Promoting effects of carminic acid-enriched cochineal extracts on capsular invasive thyroid carcinomas through targeting activation of angiogenesis in rats.
Cochineal extracts (CE) is a coccid-derived natural food colorant containing carminic acid (CA) as an active ingredient that potentiates inhibition of tissue proteolysis mediated by activation of plasma hyaluronan-binding protein (PHBP). In our previous study, dietary administered CE (CA: 28.5% in CE) has shown to promote the macroscopic development of capsular invasive carcinomas (CICs) associated with up-regulation of angiogenesis-related genes in an intracapsular invasion model of experimental thyroid cancers using rats. However, the promoting effect of CE could not be confirmed histopathologically. The purpose of the present study was to confirm the promoting effect of CE through direct injections to animals on the development of CICs using this cancer invasion model. One week after initiation with N-bis(hydroxypropyl)nitrosamine, male F344/NSlc rats were administered CA-enriched CE (CA: 52.6% in CE) by intraperitoneal injections every other day (10 mg/kg body weight) during the promotion with 0.15% sulfadimethoxine in the drinking water for 8 weeks. The multiplicities of macroscopical CICs and the mean area of early capsular invasive foci estimated by Tenascin (TN)-C-immunoreactivity in the thyroid significantly increased with CE-treatment, while the number of TN-C-positive foci did not change with CE. Transcript level of Phbp and downstream genes unchanged; however, transcript level of angiogenesis-related genes, i.e, Vegfb and its transcription factor gene, Hif1a, those being downstream of phosphatase and tensin homolog (PTEN)/Akt signaling, up-regulated in the thyroid tissue with CE-administration. These results suggest that CE potentiates promotion activity by facilitating angiogenesis through activation of PTEN/Akt signaling without accompanying modification of PHBP-related proteolysis.
Laboratory of Veterinary Pathology,Tokyo University of Agriculture and Technology, Tokyo, Japan.
Sayaka
S
Kemmochi
Keisuke
K
Shimamoto
Ayako
A
Shiraki
Nobuhiko
N
Onda
Keiji
K
Hasumi
Kazuhiko
K
Suzuki
Kunitoshi
K
Mitsumori
Makoto
M
Shibutani
D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use; D000818:Animals; D002329:Carmine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004195:Disease Models, Animal; D060766:Drinking Water / Q000008:administration & dosage / Q000737:chemistry; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008297:Male; D009602:Nitrosamines / Q000633:toxicity; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction; D013412:Sulfadimethoxine / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D015854:Up-Regulation
D043925:Angiogenesis Inducing Agents; D060766:Drinking Water; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009602:Nitrosamines; D010936:Plant Extracts; D013412:Sulfadimethoxine; C012457:diisopropanolnitrosamine; D002329:Carmine; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat