Enhancement of doxorubicin-induced antitumor activity and reduction of adverse reactions by cucurbitacin I

Abstract Using the concept of biochemical modulation, we have previously shown that cucurbitacin E enhances doxorubicin (DOX)-induced antitumor activity. Unlike cucurbitacin E, another derivative called cucurbitacin I has antioxidative ability. However, it is feared that the antioxidative ability of cucurbitacin I will improve DOX-induced adverse reactions whereas reduce its antitumor activity by cucurbitacin I induced suppression on DOX generated reactive oxygen species. In the present study, compared to DOX treatment alone, a combination of cucurbitacin I and DOX produced a significant increase in cytotoxicity (M5076 ovarian sarcoma cell) in vitro and decreased tumor size and weight with a significant increase in DOX concentration in the tumor, using M5076 ovarian sarcoma bearing mice in vivo . Furthermore, the combination significantly suppressed the DOX-induced increase in lipid peroxide (LPO) level in the heart, which is considered to be an index of DOX-induced cardiotoxicity. Thus, it was surmised that cucurbitacin I was responsible for reducing heart damage. It was speculated that the radical trapping effect of cucurbitacin I on free radical lipids directly suppressed the increase in LPO level and DOX-induced cardiotoxicity. Although cucurbitacin I did not have a significant effect on the DOX influx system, it suppressed DOX efflux and increased DOX concentration in tumor cells. In M5076 ovarian sarcoma cells, multidrug resistance-associated protein inhibitors significantly inhibited DOX efflux, similar to cucurbitacin I. Furthermore, cucurbitacin I significantly decreased glutathione (GSH) levels in tumors, similar to DL-buthionine sufoximine (an inhibitor of GSH synthesis). Thus, it is speculated that cucurbitacin I acted via both routes. Based on these results, we conclude that cucurbitacin I increases DOX-induced antitumor activity with enhanced cytotoxicity and elevates DOX levels, thereby inhibiting DOX efflux from tumor cells.