Differential interactions of Pgp inhibitor thaliblastine with adriamycin, etoposide, taxol and anthrapyrazole CI941 in sensitive and multidrug-resistant human MCF-7 breast cancer cells.
The reversing effect of p-glycoprotein (Pgp) inhibitors on the multidrug resistance (MDR) phenotype is well established in a variety of MDR cell lines. The interactions of these inhibitors with individual MDR drugs in the respective parental lines, however, is less documented. This kind of information is not only essential for understanding of the outcome of clinical trials for MDR modulation in heterogeneous tumor populations but also important for evaluating of new Pgp blockers. Interaction of the Pgp inhibitor, thaliblastine (TBL), with several MDR drugs was therefore investigated in sensitive human breast cancer cell line (MCF-7) as well as adriamycin (AdR) selected MDR subline MCF/AdR. While the resistance to anthrapyrazole CI941 was completely overcome by simultaneous exposure to TBL (8 microM) in a 48 h exposure MTT assay compared with MCF-7 cells exposed to the same combination, only partial reversal was achieved in the case of AdR and etoposide (VP-16), but 240-fold hypersensitivity (or collateral sensitivity) was obtained in the MCF/AdR cells treated with taxol plus TBL, with IC50s of 0.10 +/- 0.03 microM and 24.6 +/- 5.0 microM in the resistant and sensitive cell lines, respectively. In the parental MCF-7 cells, on the other hand, no change of AdR cytotoxicity by simultaneous exposure to TBL was observed. There was an enhancement of CI941 cytotoxicity but an antagonism against taxol and VP-16 obtained upon addition of TBL to the treatment with the drugs in the MCF-7 parental cell line. Our results demonstrate that while TBL can overcome the resistance to each of the MDR drugs studied in MCF/AdR cells, albeit to a different extent varying from the partial reversal to the hypersensitivity, TBL co-exposure does not uniformly increase the cytotoxicity of these drugs in the parental MCF-7 cells.
Chen
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Dana-Farber Cancer Institute, Division of Cancer Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Teicher
B A
BA
Frei
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E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000880:Anthraquinones / Q000378:metabolism; D000970:Antineoplastic Agents / Q000378:metabolism*; D001060:Aporphines / Q000378:metabolism*; D044182:Benzylisoquinolines; D001943:Breast Neoplasms / Q000378:metabolism*; D004317:Doxorubicin / Q000378:metabolism; D004347:Drug Interactions; D005047:Etoposide / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000378:metabolism*; D017239:Paclitaxel / Q000378:metabolism; D011720:Pyrazoles / Q000378:metabolism; D047069:Pyrazolones; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000880:Anthraquinones; D000970:Antineoplastic Agents; D001060:Aporphines; D044182:Benzylisoquinolines; D007546:Isoquinolines; D011720:Pyrazoles; D047069:Pyrazolones; C050637:losoxantrone; D005047:Etoposide; D004317:Doxorubicin; C073328:thalicarpine; D017239:Paclitaxel