Extensive intracellular accumulation of ID-6105, a novel anthracycline, in SK-OV-3 ovarian cancer cells.

Abstract

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.

• Authors: Dae Hwan Shin, Kyu Seok Choi, Sang-Ae Park, Byung Suk Cho, Hong-Sub Lee, Jung-Su Ryu, Tae-Yong Kim, Chong-Kil Lee, Sukgil Song, Youn Bok Chung
• Journal: Archives of pharmacal research (Arch Pharm Res) Vol. 31 Issue 10 Pg. 1355-61 (Oct 2008) ISSN: 0253-6269 [Print] Korea (South)
• PMID: 18958428 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 11-hydroxyaclacinomycin X
• Antibiotics, Antineoplastic
• Antineoplastic Agents
• Indicators and Reagents
• Aclarubicin
• Doxorubicin

Topics

• Aclarubicin (analogs & derivatives, metabolism, pharmacology)
• Antibiotics, Antineoplastic (metabolism, pharmacology)
• Antineoplastic Agents (metabolism, pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Chromatography, High Pressure Liquid
• Doxorubicin (metabolism, pharmacology)
• Female
• Humans
• Indicators and Reagents
• Ovarian Neoplasms (drug therapy, metabolism, pathology)