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Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells

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Abstract

Temozolomide is a standard chemotherapy agent for malignant gliomas, but the efficacy is still not satisfactory. Therefore, combination chemotherapy using temozolomide with other anti-tumor compounds is now under investigation. Here we studied the mechanism of the synergistic anti-tumor effect achieved by temozolomide and doxorubicin, and elucidated the inhibitory effect of temozolomide on P-glycoprotein (P-gp). Temozolomide significantly enhanced sensitivity to P-gp substrate in glioma cells, particularly in P-gp-overexpressed cells. Synergetic effects, as determined by isobologram analysis, were observed by combining temozolomide and doxorubicin. Subsequently, flow cytometry was utilized to assess the intracellular retention of doxorubicin in cells treated with doxorubicin with or without temozolomide. Temozolomide significantly increased the accumulation of doxorubicin in these cells. The P-gp adenosine triphosphatase (ATPase) assay showed that temozolomide inhibited the ATPase activity of P-gp. In addition, temozolomide combined with doxorubicin significantly prolonged the survival of 9L intracranial allografted glioma-bearing rats compared to single agent treatment. Collectively, our findings suggest that temozolomide can reverse doxorubicin resistance by directly affecting P-gp transport activity. Combination chemotherapy using temozolomide with other agents may be effective against gliomas in clinical applications.

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology in Japan to R.S. (#26293319).

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Authors and Affiliations

  1. Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan

    Rong Zhang, Ryuta Saito, Ichiyo Shibahara, Shinichiro Sugiyama, Masayuki Kanamori, Yukihiko Sonoda & Teiji Tominaga

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  1. Rong Zhang
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  2. Ryuta Saito
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  3. Ichiyo Shibahara
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  4. Shinichiro Sugiyama
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  6. Yukihiko Sonoda
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  7. Teiji Tominaga
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Correspondence to Ryuta Saito.

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Zhang, R., Saito, R., Shibahara, I. et al. Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells. J Neurooncol 126, 235–242 (2016). https://doi.org/10.1007/s11060-015-1968-x

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  • DOI: https://doi.org/10.1007/s11060-015-1968-x

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