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Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein

Leukemia volume 15, pages 1377–1387 (2001)Cite this article

Abstract

The appearance of multidrug-resistant (MDR) proteins or the acquisition of a defective apoptotic programme are major drawbacks in the treatment of cancers since both induce a resistance to classical chemotherapy. However, a link between the two mechanisms has not, as yet, been clearly established. In this study, HL-60 cells cultured in the continual presence of a sub-lethal dose of doxorubicin (dox; HL-60/Dox) were used as a model to study acquired chemoresistance. During the induction of chemoresistance, the appearance of a functional P-glycoprotein (P-gp), in addition to the expression of anti-apoptotic Bcl-2, Bcl-XL and pro-apoptotic Bax proteins was assessed. Parental cells which are sensitive to dox, have no P-gp activity and express Bcl-2 and Bax. After 4 weeks of treatment, a functional P-gp was detected in HL-60/Dox cells. In addition, the synthesis of Bcl-2 appeared to be replaced by Bcl-XL while that of Bax remained unchanged. These cells were also resistant to apoptosis induced by both P-gp and non-P-gp substrates. This inability to induce apoptosis could have resulted from the induction of the expression of the inhibitor of apoptosis protein (XIAP). Our data show that acquired chemoresistance could involve a parallel induction of P-gp and an impairment of the apoptotic pathway.

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Acknowledgements

This study was sponsored by a grant from the ‘Le comité departemental de la Loire Atlantique de la Ligue Nationale contre le Cancer’ and the ‘Association pour la Recherche sur le Cancer, No.5402’. MC was a recipient of a grant from ‘La Ligue Nationale contre le Cancer’. We thank Pr R Bataille and Dr Ph Juin for critical reading of this manuscript. Pr Fumoleau and Dr Cuillière are thanked for their constant support throughout this project.

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  1. INSERM U419, Nantes, France

    M Campone, F Vavasseur, MT Le Cabellec, K Meflah, FM Vallette & L Oliver

  2. Centre Régional de Lutte Contre le Cancer ‘Nantes-Atlantique’, Nantes, France

    M Campone

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Campone, M., Vavasseur, F., Le Cabellec, M. et al. Induction of chemoresistance in HL-60 cells concomitantly causes a resistance to apoptosis and the synthesis of P-glycoprotein. Leukemia 15, 1377–1387 (2001). https://doi.org/10.1038/sj.leu.2402222

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