Abstract
ObjectiveMucositis 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.DesignFemale 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.ResultsCompared 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.ConclusionGrape 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.
Highlights
Mucositis is a serious, debilitating consequence of cancer therapy, which significantly reduces quality of life in cancer patients [1]
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 was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum
Summary
Mucositis is a serious, debilitating consequence of cancer therapy, which significantly reduces quality of life in cancer patients [1]. Mucositis is a painful condition associated with inflammation and ulceration of the gastrointestinal tract; most commonly affecting the mucosa of the mouth (oral mucositis) and small intestine (intestinal mucositis). The chemotherapy dose administered to cancer patients often be sub-optimal; new regimens that reduce side-effects, maintaining efficacy are sought. Current mucositis treatments are largely ineffective as they target only the symptoms, but not the pathogenesis of the condition [5]. It is important to seek new alternative treatments which target mucositis and enhance chemotherapeutic action without compromising the well-being of the patient. The optimal combination of agents which could enhance both chemotherapeutic cytotoxicity against cancer cells and have minimal impact on normal cells, has not yet been determined
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