 in PC cells. In conclusion, CMC2.24, a potential Ras inhibitor, is an efficacious agent for PC treatment in preclinical models, deserving further evaluation.

Original languageEnglish (US)
Pages (from-to)1130-1143
Number of pages14
JournalMolecular Carcinogenesis
Volume57
Issue number9
DOIs
StatePublished - Sep 1 2018

Keywords

  • CMC2.24
  • curcumin
  • ERK
  • Kras
  • pancreatic cancer
  • Ras

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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    Mallangada, N. A., Vargas, J. M., Thomas, S., DiGiovanni, M. G., Vaeth, B. M., Nemesure, M. D., Wang, R., LaComb, J. F., Williams, J. L., Golub, L. M., Johnson, F., & Mackenzie, G. (2018). A novel tricarbonylmethane agent (CMC2.24) reduces human pancreatic tumor growth in mice by targeting Ras. Molecular Carcinogenesis, 57(9), 1130-1143. https://doi.org/10.1002/mc.22830