Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent

Abstract

Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3-like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood-brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.

Impact of Autophagy Inhibition at Different Stages on Cytotoxic Effect of Autophagy Inducer in Glioblastoma Cells

“…This is supported by our findings that induction of robust apoptosis was always accompanied by accumulation of degradative AVs. Supporting this, a previous research showed that CQ-induced AV accumulation induced GBM cells to undergo apoptosis [39]. However, the underlying mechanism is still need to be further studied.…”

Chloroquine inhibits the malignant phenotype of glioblastoma partially by suppressing TGF-beta

“…Results have yet to be published, but their work will evaluate the maximum tolerated dose (treatment period: up to 12 months), the time to tumor progression as well as the overall survival (ClinicalTrials.gov Identifier: NCT02071537). Interestingly, in several other clinical trials (initiated or soon to be initiated), CQ or its closely related analog hydroxychloroquine (HCQ) are used in combination with other compounds and/or with radiation against multiple types of advanced cancers; out of the latest 39 phase I or II trials recently launched in various types of tumors including malignant gliomas, in only three is CQ/ HCQ used as a monotherapy, none of which are conducted on GBM-bearing subjects [16][17][18]48]. Additionally, since GBM cells easily escape immune surveillance, inhibiting the TGF-β-induced general immunosuppression with CQ could greatly contribute to both the treatment efficacy as well as the clinical management of afflicted patients [49,50].…”

Male contraceptive Adjudin is a potential anti-cancer drug

“…One approach, which is specially promising in the pursuit of anti-cancer agents, is to evaluate the ‘old drugs’ that could be used singly or in combination for cancer treatment. Chloroquine, the effective anti-malarial and anti-rheumatoid drug and metformin, the antidiabetic drug are the typical examples of ‘old drugs’ used in the clinical treatment of cancer [5,6]. The advantage of using ‘old drugs’ is that these agents have already been proved for their safety.…”

“…This approach indeed has aroused greater interest than in the past [4]. For instance, Chloroquine, the effective anti-malarial and antirheumatoid drug, has emerged to be used in the clinical treatment of glioblastoma [5,6]. Moreover, using old drugs has the additional benefits of reducing the time for clinical trials.…”