title: Inhibition of autophagy at a late stage enhances imatinib-induced cytotoxicity in human malignant glioma cells.
abstract: Malignant gliomas are common primary tumors of the central nervous system. The prognosis of patients with malignant glioma is poor in spite of current intensive therapy and thus novel therapeutic modalities are necessary. Imatinib mesylate, a tyrosine kinase inhibitor, is effective in the therapy of tumors including leukemias but not as a monotherapy for malignant glioma. Recently, it is thought that the adequate modulation of autophagy can enhance efficacy of anticancer therapy. The outcome of autophagy manipulation, however, seems to depend on the autophagy initiator, the combined stimuli, the extent of cellular damage and the type of cells, and it is not yet fully understood how we should modulate autophagy to augment efficacy of each anticancer therapy. In this study, we examined the effect of imatinib with or without different types of autophagy inhibitors on human malignant glioma cells. Imatinib inhibited the viability of U87-MG and U373-MG cells in a dose dependent manner and caused nonapoptotic autophagic cell death. Suppression of imatinib-induced autophagy by 3-methyladenine or small interfering RNA against Atg5, which inhibit autophagy at an early stage, attenuated the imatinib-induced cytotoxicity. In contrast, inhibition of autophagy at a late stage by bafilomycin A1 or RTA 203 enhanced imatinib-induced cytotoxicity through the induction of apoptosis following mitochondrial disruption. Our findings suggest that therapeutic efficiency of imatinib for malignant glioma may be augmented by inhibition of autophagy at a late stage, and that appropriate modulation of autophagy may sensitize tumor cells to anticancer therapy.
authors.affiliation: Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. tshingu@mdanderson.org
authors.forename: Takashi
authors.initials: T
authors.lastname: Shingu
authors.forename: Keishi
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Oliver
authors.initials: O
authors.lastname: Bögler
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Akiyama
authors.forename: Kouzo
authors.initials: K
authors.lastname: Moritake
authors.forename: Naoki
authors.initials: N
authors.lastname: Shinojima
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Tamada
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Yokoyama
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5; D001549:Benzamides; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D020935:MAP Kinase Signaling System / Q000187:drug effects; D018942:Macrolides / Q000494:pharmacology*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors; D017239:Paclitaxel / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C502778:ATG5 protein, human; D000970:Antineoplastic Agents; D000071187:Autophagy-Related Protein 5; D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D010879:Piperazines; D011743:Pyrimidines; C534504:RTA 203; C025946:3-methyladenine; C040929:bafilomycin A1; D000068877:Imatinib Mesylate; D048049:Extracellular Signal-Regulated MAP Kinases; D000225:Adenine; D017239:Paclitaxel; D002945:Cisplatin