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Combretastatin augments the anticancer effect of vincristine either in vivo or in vitro
Author(s) -
ElMoselhy Mohamed Ahmed,
Aboubakr Esam Mohamed,
Ali Omar Mohamed,
Taye Ashraf
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb492
Subject(s) - combretastatin , vincristine , in vivo , medicine , pharmacology , hepatocellular carcinoma , saline , in vitro , tubulin , pathology , chemistry , chemotherapy , biology , biochemistry , cyclophosphamide , microtubule , microbiology and biotechnology
Hepatocellular carcinoma (HCC) is a serious healthcare problem worldwide especially in the Middle East because of its increasing morbidity and mortality. Aim The present study was conducted both in vivo and in vitro to investigate the anti‐cancer effect of combretastatin either alone or in combination with vincristine and the mechanisms underlying this effect. Methods In vivo study: a total 50 Wister albino rats were divided into five groups 10 rats for each, first group was i.p injected with normal saline and used as a normal groups. The other four group were injected i.p with 200mg/kg DENA. Two weeks later animals were orally administered 3ml/kg CCl4 once a week for 8 successive weeks. At the end of 8 th week animals were divided into the following groups: Normal group, control group (hepatocellular carcinoma induced), combretastatin (200mg/kg) i.p treated group, combretastatin (100 mg/kg) i.p + vincristine (25 mg/kg) i.p treated group and vincristine (50 mg/kg) i.p treated group. The following parameters were assessed GSH, MDA, AFP, ALT, AST, tissue carbonyl content, number of hepatic nodules, histopathological examination of the hepatic tissue, tubulin inhibition in the hepatic tissue and the relative hepatic weight. In vitro study human hepatocarcinoma cell line (HepG2) were used to evaluate the cytotoxic and tubulin protein inhibitory effects of the tested drugs. Results The results of the in vivo study revealed that combretastatin, combretastatin + vincristine and vincristine groups showed a significant decrease in GSH, AFP, number of hepatic nodules, ALT, AST and tubulin concentration in the hepatic tissue compare to the control group. Moreover the co‐administration of combretastatin with vincristine showed a significant increment in these parameters compared to single administration of combretastatin or vincristine, also MDA concentration and tissue carbonyl content concentrations were significantly increased compared to control group. On the other hand tubulin concentration and the relative hepatic weight were significantly less than control group. Also the results of the in vitro study revealed that both combretastatin and vincristine showed significant cytotoxic and tubulin inhibitory effects, while these effects were significantly enhanced by simultaneous administration of both drugs. Conclusion combretastatin showed a promising anticancer activity against hepatocellular carcinoma by three mechanisms; tubulin inhibition leading to hepatic tumor blood supply shutdown, decrease reduced glutathione concentrations and oxidative stress generation. Furthermore these effects were greatly enhanced by co‐administration with vincristine. Moreover the present study suggests that we can greatly enhance the anti‐cancer activity of narrow therapeutic windows drugs such as vincristine by co‐administration with combretatstatin leading to fewer side effects.