Characterization of PPAR dual ligand MCC-555 in AOM-induced colorectal tumorigenesis.
Colorectal cancer (CRC) is one of the most commonly diagnosed cancers. Peroxisome proliferator-activated receptor γ (PPARγ) agonists represent a potentially important family of chemopreventive/therapeutic compounds for cancer treatment by affecting cell proliferation, differentiation, and apoptosis. Dual ligands for PPARα and PPARγ, such as netoglitazone (MCC-555), have been developed to improve treatment of metabolic syndromes, including hyperglycemia and hyperlipidemia. Interestingly, these dual ligands also possess anti-proliferative activities against a variety of cancer cell lines with a greater potency than conventional PPARγ specific ligands. In this study, chemopreventive properties of MCC-555 in colorectal tumorigenesis were evaluated using azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in A/J mice. We found that MCC-555 suppressed AOM-induced ACF in A/J mice, compared to the control group. Administration of MCC-555 resulted in decreased mitoses and increased apoptotic cells in the colon. Furthermore, expression of tumor suppressor protein MUC2 was increased in MCC-555 treated mice. Our data clearly suggest that MCC-555 has an effect on the early events of colon carcinogenesis, thus providing evidence that MCC-555 could be a potential preventive compound for CRC.
Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996, USA.
Temjenmongla
T
Imchen
Jorden
J
Manasse
Kyung-Won
KW
Min
Seung Joon
SJ
Baek
D058739:Aberrant Crypt Foci / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001397:Azoxymethane / Q000633:toxicity*; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D051379:Mice; D008815:Mice, Inbred Strains; D008938:Mitosis / Q000187:drug effects; D055262:Mucin-2 / Q000096:biosynthesis; D047495:PPAR gamma / Q000819:agonists*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D000970:Antineoplastic Agents; C524626:Muc2 protein, mouse; D055262:Mucin-2; D047495:PPAR gamma; D045162:Thiazolidinediones; D001397:Azoxymethane; C115174:netoglitazone
ACF; ANOVA; AOM; Aberrant crypt foci; Azoxymethane; CMC; CRC; Colon cancer; H&E; MCC-555; PPAR; PPAR ligand; TUNEL; TdT; TdT-mediated deoxyuridine triphosphate nick-end labeling; aberrant crypt foci; analysis of variance; azoxymethane; carboxyl methyl cellulose; colorectal cancer; hematoxylin and eosin; peroxisome proliferator-activated receptor; terminal deoxynucleotidyl transferase