title: Temozolomide reverses doxorubicin resistance by inhibiting P-glycoprotein in malignant glioma cells.
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.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan. ryuta@nsg.med.tohoku.ac.jp.
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan.
authors.forename: Ichiyo
authors.initials: I
authors.lastname: Shibahara
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sugiyama
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan.
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, 1-1 Seiryo-cho, Aobaku, Sendai, 980-8574, Miyagi, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051381:Rats; D016019:Survival Analysis; D000077204:Temozolomide
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D003606:Dacarbazine; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D000077204:Temozolomide
keywords: Brain tumor; Chemotherapy; Doxorubicin; P-glycoprotein; Temozolomide