Novel Ras pathway inhibitor induces apoptosis and growth inhibition of K-ras-mutated cancer cells in vitro and in vivo.

Abstract

MT477 is a novel quinoline with potential activity in Ras-mutated cancers. In this study, MT477 preferentially inhibited the proliferation of K-ras-mutated human pulmonary (A549) and pancreatic (MiaPaCa-2) adenocarcinoma cell lines, compared with a non-Ras-mutated human lung squamous carcinoma cell line (H226) and normal human lung fibroblasts. MT477 treatment induced apoptosis in A549 cells and was associated with caspase-3 activation. MT477 also induced sub-G1 cell-cycle arrest in A549 cells. Although we found that MT477 partially inhibited protein kinase C (PKC), it inhibited Ras directly followed in time by inhibition of 2 Ras downstream molecules, Erk1/2 and Ral. MT477 also caused a reorganization of the actin cytoskeleton and formation of filopodias in A549 cells; this event may lead to decreased migration and invasion of tumor cells. In a xenograft mouse model, A549 tumor growth was inhibited significantly by MT477 at a dose of 1 mg/kg (P < 0.05 vs vehicle control). Taken together, these results support the conclusion that MT477 acts as a direct Ras inhibitor. This quinoline, therefore, could potentially be active in Ras-mutated cancers and could be developed extensively as an anticancer molecule with this in mind.

• Authors: Piotr Jasinski, Pawel Zwolak, Kaoru Terai, Arkadiusz Z Dudek
• Journal: Translational research : the journal of laboratory and clinical medicine (Transl Res) Vol. 152 Issue 5 Pg. 203-12 (Nov 2008) ISSN: 1931-5244 [Print] United States
• PMID: 19010291 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Quinolines
• dimethyl 5,6-dihydro-7-methoxy-5,5-dimethyl-6-(2-(2,5-dioxopyrrolidin-1-yl)acetyl)-1H-1-(4,5-dimethoxycarbonyl-1,3-dithiolo-2-spiro)thiopyrano(2,3-c)quinoline-2,3-dicarboxylate
• Protein Kinase C
• Caspase 3
• Oncogene Protein p21(ras)

Topics

• Actin Cytoskeleton (drug effects)
• Adenocarcinoma (drug therapy, metabolism, pathology)
• Animals
• Apoptosis (drug effects)
• Caspase 3 (metabolism)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Fibroblasts (cytology)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Mutation
• Oncogene Protein p21(ras) (antagonists & inhibitors, genetics, metabolism)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Protein Kinase C (antagonists & inhibitors, metabolism)
• Quinolines (pharmacology)
• Signal Transduction (drug effects)
• Xenograft Model Antitumor Assays