PKC-alpha inhibitor MT477 slows tumor growth with minimal toxicity in in vivo model of non-Ras-mutated cancer via induction of apoptosis

Piotr Jasinski, Pawel Zwolak, Kaoru Terai, Daniel Borja-Cacho, Arkadiusz Z. Dudek

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Summary: MT477 is a novel thiopyrano[2,3-c]quinoline with anti-cancer activity. The purpose of the present study was to evaluate different doses and treatment schedules of MT477 in an in vivo xenograft model of non-Ras-mutated cancer, as well as determine its biological effects and mechanism of action via the four conventional PKC isoforms: α, βI, βII, and γ. Here, we show that MT477 inhibits the activity of PKC-α and its downstream targets, ERK1/2 and Akt, before it has an effect on Ras activity. MT477 treatment of cultured H226 cells induced apoptosis and increased focal cell adhesion and formation of actin stress fibers. H226 tumor size in mice continuously treated with intraperitoneal MT477 (1 mg/kg) was 62.1± 15.3% smaller than the average tumor size in control mice. Blood serum chemistry revealed minimal toxicity in mice. Taken together, these results support the conclusion that MT477 acts as a direct PKC-α inhibitor in non-Ras mutated cancer, with maximum effectiveness when given in a continuous treatment schedule.

Original languageEnglish (US)
Pages (from-to)33-40
Number of pages8
JournalInvestigational New Drugs
Volume29
Issue number1
DOIs
StatePublished - Feb 2011

Keywords

  • Actin structure
  • In vivo toxicity
  • MT477
  • New drug development
  • Protein kinase C-alpha

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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