Re-purposing Chloroquine for Glioblastoma: Potential Merits and Confounding Variables

Abstract

There is a growing evidence that antimalarial chloroquine could be re-purposed for cancer treatment. A dozen of clinical trials have been initiated within the past 10 years to test the potential of chloroquine as an adjuvant treatment for therapy-refractory cancers including glioblastoma, one of the most aggressive human cancers. While there is considerable evidence for the efficacy and safety of chloroquine the mechanisms underlying the tumor suppressive actions of this drug remain elusive. Up until recently, inhibition of the late stage of autophagy was thought to be the major mechanism of chloroquine-mediated cancer cells death. However, recent research provided compelling evidence that autophagy-inhibiting activities of chloroquine are dispensable for its ability to suppress tumor cells growth. These unexpected findings necessitate a further elucidation of the molecular mechanisms that are essential for anti-cancer activities of CHQ. This review discusses the versatile actions of chloroquine in cancer cells with particular focus on glioma cells.

Keywords: autophagy; chloroquine; glioblastoma; glioma stem-like cells; radio-sensitization.

Figure 1

Antagonistic pleiotropy of multifunctional hub proteins modulated by CHQ. (i) CHQ accumulation in the lysosome inhibits the lysosome-autophagosome fusion and impairs degradation of proteins including the ubiquitin (Ub)-binding protein p62 and its binding partner pro-apoptotic LC3-II. (ii) CHQ intercalates into the DNA helix and cause relaxation of chromatin structure, which may be the mechanism of ClQ-mediated activation of a DNA damage-inducible kinase ATM. (iii) CHQ modulates activities of pleiotropic transcription factors p53 and NF-κB and may influence cross-talk between these pathways. (iv) p62 functional duality and positive p62 / NF-κB feedback loop. (v) Augmentation of pro-apoptotic activities of p53 may be a possible mechanism of CHQ-mediated radiosensitization. (vi) Autophagy inhibition by ClQ may counteract autophagic activation by TMZ and thereby sensitize glioma cells to chemotherapy.