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

Piotr Jasinski, Pawel Zwolak, Kaoru Terai, Arkadiusz Z Dudek

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)203-212
Number of pages10
JournalTranslational Research
Volume152
Issue number5
DOIs
StatePublished - Nov 2008

Bibliographical note

Funding Information:
Supported by a grant from Medisyn Technologies and a grant from the Experimental Therapeutics Fund of the University of Minnesota.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

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