Abstract
Abstract Purpose: Chemotherapy using antitumor agents plays an important role in clinical cancer therapy. Among the treatments involving antitumor agents, the enhancement of antitumor activity was observed by combined chemotherapy. We have shown previously that some amino acids included theanine, taurine and anserine et al. as food components, increased doxorubicin (DOX) induced antitumor effect in vitro and in vivo. These effects by combined amino acids have depended on the increased DOX concentration in the tumor cells. Furthermore, these suppressions of DOX efflux by theanine and taurine were caused by the inhibitions of glutamate transporter and taurine transporter, respectively. The effect of anserine on DOX influx might connect with dipeptide transporter. Thus, other amino acid and unique peptides may act to DOX transport. In this study, the effects of cyclodipeptide on the transport of DOX and its cytotoxicity on tumor cell were clarified. Methods: Cyclo-leucine-proline (cyclo-Leu-Pro), cyclo-phenylalanine-proline (cyclo-Phe-Pro) and cyclo-glycine-proline (cyclo-Gly-Pro) as cyclodipeptide was used in this study. In transport of DOX, DOX influx or efflux was determined with combined cyclodipeptide in M5076 ovarian sarcoma cells or P388 leukemia cells. DOX concentration in tumor cell was measured using spectrofluorometer (Ex. 470 nm, Em. 580 nm). The cytotoxic study of DOX with combined cyclodipeptide was performed using WST-8. Results and Discussion: Cyclo-Phe-Pro and cyclo-Gly-Pro did not affect DOX influx and efflux in M5076 ovarian sarcoma cells and P388 leukemia cells. By combined cyclo-Leu-Pro, DOX influx into both M5076 ovarian sarcoma cells and P388 leukemia cells changed, compared to that of DOX only group. Into M5076 ovarian sarcoma, cyclo-Leu-Pro had strong effect in increased DOX influx in particular. And cyclo-Leu-Pro showed a tendency to suppress DOX efflux from M5076 ovarian sarcoma. In this studies of influx and efflux, concentration of cyclo-Leu-Pro existed optimum amount for increased DOX concentration in tumor cells. It is expected that cyclo-Leu-Pro induces the increment of DOX concentration in the tumor in vivo. DOX had the cytotoxic effects on M5076 ovarian sarcoma cells or P388 leukemia cells in culture. The combined cyclo-Leu-Pro with DOX increased cytotoxic effect, compared to that in the DOX alone group. In conclusion, cyclo-Leu-Pro has increased effect on DOX influx and inhibited effect on DOX efflux, and DOX induced cytotoxicity. It is expected that the combined cyclo-Leu-Pro will improve cancer chemotherapy by DOX. Moreover, cyclo-Leu-Pro may be help to prevent adverse effect since it will be able to decrease DOX dose. Citation Format: Ikumi Sugiyama, Yasuyuki Sadzuka. The effects of cyclodipeptide on the transport of doxorubicin and its cytotoxicity on tumor cell [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2139. doi:10.1158/1538-7445.AM2017-2139
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