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 imatinibinduced 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.

Autophagy Inhibition Promotes Gambogic Acid-induced Suppression of Growth and Apoptosis in Glioblastoma Cells

“…Several important anticancer agents, including arsenic trioxide, 5-FU, tamoxifen, imatinib, paclitaxel and cisplatin , has been shown to induce atutophagy in a few types of cancer cells (Bursch et al, 1996;Paglin et al, 2001;Carew et al, 2007;Shingu et al, 2009;Goussetis et al, 2010;Liu et al, 2011;Xi et al, 2011;Yang et al, 2011). In the present study, we have demonstrated that autophagy is also induced in glioblastoma cells during the course of GA treatment.…”

“…The induction of these two different types of autophagy may depend on different stimuli and cell types. Although the exact mechanisms of the two autophagy are not clear, it seems that the suppression of cytoprotective autophagy and the enhancement of cytotoxic autophagy might augment cytotoxic effects of anticancer drugs (Kanzawa et al, 2004;Takeuchi et al, 2005;Shingu et al, 2009;Pandey and Chandravati, 2012). In this study, we found that GA induced an apparent autophagy in GBM cells, and inhibition of autophagy could lead to enhancement of GA-mediated cytotoxicity through increasing apoptosis.…”

Autophagy protects breast cancer cells from epirubicin-induced apoptosis and facilitates epirubicin-resistance development

“…Moreover, inhibition of autophagy by BAF enhanced imatinib induced-cytotoxicity. 34 Although our study as well as other previous studies have observed that the inhibition of autophagy with BAF in the late stage increased the caspase-9 activity and autophagy was inhibited with sh-BECN1 (Fig. 3E, red).…”

“…Recently, some studies have reported that inhibiting autophagy with BAF boosts the cytotoxicity of cancer therapeutic agents. 19,34 Our results showed that MCF-7 cells exhibited significant toxic effects after exposure to 5, 10 and 20 nM BAF over 24 h, while no toxic effects were detected when exposed to 1 nM BAF for 72 h (Fig. 4A).…”

Autophagy-active beclin-1 correlates with favourable clinical outcome in non-Hodgkin lymphomas

“…18 Not surprising, autophagy has been shown to have an active role in cancer development and progression, 19,20 as well as in the cytotoxic response to anticancer drugs. [21][22][23][24] In T lymphocytes autophagy has been implicated in survival and cytokine-induced proliferation, as well as in cell death after growth factor-withdrawal. 25,26 The expression level of beclin-1 changes during T and B lymphocyte maturation and T-cell activation.…”