Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer

Sci Rep. 2016 Nov 14;6:37046. doi: 10.1038/srep37046.

Abstract

Colorectal cancer (CRC) is the second highest cause of cancer-related deaths. A successful strategy to improve chemopreventive efficacies is by down-regulating tumor polyamines and enhancing NK cell activities. Colonic carcinogenesis was induced by azoxymethane (AOM) in male F344 rats. Eight weeks after AOM treatment, animals were fed diets containing Rosuvastatin and difluromethylornithine (DFMO) individually and in combination for 40 weeks. Both agents showed significant suppression of adenocarcinoma multiplicity and incidence with no toxicity compared to untreated rats. Low-dose Rosuvastatin plus DFMO suppressed colon adenocarcinoma multiplicity by 76% compared to low-dose Rosuvastatin (29%) and DFMO (46%), suggesting additive efficacy. Furthermore, low-dose combination caused a delay in colonic adenocarcinoma progression. DFMO, Rosuvastatin and/or combinations significantly decreased polyamine content and increased intra-tumoral NK cells expressing perforin plus IFN-γ compared to untreated colon tumors. Further ex-vivo analysis of splenic NK cells exposed to DFMO, Rosuvastatin or combination resulted in an increase of NKs with perforin expression. This is the first report on Rosuvastatin alone or combination strategy using clinically relevant statin plus DFMO doses which shows a significant suppression of colon adenocarcinomas, and their potential in increasing functional NK cells. This strategy has potential for further testing in high risk individuals for colon cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / drug therapy
  • Adenocarcinoma / epidemiology
  • Adenocarcinoma / immunology
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / epidemiology
  • Colonic Neoplasms / immunology
  • Cyclin D1 / genetics
  • Cyclin D1 / metabolism
  • Disease Progression
  • Drug Therapy, Combination
  • Eflornithine / therapeutic use*
  • Interferon-gamma / metabolism
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Male
  • Perforin / metabolism
  • Polyamines / metabolism
  • RNA, Neoplasm / isolation & purification
  • RNA, Neoplasm / metabolism
  • Rats
  • Rats, Inbred F344
  • Rosuvastatin Calcium / therapeutic use*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Antineoplastic Agents
  • Polyamines
  • RNA, Neoplasm
  • Transcription Factors
  • beta Catenin
  • Perforin
  • Cyclin D1
  • Interferon-gamma
  • Rosuvastatin Calcium
  • Eflornithine