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

Abstract

<jats:sec> <jats:title>OBJECT</jats:title> <jats:p>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.</jats:p></jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>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.</jats:p></jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>All agents blocked cellular autophagy and exerted cytotoxic effects on drug-sensitive and drug-resistant glioma cells with varying degrees of potency (QNX &gt; MFQ &gt; HCQ &gt; CQ &gt; 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.</jats:p></jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p>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.</jats:p></jats:sec>

Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma

“…Indeed, antimalarial compounds, which share the ability to activate p53 and inhibit NF-ĸB, have been shown to be cytotoxic to glioma cells. 24 It is not surprising that TMZ was unable to increase survival in the A1207 model, since we found that A1207 expresses MGMT by western blot. MGMT expression is known to render the DNA O 6 alkylating agent TMZ ineffective because of its DNA repair function.…”

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status

“…Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of TNF-α and IL-6. It also works as a novel class of autophagy inhibitor [81], which may interfere with viral infection and replication. Several studies have found that chloroquine interfered with the glycosylation of cellular receptors of SARS-CoV [80] and functioned at both entry and at post-entry stages of the COVID-19 infection in Vero E6 cells [82].…”

Discovery of Novel Cinchona‐Alkaloid‐Inspired Oxazatwistane Autophagy Inhibitors

“…However, the original cinchona alkaloids (Figure 1) did not inhibit autoph-agy at concentrations up to 30 mm (Table S1 in the Supporting Information). [19] Structure-activity relationships revealed that the unsubstituted b-iso-cupreidine, b-iso-quinidine,a nd b-iso-cinchonine (3, 4a,a nd 4b,r espectively) were not active at ac oncentration of 10 mm,t hus suggesting that substitution of the quinoline is required for activity.V arying the substitution at C2 produced several compounds that were active in the low micromolar range. Large 4-substituted phenyls (biphenyl or biphenyl ethers) were less well tolerated, however, a4 -fluorophenyl substituent significantly increased potencyt o 0.65 mm (5b).…”

“…derivatives were accessed through C5 nitration to yield 14 (Scheme 1), [12] and subsequent reduction of the nitro group and acylationy ielded ureas or amides (15 a,b). Forf unctionalization at C6 (Scheme 1b), b-isocupreidine (3)w as converted into the triflate 16 to enable Suzuki couplings (17 a-c), Buchwald-Hartwig aminations (18 a,b), and Sonogashira couplings (19). Furthermore,etherification of 3 with chloroethyl ethyl ether and potassium tert-butoxide was successful and afforded compound 20.Inaddition, the lactone analogue 21 was synthesized from quinidine (2b;S cheme 1cand Scheme S1 in the Supporting Information).…”