PKC-alpha inhibitor MT477 slows tumor growth with minimal toxicity in in vivo model of non-Ras-mutated cancer via induction of apoptosis.
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.
Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Mayo Mail Code 480, 420 Delaware Street SE, Minneapolis, MN 55455, USA.
Piotr
P
Jasinski
Pawel
P
Zwolak
Kaoru
K
Terai
Daniel
D
Borja-Cacho
Arkadiusz Z
AZ
Dudek
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D022001:Focal Adhesions / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051571:Protein Kinase C-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000009:adverse effects* / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
D007527:Isoenzymes; D011804:Quinolines; C530123:dimethyl 5,6-dihydro-7-methoxy-5,5-dimethyl-6-(2-(2,5-dioxopyrrolidin-1-yl)acetyl)-1H-1-(4,5-dimethoxycarbonyl-1,3-dithiolo-2-spiro)thiopyrano(2,3-c)quinoline-2,3-dicarboxylate; D051057:Proto-Oncogene Proteins c-akt; D051571:Protein Kinase C-alpha; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3; D018631:ras Proteins