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Article

Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria

  • Authors:
    • Kovooru Lohitesh
    • Heena Saini
    • Abhilasha Srivastava
    • Sudeshna Mukherjee
    • Aniruddha Roy
    • Rajdeep Chowdhury
  • View Affiliations / Copyright

    Affiliations: Department of Biological Sciences, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan 333031, India, Department of Pharmacy, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan 333031, India
  • Pages: 2787-2796
    |
    Published online on: April 16, 2018
       https://doi.org/10.3892/or.2018.6373
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Abstract

Glioblastoma multiforme (GBM), often referred to as a grade IV astrocytoma, is the most invasive type of tumor arising from glial cells. The main treatment options for GBM include surgery, radiation and chemotherapy. However, these treatments tend to be only palliative rather than curative. Poor prognosis of GBM is due to its marked resistance to standard therapy. Currently, temozolomide (TMZ), an alkylating agent is used for treatment of GBM. However, GBM cells can repair TMZ‑induced DNA damage and therefore diminish the therapeutic efficacy of TMZ. The potential to evade apoptosis by GBM cells accentuates the need to target the non‑apoptotic pathway and/or inhibition of pro‑survival strategies that contribute to its high resistance to conventional therapies. In recent studies, it has been demonstrated that HDAC inhibitors, such as vorinostat (suberoyl anilide hydroxamic acid; SAHA) can induce autophagy in cancer cells, thereby stimulating autophagosome formation. In addition, a lysosomotropic agent such as chloroquine (CQ) can result in hyper‑accumulation of autophagic vacuoles by inhibiting autophagosome‑lysosome fusion, which can drive the cell towards apoptosis. Hence, we postulated that combination treatment with SAHA and CQ may lead to increased formation of autophagosomes, resulting in its hyper‑accumulation and ultimately inducing cell death in GBM cells. In the present study, we demonstrated that CQ co‑treatment enhanced SAHA‑mediated GBM cell apoptosis. Inhibition of the early stage of autophagy by 3‑methyladenine pre‑treatment reduced cell death confirming that apoptosis induced by CQ and SAHA was dependent on autophagosome accumulation. We also demonstrated that autophagy inhibition led to enhanced ROS, mitochondria accumulation and reduced mitochondrial membrane potential resulting in cell death. The present study provides cellular and molecular evidence concerning the combined effect of SAHA and CQ which can be developed as a therapeutic strategy for the treatment of glioblastoma in the future.
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Copy and paste a formatted citation
Spandidos Publications style
Lohitesh K, Saini H, Srivastava A, Mukherjee S, Roy A and Chowdhury R: Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria. Oncol Rep 39: 2787-2796, 2018.
APA
Lohitesh, K., Saini, H., Srivastava, A., Mukherjee, S., Roy, A., & Chowdhury, R. (2018). Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria. Oncology Reports, 39, 2787-2796. https://doi.org/10.3892/or.2018.6373
MLA
Lohitesh, K., Saini, H., Srivastava, A., Mukherjee, S., Roy, A., Chowdhury, R."Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria". Oncology Reports 39.6 (2018): 2787-2796.
Chicago
Lohitesh, K., Saini, H., Srivastava, A., Mukherjee, S., Roy, A., Chowdhury, R."Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria". Oncology Reports 39, no. 6 (2018): 2787-2796. https://doi.org/10.3892/or.2018.6373
Copy and paste a formatted citation
x
Spandidos Publications style
Lohitesh K, Saini H, Srivastava A, Mukherjee S, Roy A and Chowdhury R: Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria. Oncol Rep 39: 2787-2796, 2018.
APA
Lohitesh, K., Saini, H., Srivastava, A., Mukherjee, S., Roy, A., & Chowdhury, R. (2018). Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria. Oncology Reports, 39, 2787-2796. https://doi.org/10.3892/or.2018.6373
MLA
Lohitesh, K., Saini, H., Srivastava, A., Mukherjee, S., Roy, A., Chowdhury, R."Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria". Oncology Reports 39.6 (2018): 2787-2796.
Chicago
Lohitesh, K., Saini, H., Srivastava, A., Mukherjee, S., Roy, A., Chowdhury, R."Autophagy inhibition potentiates SAHA‑mediated apoptosis in glioblastoma cells by accumulation of damaged mitochondria". Oncology Reports 39, no. 6 (2018): 2787-2796. https://doi.org/10.3892/or.2018.6373
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