Investigational New Drugs

, Volume 29, Issue 1, pp 33–40 | Cite as

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


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.


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



We thank Michael J. Franklin for editorial review of this manuscript.

Conflicts of Interest

Research grant from Medisyn Technologies partially supported the work described in the manuscript.


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Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Piotr Jasinski
    • 1
    • 2
  • Pawel Zwolak
    • 1
  • Kaoru Terai
    • 1
  • Daniel Borja-Cacho
    • 3
  • Arkadiusz Z. Dudek
    • 1
  1. 1.Division of Hematology, Oncology and Transplantation, Department of MedicineUniversity of MinnesotaMinneapolisUSA
  2. 2.Department of PathophysiologyMedical University of ViennaViennaAustria
  3. 3.Department of SurgeryUniversity of MinnesotaMinneapolisUSA

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