Relationship between cytotoxicity, drug accumulation, DNA damage and repair of human ovarian cancer cells treated with doxorubicin: modulation by the tiapamil analog RO11-2933.
The effect of N-(3,4-dimethoxyphenyl) N-methyl-2-(naphthyl)-m-dithiane-2-propylamine hydrochloride (RO11-2933), an analog of the calcium channel blocker tiapamil, on doxorubicin (DOX)-induced cytotoxicity and DNA damage in human ovarian cancer cells sensitive and resistant to DOX was investigated. A2780-DX2, A2780-DX3, and A2780-DX6 cell sublines were characterized by 7-, 26-, and 48-fold resistance after 2 h DOX exposure and 30-, 50-, and 500-fold resistance after 72 h DOX exposure, respectively. Increased drug efflux resulting in a lower intracellular drug accumulation, decreased DOX-induced DNA single-strand breaks (DNA SSBs), and rapid DNA repair correlated with the degree of resistance. In addition, DNA SSBs were rapidly repaired within 8 h in A2780-DX3 cells, whereas no significant repair of DNA SSBs was observed in sensitive cells. In comparison with verapamil, RO11-2933 was found to reverse DOX resistance at lower and nontoxic concentrations (2 microM as compared with 10 microM verapamil). This reversion was complete in cells with a low degree of resistance (A2780-DX1 and A2780-DX2) but partial in highly resistant cells (A2780-DX3 and A2780-DX6), and continuous exposure to RO11-2933 was essential for optimal reversal of drug resistance. Interestingly, RO11-2933 was found to inhibit the repair of DNA SSBs induced by DOX but not those induced by X-ray. These results suggest that the potentiation of DNA SSBs and the specific inhibition of DNA repair by RO11-2933 in multidrug-resistant cells could be of particular value in overcoming MDR in the clinic.
Alaoui Jamali
M A
MA
Grace Cancer Drug Center, Roswell Park Memorial Institute, Buffalo, NY 14263.
Yin
M B
MB
Mazzoni
A
A
Bankusli
I
I
Rustum
Y M
YM
D002121:Calcium Channel Blockers / Q000627:therapeutic use* / Q000633:toxicity; D002460:Cell Line / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects* / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D004347:Drug Interactions; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011437:Propylamines / Q000627:therapeutic use* / Q000633:toxicity; D013976:Tiapamil Hydrochloride; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects
D002121:Calcium Channel Blockers; D004273:DNA, Neoplasm; D011437:Propylamines; D004317:Doxorubicin; D013976:Tiapamil Hydrochloride