Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma

Khan, Imran; Baig, Mohammad Hassan; Mahfooz, Sadaf; Rahim, Moniba; Karacam, Busra; Elbasan, Elif Burce; Ulasov, Ilya V.; Dong, Jae-June; Hatiboğlu, Mustafa Aziz

doi:10.3390/ijms22031318

Cited by 27 publications

(18 citation statements)

References 212 publications

(243 reference statements)

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“…13,[94][95][96] The intricate nature of autophagy regulation by radiotherapy and chemotherapy bears a fair deal of controversy and remains a subject for more studies, especially in the context of managing treatment resistance. 94,[97][98][99] Collectively, the integration of autophagy regulation into future therapeutic explorations for glial tumors appears to represent a perspective avenue.…”

Section: Discussionmentioning

confidence: 99%

Repurposing autophagy regulators in brain tumors

Petrosyan

Fares

Cordero

et al. 2022

Intl Journal of Cancer

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Malignant brain tumors, such as glioblastoma multiforme (GBM) and brain metastases, continue to be an unmet medical challenge. Despite advances in cancer diagnostics and therapeutics, tumor cell colonization in the central nervous system renders most treatment options ineffective. This is primarily due to the selective permeability of the blood‐brain barrier (BBB), which hinders the crossing of targeting agents into the brain. As such, repositioning medications that demonstrate anticancer effects and possess the ability to cross the BBB can be a promising option. Antidepressants, which are BBB‐permeable, have been reported to exhibit cytotoxicity against tumor cells. Autophagy, specifically, has been identified as one of the common key mediators of antidepressant's antitumor effects. In this work, we provide a comprehensive overview of US Food and Drug Administration (FDA)‐approved antidepressants with reported cytotoxic activities in different tumor models, where autophagy dysregulation was demonstrated to play the main part. As such, imipramine, maprotiline, fluoxetine and escitalopram were shown to induce autophagy, whereas nortriptyline, clomipramine and paroxetine were identified as autophagy inhibitors. Sertraline and desipramine, depending on the neoplastic context, were demonstrated to either induce or inhibit autophagy. Collectively, these medications were associated with favorable therapeutic outcomes in a variety of cancer cell models, including brain tumors.

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Section: Discussionmentioning

confidence: 99%

Repurposing autophagy regulators in brain tumors

Petrosyan

Fares

Cordero

et al. 2022

Intl Journal of Cancer

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“…These data confirm recent findings that have demonstrated a worse prognostic behavior in GBM patients with high levels of autophagy-related genes and MGMT promoter unmethylated ( 57 ). However, autophagy can have a tumor suppressor function in GBM destroying damaging unfolded proteins, oncogenic protein substrates, and injured organelles ( 58 , 59 ). Recently, it has been reported that elevated levels of ATGs were linked to better survival in glioma patients ( 60 – 62 ).…”

Section: Discussionmentioning

confidence: 99%

Immunoexpression of p62/SQSTM1/Sequestosome‑1 in human primary and recurrent IDH1/2 wild‑type glioblastoma: A pilot study

et al. 2022

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Asbstract. p62/SQSTM1/Sequestosome-1 is an autophagic protein that serves a crucial role in cellular metabolism, proliferation and malignant growth. Notably, autophagy may influence the development and resistance to therapy of numerous types of human cancer. In the present pilot study, the immunohistochemical pattern of p62 was analyzed in a cohort of patients with isocitrate dehydrogenase (IDH)1/2 wild-type glioblastoma (GBM), in primary and recurrent samples, in order to verify the concordance or discordance between the primary and recurrent tumors. In addition, the association between p62, and patient outcome and O 6 -methylguanine-DNA methyltransferase (MGMT) status was assessed. The results revealed p62 immunoexpression in the nucleus and cytoplasm of neoplastic elements in 45% of primary and 55% of recurrent cases of GBM. A discordant p62 immunoreactivity was detected in 35% of cases, with a variation either with positive or negative conversion of p62 status. Statistically, p62 expression and MGMT status exhibited a significant prognostic value by univariate analysis, whereas only MGMT promoter methylation status emerged as an independent prognostic factor by multivariate analysis. Finally, the most favorable prognosis was documented when the same GBM case was positively concordant for both p62 expression and MGMT methylated status. Since little data are available regarding the association between p62 expression and MGMT in GBM, further investigations may be required to determine if new targeted therapies may be addressed against autophagy-related proteins, such as p62.

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“…The higher mtDNA/nDNA ratio that we observed may be linked to increased mitochondrial turnover, as suggested by the observations that OXPHOS was better preserved in resistant cells and that the autophagy/mitophagy inhibitor CQ preferentially killed resistant cells in clonogenic assays. Inhibiting autophagy in general has been widely studied to treat chemoresistant GBM [ 43 ]. Buccarelli et al [ 44 ] linked it to mitochondrial quality control by showing that inhibition of autophagy with quinacrine, a compound that is able to cross the BBB, increased the susceptibility of GBM stem cells to TMZ by triggering ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells

Zampieri

Sboarina

Cacace

et al. 2021

IJMS

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Glioblastoma represents the highest grade of brain tumors. Despite maximal resection surgery associated with radiotherapy and concomitant followed by adjuvant chemotherapy with temozolomide (TMZ), patients have a very poor prognosis due to the rapid recurrence and the acquisition of resistance to TMZ. Here, initially considering that TMZ is a prodrug whose activation is pH-dependent, we explored the contribution of glioblastoma cell metabolism to TMZ resistance. Using isogenic TMZ-sensitive and TMZ-resistant human glioblastoma cells, we report that the expression of O6-methylguanine DNA methyltransferase (MGMT), which is known to repair TMZ-induced DNA methylation, does not primarily account for TMZ resistance. Rather, fitter mitochondria in TMZ-resistant glioblastoma cells are a direct cause of chemoresistance that can be targeted by inhibiting oxidative phosphorylation and/or autophagy/mitophagy. Unexpectedly, we found that PARP inhibitor olaparib, but not talazoparib, is also a mitochondrial Complex I inhibitor. Hence, we propose that the anticancer activities of olaparib in glioblastoma and other cancer types combine DNA repair inhibition and impairment of cancer cell respiration.

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Deciphering the Role of Autophagy in Treatment of Resistance Mechanisms in Glioblastoma

Cited by 27 publications

References 212 publications

Repurposing autophagy regulators in brain tumors

Repurposing autophagy regulators in brain tumors

Immunoexpression of p62/SQSTM1/Sequestosome‑1 in human primary and recurrent IDH1/2 wild‑type glioblastoma: A pilot study

Olaparib Is a Mitochondrial Complex I Inhibitor That Kills Temozolomide-Resistant Human Glioblastoma Cells

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