Extensive intracellular accumulation of ID-6105, a novel anthracycline, in SK-OV-3 ovarian cancer cells.
We investigated the anticancer activity of 11-hydroxyaclacinomycin X (ID-6105), a novel anthracycline, on weakly doxorubicin (Dox)-resistant SK-OV-3 ovarian cancer cells, and elucidated the relationship between its anticancer activity and accumulation in cells compared with those of Dox. Accumulation of ID-6105 in the cells was time-and concentration-dependent, a result of drug-induced cytotoxicity in the cells. SK-OV-3 cells were preloaded with ID-6105 or Dox for 12 h at concentrations ranging from 100 to 2000 nM and then incubated with drug-free medium for 0-48 h. Cell viability was measured using a proliferation-based assay (XTT assay). The inhibitory effects of ID-6105 on cell viability were more pronounced than those of Dox. The IC(50) values of ID-6105 after 24-and 48-h incubation with drug-free medium were 1.58 and 0.084 microM, while those of Dox were 2 and 0.334 microM, respectively. To investigate the relationship between the intracellular levels and the cytotoxic effects of the drugs, we preloaded SKOV-3 cells with ID-6105 or Dox (100-2000 nM) for 12 h and then measured the intracellular levels of drugs by HPLC in drug-free medium for 0-48 h. After preloading the drugs, the intracellular concentrations of ID-6105 at time 0 were 1.3-, 1.8-, and 1.4-fold larger than those of Dox at initial concentrations of 500, 1000, and 2000 nM, respectively. The extent of ID-6105 accumulation in the cells was more pronounced than that of Dox. These findings suggest that ID-6105 effluxed less from the cells than Dox, resulting in its extensive cytotoxicity compared with that of Dox. These results show that accumulation of ID-6105 within tumor cells may be important for the inhibitory effects of this drug in cancer cells. ID-6105 has an antiproliferative effect on SK-OV-3 cells that is due to its cytotoxicity. This effect is more pronounced than that of Dox, and may be attributed to extensive accumulation of ID-6105 in the cells.
Shin
Dae Hwan
DH
National Research Laboratory of PK/PD, CBITRC, Biotechnology Research Institute, College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763, Korea.
Choi
Kyu Seok
KS
Park
Sang-Ae
SA
Cho
Byung Suk
BS
Lee
Hong-Sub
HS
Ryu
Jung-Su
JS
Kim
Tae-Yong
TY
Lee
Chong-Kil
CK
Song
Sukgil
S
Chung
Youn Bok
YB
D015250:Aclarubicin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
C099664:11-hydroxyaclacinomycin X; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D007202:Indicators and Reagents; D015250:Aclarubicin; D004317:Doxorubicin