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Antitumor and anticytopenic effect of propolis and related polyphenolic compounds in combination with chemotherapeutic irinotecan

Effects of ethanolic extract of propolis (EEP), water-soluble derivate of propolis (WSDP), quercetin and naringin combined with anticancer drug irinotecan on the Ehrlich ascites tumor (EAT) in Swiss albino mice and cell lines (human larynx carcinoma HEp2 and resistant VK-2) in vitro were investigated. Test components (100 mg kg-1) and/or irinotecan (50 mg kg-1) were given intraperitoneally prior or after the intraperitonel injection of EAT (2 x106) cells. Antitumor, genotoxic, hemostimulative and immunomodulatory effects were investigated. We found complete abrogation of tumor growth and survival of 50% animals treated preventively with irinotecan combined with WSDP and EEP. When given therapeutically combined treatment with test components and irinotecan increased life span in all tested groups. Total number of cells present in the peritoneal cavity was significantly (p<0.05) reduced in EAT-bearing mice treated preventively or curatively with test components combined with irinotecan, indicating synergistic cytotoxic effects. In treated mice the number of polymorphonuclear (PMN) cells in the peritoneal cavity was significantly (p<0.05) increased as well as the number of macrophages in combined treatments. WSDP combined with irinotecan in preventive and EEP combined with irinotecan in therapeutic treatment increased the macrophage spreading activity. Propolis (100 &#61549; g ml-1) and flavonoids (100 &#61549; M) decreased function of P-gp of HEp2 cells, while this effect in resistant VK-2 cells was slightly increased. All test compounds combined with irinotecan in concentration of 1 and 10 &#956; M decreased activity of P-gp pumps. On the other hand all test compounds combined with vincristine 0.05 &#956; M showed enhanced P-gp activity ; while naringin and quercetin combined with vincristine 0.5 &#61549; M decreased activity of P-gp. These results suggested that propolis and flavonoids can modulate P-gp function and that they could be used in some combination as safe and potent MDR reversing agents in clinical chemotherapy. EEP and naringin significantly (p<0.05) decreased viability of HEp2 cells. WSDP, narigin and quercetin combined with irinotecan 10 &#61549; M significantly (p<0.05) decreased viability of cells. Moreover, test compounds when given preventively and/or therapeutically increased DNA protection of leukocytes, hepatocytes and kidney cells from damages caused by toxic metabolites of irinotecan as detected by alkaline comet assay and micronucleus assay. To conclude, the results of present study suggest that clinical trials using a WSDP, EEP, quercetin and naringin combined with cytostatic drugs may be beneficial in maximizing antitumor activity and minimizing post-chemotherapeutic reactions.

Propolis; flavonoids; irinotecan; tumor resistance; P-gp pumps activity

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