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Neurosurg Focus. 2015 Mar;38(3):E12. doi: 10.3171/2014.12.FOCUS14748.

Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors.

Author information

1
Department of Radiation Oncology, New York University School of Medicine, New York, New York;

Abstract

OBJECT:

Chloroquine (CQ) is a quinoline-based drug widely used for the prevention and treatment of malaria. More recent studies have provided evidence that this drug may also harbor antitumor properties, whereby CQ possesses the ability to accumulate in lysosomes and blocks the cellular process of autophagy. Therefore, the authors of this study set out to investigate whether CQ analogs, in particular clinically established antimalaria drugs, would also be able to exert antitumor properties, with a specific focus on glioma cells.

METHODS:

Toward this goal, the authors treated different glioma cell lines with quinine (QN), quinacrine (QNX), mefloquine (MFQ), and hydroxychloroquine (HCQ) and investigated endoplasmic reticulum (ER) stress-induced cell death, autophagy, and cell death.

RESULTS:

All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX > MFQ > HCQ > CQ > QN). Furthermore, all quinoline-based drugs killed glioma cells that were highly resistant to temozolomide (TMZ), the current standard of care for patients with glioma. The cytotoxic mechanism involved the induction of apoptosis and ER stress, as indicated by poly(ADP-ribose) polymerase (PARP) cleavage and CHOP/GADD153. The induction of ER stress and resulting apoptosis could be confirmed in the in vivo setting, in which tumor tissues from animals treated with quinoline-based drugs showed increased expression of CHOP/GADD153, along with elevated TUNEL staining, a measure of apoptosis.

CONCLUSIONS:

Thus, the antimalarial compounds investigated in this study hold promise as a novel class of autophagy inhibitors for the treatment of newly diagnosed TMZ-sensitive and recurrent TMZ-resistant gliomas.

KEYWORDS:

AFV = acidic food vacuole; CFA = colony formation assay; CQ = chloroquine; ER = endoplasmic reticulum; GBM = glioblastoma multiforme; HCQ = hydroxychloroquine; IC50 = half maximal inhibitory concentration; IHC = immunohistochemistry; MFQ = mefloquine; PARP = poly(ADP-ribose) polymerase; QBA = quinoline-based antimalarial; QN = quinine; QNX = quinacrine; TMZ = temozolomide; U251-TMZR cells = TMZ-resistant U251 cells; antimalaria compound; autophagy; chloroquine; endoplasmic reticulum stress; glioma

PMID:
25727221
DOI:
10.3171/2014.12.FOCUS14748
[Indexed for MEDLINE]

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