Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells.
OBJECTIVE
Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells.


METHODS
Female Dark Agouti rats were gavaged with grape seed extract (400-1000 mg/kg) or water (day 3-11) and were injected intraperitoneally with 5-Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5-Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) assay.


RESULTS
Compared with 5-Fluorouracil controls, grape seed extract (400-1000 mg/kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. Grape seed extract was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum. Grape seed extract (10-25 ug/mL) significantly enhanced the growth-inhibitory effects of 5-Fluorouracil by 26% (P<0.05) in Caco-2 cells and was more potent than 5-Fluorouracil at 50-100 µg/mL.


CONCLUSIONS
Grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells.
School of Agriculture, Food and Wine, Waite Campus, University of Adelaide, South Australia, Australia ; Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, North Adelaide, South Australia, Australia.
Ker Yeaw
KY
Cheah
Centre for Paediatric and Adolescent Gastroenterology, Children, Youth and Women's Health Service, North Adelaide, South Australia, Australia ; School of Animal and Veterinary Sciences, Roseworthy Campus, University of Adelaide, South Australia, Australia.
Gordon Stanley
GS
Howarth
School of Agriculture, Food and Wine, Waite Campus, University of Adelaide, South Australia, Australia.
Susan Elaine Putnam
SE
Bastian
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005472:Fluorouracil; D056604:Grape Seed Extract / Q000494:pharmacology*; D006801:Humans; D007274:Injections, Intraperitoneal; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007583:Jejunum / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D052016:Mucositis / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D009195:Peroxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D012720:Severity of Illness Index
D000975:Antioxidants; D056604:Grape Seed Extract; D009195:Peroxidase; D005472:Fluorouracil