Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells
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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.
KeywordsBrain tumor Chemotherapy P-glycoprotein Temozolomide Doxorubicin
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).
Compliance with ethical standards
Conflict of Interest
The authors declare that they have no competing interests.
- 3.Caraglia M, Addeo R, Costanzo R, Montella L, Faiola V, Marra M, Abbruzzese A, Palmieri G, Budillon A, Grillone F, Venuta S, Tagliaferri P, Del Prete S (2006) Phase II study of temozolomide plus pegylated liposomal doxorubicin in the treatment of brain metastases from solid tumours. Cancer Chemother Pharmacol 57(1):34–39PubMedCrossRefGoogle Scholar
- 4.Ananda S, Nowak AK, Cher L, Dowling A, Brown C, Simes J, Rosenthal MA (2011) Phase 2 trial of temozolomide and pegylated liposomal doxorubicin in the treatment of patients with glioblastoma multiforme following concurrent radiotherapy and chemotherapy. J Clin Neurosci 18(11):1444–1448PubMedCrossRefGoogle Scholar
- 13.Dai CL, Tiwari AK, Wu CP, Su XD, Wang SR, Liu DG, Ashby CR Jr, Huang Y, Robey RW, Liang YJ, Chen LM, Shi CJ, Ambudkar SV, Chen ZS, Fu LW (2008) Lapatinib (Tykerb, GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of atp-binding cassette subfamily B member 1 and G member 2. Cancer Res 68(19):7905–7914PubMedPubMedCentralCrossRefGoogle Scholar
- 15.Saito R, Bringas JR, Panner A, Tamas M, Pieper RO, Berger MS, Bankiewicz KS (2004) Convection-enhanced delivery of tumor necrosis factor-related apoptosis-inducing ligand with systemic administration of temozolomide prolongs survival in an intracranial glioblastoma xenograft model. Cancer Res 64(19):6858–6862PubMedCrossRefGoogle Scholar