title: Potentiating NK cell activity by combination of Rosuvastatin and Difluoromethylornithine for effective chemopreventive efficacy against Colon Cancer.
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.
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Bryant
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Misty
authors.initials: M
authors.lastname: Brewer
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Duff
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Singh
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology Oncology Section, Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000453:epidemiology / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D004359:Drug Therapy, Combination; D000518:Eflornithine / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D054353:Perforin / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D012334:RNA, Neoplasm / Q000302:isolation & purification / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D000068718:Rosuvastatin Calcium / Q000627:therapeutic use*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D011073:Polyamines; D012334:RNA, Neoplasm; D014157:Transcription Factors; D051176:beta Catenin; D054353:Perforin; D019938:Cyclin D1; D007371:Interferon-gamma; D000068718:Rosuvastatin Calcium; D000518:Eflornithine