Synergistic Genotoxic Effects and Modulation of Cell Cycle by Ginger Ethanolic Extracts in Adjunct to Doxorubicin in Human Lymphocytes In Vitro.

Background: Several natural phytochemicals are increasingly used, as an adjunct to chemotherapy, to reduce drug adverse effects. Zingiber officinale rhizome (ginger) product has been reported to be effective against nausea and vomiting in patients receiving emetogenic chemotherapy such as cisplatin/doxorubicin (DXR). In addition, its ethanolic extract of Zingiber officinale rhizome (EEZOR) has been reported to possess anticarcinogenic properties. However, the mechanism for anticancer activity of ginger especially when used in combination with chemotherapy has not well elucidated, one of its possible mechanisms might involve its genotoxicity. Objective: To investigate genotoxic and cytotoxic potentials of EEZOR alone and EEZOR pretreatments followed by 0.1 mcg/ ml DXR, a genotoxic chemotherapeutic agent in human lymphocytes by sister chromatid exchange (SCE) assay in vitro. The effect on cell cycle kinetics was also explored. Material and Method: Human lymphocytes were treated with EEZOR alone at 25-500 mcg/ml and EEZOR pretreated at 12.5-200 mcg/ml followed by 0.1 mcg/ml DXR. SCE levels and cell cycle kinetics were evaluated. Results: EEZOR significantly induced biphasic SCE at 50 and 400 mcg/ml (p<0.05). However, cytotoxicity manifested at 500 mcg/ml. All EEZOR pretreatments at 12.5, 25, 50, and 100 mcg/ml, except at 200 mcg/ml, prior to DXR, moderately enhanced DXR-induced genotoxicity by 1.3 times (p<0.05). Both EEZOR alone and EEZOR prior to DXR at certain concentrations delayed cell cycle. Conclusion: At specific doses, EEZOR could induce genotoxicity and in pretreatments could moderately enhance DXRinduced genotoxicity and delay cell cycle. This finding suggests that dosage use of EEZOR needs to be adjusted for long-term safety. In addition, EEZOR in adjunct to DXR might have potential benefits not only as an emetic agent but also in chemotherapy. Further in vivo animal and human studies to support this evidence is essentially needed. Keywords: Cell cycle, Genotoxicity, Doxorubicin, Human lymphocyte, Sister chromatid exchange, Zingiber officinale rhizome