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Relationship between cytotoxicity, drug accumulation, DNA damage and repair of human ovarian cancer cells treated with doxorubicin: modulation by the tiapamil analog RO11-2933

  • Drug Accumulation, DNA Damage, Tiapamil Analog, RO11-2933, Doxorubicin, Cytotoxicity
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Summary

The effect ofN-(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 μM as compared with 10 μM 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.

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Abbreviations

RO11-2933:

N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl)-m-dithiane-2-propylamine hydrochloride

DOX:

doxorubicin-HCl

SSBs:

single-strand breaks

MDR:

multidrug resistance

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Author notes

  1. Ming-biao Yin (Visiting Scientist)

    Present address: Chinese Academy of Medical Sciences, Beijing, China

  2. Alessandra Mazzoni

    Present address: Servizio di Farmacologia, Istituto Nazionale per la Ricerca sul Cancro, viale Benedetto XV 10, 16132, Genova, Italy

Authors and Affiliations

  1. Grace Cancer Drug Center, Roswell Park Memorial Institute, 666 Elm Street, 14263, Buffalo, NY, USA

    M. Abdellah Alaoui Jamali, Ming-biao Yin (Visiting Scientist), Alessandra Mazzoni, Issam Bankusli & Youcef M. Rustum

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  1. M. Abdellah Alaoui Jamali
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  2. Ming-biao Yin
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  3. Alessandra Mazzoni
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  4. Issam Bankusli
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  5. Youcef M. Rustum
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This work was supported in part by CA 18420 and CA 21071

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Alaoui Jamali, M.A., Yin, Mb., Mazzoni, A. et al. Relationship between cytotoxicity, drug accumulation, DNA damage and repair of human ovarian cancer cells treated with doxorubicin: modulation by the tiapamil analog RO11-2933. Cancer Chemother. Pharmacol. 25, 77–83 (1989). https://doi.org/10.1007/BF00692343

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  • DOI: https://doi.org/10.1007/BF00692343

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