Quinoline-based antimalarial drugs: a novel class of autophagy inhibitors.
OBJECTIVE
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.
Department of Radiation Oncology, New York University School of Medicine, New York, New York;
Encouse B
EB
Golden
Hee-Yeon
HY
Cho
Florence M
FM
Hofman
Stan G
SG
Louie
Axel H
AH
Schönthal
Thomas C
TC
Chen
D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D008819:Mice, Nude; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011804:Quinolines / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000962:Antimalarials; D000970:Antineoplastic Agents; D011804:Quinolines; C037219:quinoline; D011065:Poly(ADP-ribose) Polymerases
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