PRECLINICAL STUDIES

Investigational New Drugs

, Volume 26, Issue 3, pp 223-232

First online:

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 JasinskiAffiliated withDivision of Hematology, Oncology and Transplantation, Department of Medicine, University of MinnesotaDepartment of Pathophysiology, Medical University of Vienna
  • , Brandon WelshAffiliated withDivision of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota
  • , Jorge GalvezAffiliated withMolecular Connectivity & Drug Design Research Unit, Department of Physical Chemistry, University of Valencia
  • , David LandAffiliated withMedisyn Technologies, Inc.
  • , Pawel ZwolakAffiliated withDivision of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota
  • , Lori GhandiAffiliated withDivision of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota
  • , Kaoru TeraiAffiliated withDivision of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota
  • , Arkadiusz Z. DudekAffiliated withDivision of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota Email author 

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Summary

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.

Keywords

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