Inhibition of autophagy at a late stage enhances imatinib‐induced cytotoxicity in human malignant glioma cells
Open accessAbstract
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. © 2008 Wiley‐Liss, Inc.
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In treatment regimens utilizing cytotoxic drugs combined with agents that inhibit autophagy at an early stage, the cytotoxic effect was hindered.
“It has been reported that in treatment regimens utilizing cytotoxic drugs combined with agents that inhibit autophagy at an early stage, the cytotoxic effect was hindered.”
From AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields) (2018) · cites this paper as [45]
Inhibition at late stages in autophagy (e.g., using bafilomycin or CQ) led to enhanced efficacy of the same treatment as reflected by increased cytotoxic effect.
“On the other hand, inhibition at late stages in autophagy (e.g., using bafilomycin or CQ) led to enhanced efficacy of the same treatment as reflected by increased cytotoxic effect, suggesting that accumulation of autolysosomes is necessary for cell death induction45,46.”
From AMPK-dependent autophagy upregulation serves as a survival mechanism in response to Tumor Treating Fields (TTFields) (2018) · cites this paper as [45]
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- Authors
- Shingu, T., Fujiwara, K., Bögler, O., Akiyama, Y., Moritake, K., Shinojima, N., Tamada, Y., Yokoyama, T., & Kondo, S.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Shimane University (JP)
- Corresponding author
- Shingu, Takashi
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2008-12
- Volume
- 124
- Issue
- 5
- Pages
- 1060-1071
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2022040605
- Cited by
- 174
- References
- 47
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 7 · 2020: 9 · 2019: 12 · 2018: 9 · 2017: 3 · 2016: 14 · 2015: 14 · 2014: 20 · 2013: 22 · 2012: 15
- FWCI
- 8.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- high-grade glioma, imatinib, autophagy inhibition, autophagic cell death, apoptosis, bafilomycin A1, 3-methyladenine, ATG5, U87 cells, U373 cells, tyrosine kinase inhibitors, combination therapy, mitochondrial disruption
- MeSH terms
- Imatinib Mesylate, Autophagy-Related Protein 5, Adenine, Antineoplastic Agents, Autophagy, Benzamides, Brain Neoplasms, Cisplatin, Glioma, Humans, Microtubule-Associated Proteins, Piperazines, Pyrimidines, Paclitaxel, Macrolides, Bridged Bicyclo Compounds, Heterocyclic, MAP Kinase Signaling System, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, Membrane Potential, Mitochondrial
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