A novel quinoline, MT477: Suppresses cell signaling through Ras molecular pathway, inhibits PKC activity, and demonstrates in vivo anti-tumor activity against human carcinoma cell lines

Piotr Jasinski, Brandon Welsh, Jorge Galvez, David Land, Pawel Zwolak, Lori Ghandi, Kaoru Terai, Arkadiusz Z. Dudek

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41 Scopus citations

Abstract

MT477 is a novel thiopyrano[2,3-c]quinoline that has been identified using molecular topology screening as a potential anticancer drug with a high activity against protein kinase C (PKC) isoforms. The objective of the present study was to determine the mechanism of action of MT477 and its activity against human cancer cell lines. MT477 interfered with PKC activity as well as phosphorylation of Ras and ERK1/2 in H226 human lung carcinoma cells. It also induced poly-caspase-dependent apoptosis. MT477 had a dose-dependent (0.006 to 0.2 mM) inhibitory effect on cellular proliferation of H226, MCF-7, U87, LNCaP, A431 and A549 cancer cell lines as determined by in vitro proliferation assays. Two murine xenograft models of human A431 and H226 lung carcinoma were used to evaluate tumor response to intraperitoneal administration of MT477 (33 μg/kg, 100 μg/kg, and 1 mg/kg). Tumor growth was inhibited by 24.5% in A431 and 43.67% in H226 xenografts following MT477 treatment, compared to vehicle controls (p < 0.05). In conclusion, our empirical findings are consistent with molecular modeling of MT477's activity against PKC. We also found, however, that its mechanism of action occurs through suppressing Ras signaling, indicating that its effects on apoptosis and tumor growth in vivo may be mediated by Ras as well as PKC. We propose, therefore, that MT477 warrants further development as an anticancer drug.

Original languageEnglish (US)
Pages (from-to)223-232
Number of pages10
JournalInvestigational New Drugs
Volume26
Issue number3
DOIs
StatePublished - Jun 2008

Bibliographical note

Funding Information:
Financial Support: Research grant from Medisyn Technologies partially supported the work described in the manuscript. P.Jasinski.B.Welsh.P.Zwolak.L.Ghandi.K.Terai. A. Z. Dudek (*) Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA e-mail: dudek002@umn.edu

Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.

Keywords

  • Caspase-dependent apoptosis
  • MT477
  • New drug development
  • Protein Kinase C
  • Ras-MEK-ERK pathway inhibition

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