Enhancement of doxorubicin concentration in the M5076 ovarian sarcoma cells by cucurbitacin E co-treatment.
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.
Sadzuka
Yasuyuki
Y
School of Pharmacy, Iwate Medical University, Shiwa-gun, Iwate 028-3694, Japan. ysadzuka@iwate-med.ac.jp
Hatakeyama
Haruna
H
Sonobe
Takashi
T
D000818:Animals; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000378:metabolism*; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D012509:Sarcoma / Q000188:drug therapy / Q000378:metabolism*; D014315:Triterpenes / Q000008:administration & dosage* / Q000378:metabolism*
D011422:Propionates; D011804:Quinolines; D014315:Triterpenes; C059141:verlukast; D004317:Doxorubicin; C102326:cucurbitacin E