, Volume 23, Issue 11–12, pp 563–575 | Cite as

Targeting autophagy for combating chemoresistance and radioresistance in glioblastoma

  • Matthew A. Taylor
  • Bhaskar C. Das
  • Swapan K. RayEmail author


Autophagy is an evolutionarily conserved catabolic process that plays an essential role in maintaining cellular homeostasis by degrading unneeded cell components. When exposed to hostile environments, such as hypoxia or nutrient starvation, cells hyperactivate autophagy in an effort to maintain their longevity. In densely packed solid tumors, such as glioblastoma, autophagy has been found to run rampant due to a lack of oxygen and nutrients. In recent years, targeting autophagy as a way to strengthen current glioblastoma treatment has shown promising results. However, that protective autophagy inhibition or autophagy overactivation is more beneficial, is still being debated. Protective autophagy inhibition would lower a cell’s previously activated defense mechanism, thereby increasing its sensitivity to treatment. Autophagy overactivation would cause cell death through lysosomal overactivation, thus introducing another cell death pathway in addition to apoptosis. Both methods have been proven effective in the treatment of solid tumors. This systematic review article highlights scenarios where both autophagy inhibition and activation have proven effective in combating chemoresistance and radioresistance in glioblastoma, and how autophagy may be best utilized for glioblastoma therapy in clinical settings.


Autophagy Cell death Chemoresistance Glioblastoma Radioresistance 



The work was supported in part by an award from the Soy Health Research Program (SHRP, United Soybean Board, Chesterfield, MO, USA), an investigator initiated research grant (SCIRF-2015-I-01) from South Carolina Spinal Cord Injury Research Fund (Columbia, SC, USA), and earlier R01 grants (CA-091460, and NS-057811) from the National Institutes of Health (Bethesda, MD, USA).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.


  1. 1.
    Hottinger AF, Stupp R, Homicsko K (2014) Standards of care and novel approaches in the management of glioblastoma multiforme. Chin J Cancer 33:32–39CrossRefGoogle Scholar
  2. 2.
    Davis ME. Glioblastoma (2016) Overview of disease and treatment. Clin J Oncol Nurs 20:1–8CrossRefGoogle Scholar
  3. 3.
    Lee DH, Ryu H-W, Won H-R et al (2017) Advances in epigenetic glioblastoma therapy. Oncotarget 8:18577–18589PubMedPubMedCentralGoogle Scholar
  4. 4.
    Bischof J, Westhoff M-A, Wagner JE et al (2017) Cancer stem cells: the potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells. Tumor Biol 39:101042831769222CrossRefGoogle Scholar
  5. 5.
    Messaoudi K, Clavreul A, Lagarce F (2015) Toward an effective strategy in glioblastoma treatment. Part I: resistance mechanisms and strategies to overcome resistance of glioblastoma to temozolomide. Drug Discov Today 20:899–905CrossRefGoogle Scholar
  6. 6.
    Brennan CW, Verhaak RGW, McKenna A et al (2013) The somatic genomic landscape of glioblastoma. Cell 155:462–477CrossRefGoogle Scholar
  7. 7.
    Liebner S, Dijkhuizen RM, Reiss Y et al (2018) Functional morphology of the blood–brain barrier in health and disease. Acta Neuropathol 135:311–336CrossRefGoogle Scholar
  8. 8.
    Lee CY (2017) Strategies of temozolomide in future glioblastoma treatment. Onco Targets Ther 10:265–270CrossRefGoogle Scholar
  9. 9.
    Kloepper J, Riedemann L, Amoozgar Z et al (2016) Ang-2/VEGF bispecific antibody reprograms macrophages and resident microglia to anti-tumor phenotype and prolongs glioblastoma survival. Proc Natl Acad Sci USA 113:4476–4481CrossRefGoogle Scholar
  10. 10.
    Kimura T, Takabatake Y, Takahashi A et al (2013) Chloroquine in cancer therapy: a double-edged sword of autophagy. Cancer Res 73:3–7CrossRefGoogle Scholar
  11. 11.
    Huang Z, Zhou L, Chen Z et al (2016) Stress management by autophagy: implications for chemoresistance. Int J Cancer 139:23–32CrossRefGoogle Scholar
  12. 12.
    Pratt J, Iddir M, Bourgault S et al (2016) Evidence of MTCBP-1 interaction with the cytoplasmic domain of MT1-MMP: implications in the autophagy cell index of high-grade glioblastoma. Mol Carcinog 55:148–160CrossRefGoogle Scholar
  13. 13.
    Shimizu S, Yoshida T, Tsujioka M et al (2014) Autophagic cell death and cancer. Int J Mol Sci 15:3145–3153CrossRefGoogle Scholar
  14. 14.
    Anguiano J, Garner T, Mahalingam M et al (2013) Chemical modulation of chaperone-mediated autophagy by retinoic acid derivatives. Nat Chem Biol 9:374–382CrossRefGoogle Scholar
  15. 15.
    Parzych KR, Klionsky DJ (2014) An overview of autophagy: morphology, mechanism, and regulation. Antioxid Redox Signal 20:460–473CrossRefGoogle Scholar
  16. 16.
    Yang Z, Klionsky DJ (2010) Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 22:124–131CrossRefGoogle Scholar
  17. 17.
    Weathers SPS, Gilbert MR (2017) Toward personalized targeted therapeutics: an overview. Neurotherapeutics 14:256–264CrossRefGoogle Scholar
  18. 18.
    Mizushima N, Levine B (2010) Autophagy in mammalian development and differentiation. Nat Cell Biol 12:823–830CrossRefGoogle Scholar
  19. 19.
    Jawhari S, Bessette B, Hombourger S et al (2017) Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival. Carcinogenesis 38:592–603CrossRefGoogle Scholar
  20. 20.
    Saran F, Chinot OL, Henriksson R et al (2016) Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy. Neuro Oncol 18:991–1001CrossRefGoogle Scholar
  21. 21.
    Huang H, Song J, Liu Z et al (2018) Autophagy activation promotes bevacizumab resistance in glioblastoma by suppressing Akt/mTOR signaling pathway. Oncol Lett 15:1487–1494PubMedGoogle Scholar
  22. 22.
    Golden EB, Cho H-Y, Jahanian A et al (2014) Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. Neurosurg Focus 37:E12CrossRefGoogle Scholar
  23. 23.
    Yuan X, Du J, Hua S et al (2015) Suppression of autophagy augments the radiosensitizing effects of STAT3 inhibition on human glioma cells. Exp Cell Res 330:267–276CrossRefGoogle Scholar
  24. 24.
    Ye H, Chen M, Cao F et al (2016) Chloroquine, an autophagy inhibitor, potentiates the radiosensitivity of glioma initiating cells by inhibiting autophagy and activating apoptosis. BMC Neurol 16:178CrossRefGoogle Scholar
  25. 25.
    Takahashi A, Kimura T, Takabatake Y et al (2012) Autophagy guards against cisplatin-induced acute kidney injury. Am J Pathol 180:517–525CrossRefGoogle Scholar
  26. 26.
    Ma B, Yuan Z, Zhang L et al (2017) Long non-coding RNA AC023115.3 suppresses chemoresistance of glioblastoma by reducing autophagy. BBA Mol Cell Res 1864:1393–1404Google Scholar
  27. 27.
    Sharma K, Le N, Alotaibi M et al (2014) Cytotoxic autophagy in cancer therapy. Int J Mol Sci 15:10034–10051CrossRefGoogle Scholar
  28. 28.
    Zhang X, Li W, Wang C et al (2014) Inhibition of autophagy enhances apoptosis induced by proteasome inhibitor bortezomib in human glioblastoma U87 and U251 cells. Mol Cell Biochem 385:265–275CrossRefGoogle Scholar
  29. 29.
    Chakrabarti M, Klionsky DJ, Ray SK (2016) miR-30e blocks autophagy and acts synergistically with proanthocyanidin for inhibition of AVEN and BIRC6 to increase apoptosis in glioblastoma stem cells and glioblastoma SNB19 cells. PLoS One 11:1–17CrossRefGoogle Scholar
  30. 30.
    Chakrabarti M, Ray SK (2016) Anti-tumor activities of luteolin and silibinin in glioblastoma cells: overexpression of miR-7-1-3p augmented luteolin and silibinin to inhibit autophagy and induce apoptosis in glioblastoma in vivo. Apoptosis 21:312–328CrossRefGoogle Scholar
  31. 31.
    Ren F, Zhang L, Zhang X et al (2016) Inhibition of glycogen synthase kinase 3β promotes autophagy to protect mice from acute liver failure mediated by peroxisome proliferator-activated receptor α. Cell Death Dis 7:e2151CrossRefGoogle Scholar
  32. 32.
    Taylor M, Ray SK (2017) Prospects of enhancing anti-cancer activities of quercetin in the treatment of glioblastoma. In: Watanabe H (ed.) Horizons in Cancer Research. Nova Science Publishers, Hauppauge, pp. 173–192Google Scholar
  33. 33.
    Chiao MT, Cheng WY, Yang YC et al (2013) Suberoylanilide hydroxamic acid (SAHA) causes tumor growth slowdown and triggers autophagy in glioblastoma stem cells. Autophagy 9:1509–1526CrossRefGoogle Scholar
  34. 34.
    Rosenfeld MR, Ye X, Supko JG et al (2014) A Phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 10:1359–1368CrossRefGoogle Scholar
  35. 35.
    Zou Y, Wang Q, Li B et al (2014) Temozolomide induces autophagy via ATM-AMPK-ULK1 pathways in glioma. Mol Med Rep 10:411–416CrossRefGoogle Scholar
  36. 36.
    Li Z, Meng X, Jin L (2016) Icaritin induces apoptotic and autophagic cell death in human glioblastoma cells. Am J Transl Res 8:4628–4643PubMedPubMedCentralGoogle Scholar
  37. 37.
    Yu Q, Liu L, Wang P et al (2017) EMAP-II sensitize U87MG and glioma stem-like cells to temozolomide via induction of autophagy-mediated cell death and G2/M arrest. Cell Cycle 16:1085–1092CrossRefGoogle Scholar
  38. 38.
    Josset E, Burckel H, Noel G et al (2013) The mTOR inhibitor RAD001 potentiates autophagic cell death induced by temozolomide in a glioblastoma cell line. Anticancer Res 33:1845–1851PubMedGoogle Scholar
  39. 39.
    Baskar R, Lee KA, Yeo R et al (2012) Cancer and radiation therapy: current advances and future directions. Int J Med Sci 9:193–199CrossRefGoogle Scholar
  40. 40.
    Tam SY, Wu VWC, Law HKW (2017) Influence of autophagy on the efficacy of radiotherapy. Radiat Oncol 12:57CrossRefGoogle Scholar
  41. 41.
    Shi F, Guo H, Zhang R et al (2017) The PI3K inhibitor GDC-0941 enhances radiosensitization and reduces chemoresistance to temozolomide in GBM cell lines. Neuroscience 346:298–308CrossRefGoogle Scholar
  42. 42.
    Luca Gravina G, Mancini A, Mattei C et al (2017) Enhancement of radiosensitivity by the novel anticancer quinolone derivative vosaroxin in preclinical glioblastoma models. Oncotarget 8:29865–29886Google Scholar
  43. 43.
    Liu R, Li J, Zhang T et al (2014) Itraconazole suppresses the growth of glioblastoma through induction of autophagy. Autophagy 10:1241–1255CrossRefGoogle Scholar
  44. 44.
    Benedetti E, Antonosante A, D’Angelo M et al (2015) Nucleolin antagonist triggers autophagic cell death in human glioblastoma primary cells and decreased in vivo tumor growth in orthotopic brain tumor model. Oncotarget 6:42091–42104PubMedPubMedCentralGoogle Scholar
  45. 45.
    Sotelo J, Briceno E, Lopez-Gonzalez MA (2006) Adding chloroquine to conventional treatment for glioblastoma multiforme. Ann Intern Med 144:337–343CrossRefGoogle Scholar
  46. 46.
    Chude CI, Amaravadi RK (2017) Targeting autophagy in cancer: update on clinical trials and novel inhibitors. Int J Mol Sci 18(6):1279CrossRefGoogle Scholar
  47. 47.
    Wu YT, Tan HL, Shui G et al (2010) Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 285:10850–10861CrossRefGoogle Scholar
  48. 48.
    Donohue E, Tovey A, Vogl AW et al (2011) Inhibition of autophagosome formation by the benzoporphyrin derivative verteporfin. J Biol Chem 286:7290–7300CrossRefGoogle Scholar
  49. 49.
    Ronan B, Flamand O, Vescovi L et al (2014) A highly potent and selective Vps34 inhibitor alters vesicle trafficking and autophagy. Nat Chem Biol 10:1013–1019CrossRefGoogle Scholar
  50. 50.
    Akin D, Wang SK, Habibzadegah-Tari P et al (2014) A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumors. Autophagy 10:2021–2035CrossRefGoogle Scholar
  51. 51.
    Takahashi A, Kimura F, Yamanaka A et al (2014) Metformin impairs growth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int 14:1–12CrossRefGoogle Scholar
  52. 52.
    Bonapace L, Bornhauser BC, Schmitz M et al (2010) Induction of autophagy-dependent necroptosis is required for childhood acute lymphoblastic leukemia cells to overcome glucocorticoid resistance. J Clin Invest 120:1310–1323CrossRefGoogle Scholar
  53. 53.
    Cloonan SM, Williams DC (2011) The antidepressants maprotiline and fluoxetine induce Type II autophagic cell death in drug-resistant Burkitt’s lymphoma. Int J Cancer 128:1712–1723CrossRefGoogle Scholar
  54. 54.
    Law BYK, Chan WK, Xu SW et al (2014) Natural small-molecule enhancers of autophagy induce autophagic cell death in apoptosis-defective cells. Sci Rep 4:1–14Google Scholar
  55. 55.
    Wang H, Li D, Li X et al (2016) Mammalian target of rapamycin inhibitor RAD001 sensitizes endometrial cancer cells to paclitaxel-induced apoptosis via the induction of autophagy. Oncol Lett 12:5029–5035CrossRefGoogle Scholar
  56. 56.
    Kwitkowski VE, Prowell TM, Ibrahim A et al (2010) FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 15:428–435CrossRefGoogle Scholar
  57. 57.
    Hess G, Herbrecht R, Romaguera J et al (2009) Phase III study to evaluate temsirolimus compared with investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822–3829CrossRefGoogle Scholar
  58. 58.
    Mizushima N, Ohsumi Y, Yoshimori T (2002) Autophagosome formation in mammalian cells. Cell Struct Funct 27:421–429CrossRefGoogle Scholar
  59. 59.
    Martinet W, Schrijvers DM, Timmermans JP, Bult H, De Meyer GR (2013) Immunohistochemical analysis of macroautophagy: recommendations and limitations. Autophagy 9:386–402CrossRefGoogle Scholar
  60. 60.
    Martinet W, Roth L, De Meyer GR (2017) Standard immunohistochemical assays to assess autophagy in mammalian tissue. Cells 6:17CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pathology, Microbiology, and ImmunologyUniversity of South Carolina School of MedicineColumbiaUSA
  2. 2.Departments of Medicine and Pharmacological SciencesIcahn School of Medicine at Mount SinaiNew YorkUSA

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