Transport and cytotoxicity of paclitaxel, docetaxel, and novel taxanes in human breast cancer cells
Language English Country Germany Media print-electronic
Document type Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
CA103314
NCI NIH HHS - United States
GM42978
NIGMS NIH HHS - United States
- MeSH
- Time Factors MeSH
- Drug Resistance, Neoplasm MeSH
- Docetaxel MeSH
- Doxorubicin pharmacology MeSH
- Antineoplastic Agents, Phytogenic pharmacology MeSH
- Inhibitory Concentration 50 MeSH
- Humans MeSH
- Membrane Transport Proteins genetics metabolism MeSH
- RNA, Messenger metabolism MeSH
- Cell Line, Tumor MeSH
- Breast Neoplasms MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 antagonists & inhibitors genetics metabolism MeSH
- Paclitaxel pharmacology MeSH
- Multidrug Resistance-Associated Protein 2 MeSH
- Multidrug Resistance-Associated Proteins genetics metabolism MeSH
- Antibiotics, Antineoplastic pharmacology MeSH
- Taxoids pharmacology MeSH
- Verapamil pharmacology MeSH
- Cell Survival drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Comparative Study MeSH
- Names of Substances
- ABCC2 protein, human MeSH Browser
- Docetaxel MeSH
- Doxorubicin MeSH
- Antineoplastic Agents, Phytogenic MeSH
- Membrane Transport Proteins MeSH
- RNA, Messenger MeSH
- ATP Binding Cassette Transporter, Subfamily B, Member 1 MeSH
- Paclitaxel MeSH
- Multidrug Resistance-Associated Protein 2 MeSH
- Multidrug Resistance-Associated Proteins MeSH
- Antibiotics, Antineoplastic MeSH
- SB T-1214 MeSH Browser
- Taxoids MeSH
- Verapamil MeSH
The resistance of tumors to classic taxanes (paclitaxel and docetaxel) presents problems in chemotherapy. Thus, new taxanes with higher antitumor activity in resistant tumors are synthesized. This study compared cytotoxicity and transport of paclitaxel and docetaxel with novel taxanes SB-T-1103, SB-T-1214, and SB-T-1216 in adriamycin-sensitive (MDA-MB-435) and -resistant (NCI/ADR-RES) human breast cancer cells. The cell lines examined differ in adriamycin transport, suggesting different expression of ABC membrane transporters. Reverse transcription-polymerase chain reaction revealed that NCI/ADR-RES cells expressed high levels of P-glycoprotein mRNA, which was absent in MDA-MB-435 cells, while the opposite was true for MRP2 mRNA. Both cell lines shared or differently expressed eight other ABC transporters and LRP. NCI/ADR-RES cells were 1,000-fold more resistant to paclitaxel and 600-fold more resistant to docetaxel in MTT assay than MDA-MB-435 cells, but almost equally sensitive to SB-T-1103, SB-T-1214, and SB-T-1216. This complied with the fact that NCI/ADR-RES cells absorbed almost 20-fold less [14C]paclitaxel, about 7-fold less docetaxel, and almost equal amounts of SB-T-1103, SB-T-1214, and SB-T-1216 as the MDA-MB-435 cells. Verapamil increased uptake of [14C]paclitaxel by NCI/ADR-RES cells 7-fold and decreased its efflux 2.5-fold; in contrast, it weakly influenced uptake and increased the efflux in MDA-MB-435 cells. SB-T-1103 and SB-T-1216 did not influence transport of paclitaxel, but SB-T-1214 decreased [14C]paclitaxel uptake in both cell lines indicating inhibition of uptake. This suggests that the novel taxanes are not inhibitors of P-glycoprotein. However, novel taxanes exert much higher activity on resistant tumor cells than classic taxanes and seem to be potential drugs for therapy in taxane-resistant tumors.
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