nsc-106399 and Sarcoma

Cucurbitacin E increases the doxorubicin (DOX) level in M5076 ovarian sarcoma via suppressed DOX efflux in vitro. An increase in DOX induced antitumor activity by cucurbitacin E in vivo has been reported previously. This paper attempts to clarify the mechanism of cucurbitacin E induced increments in the antitumor activity of DOX. MK-571, a multidrug resistance associated protein (MRP) inhibitor, significantly suppressed DOX efflux from M5076 ovarian sarcoma cells. The combination of cucurbitacin E with MK-571 also inhibited DOX efflux, whereas the efficacy was the same in each treatment. Namely, the inhibition of DOX efflux by cucurbitacin E was expected to be related to MRP. In contrast, it appeared that the effect of cucurbitacin E on DOX permeability did not relate to P-gp. The cucurbitacin E co-treatment significantly increased DOX concentration in the tumor within a short time after DOX administration, whereas the same treatment decreased the DOX concentration in normal tissues. The different effects of cucurbitacin E between tumor and normal tissues was speculated to be related to differences in DOX transport system on cell membrane. In DOX therapy, cucurbitacin E co-treatment was expected to increase DOX induced antitumor activity without an increase in adverse reactions due to DOX.

Topics: Animals; Cell Line, Tumor; Doxorubicin; Drug Synergism; Drug Therapy, Combination; Female; Leukemia P388; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Ovarian Neoplasms; Propionates; Quinolines; Sarcoma; Triterpenes

We screened various food components for their ability to inhibit doxorubicin (DOX) permeability in tumor cells in vitro with the aim of finding novel modulators. Capsaicin did not change DOX permeability in the tumor cells, although the capsaicin derivatives gingerol and ferulic acid tended to promote DOX efflux. Combinations of these components with DOX were also not effective. In contrast, cucurbitacin E significantly promoted DOX influx into tumor cells and increased DOX concentration in tumor cells. Furthermore, combined cucurbitacin E significantly suppressed DOX efflux from tumor cells and was shown to maintain the DOX level in tumor cells. It was also confirmed that the combination of cucurbitacin E with DOX resulted in effective cytotoxicity for tumor cells in culture. Additionally, the combination of cucurbitacin E and DOX showed increased cytotoxicity when compared to each treatment alone. In vivo, DOX alone treatment did not change the time course of tumor size or tumor weight of M5076 ovarian sarcoma, compared to control levels. In contrast, the combination of cucurbitacin E with DOX resulted in decreased tumor size and tumor weight, compared to that in DOX alone group, indicating effective antitumor activity. In conclusion, the combination of cucurbitacin E with DOX may be an effective tool with treated application in the cancer chemotherapy.

Topics: Animals; Antibiotics, Antineoplastic; Biological Transport; Capsaicin; Carcinoma, Ehrlich Tumor; Catechols; Cell Line, Tumor; Coumaric Acids; Doxorubicin; Drug Screening Assays, Antitumor; Drug Synergism; Fatty Alcohols; Female; Male; Mice; Neoplasm Transplantation; Ovarian Neoplasms; Permeability; Sarcoma; Triterpenes