Transcriptional profiling of mefloquine-induced disruption of calcium homeostasis in neurons in vitro

Dow, Geoffrey S.; Caridha, Diana; Goldberg, Michelle; Wolf, Lesley; Koenig, Michael L.; Yourick, Debra L.; Wang, Zhining

doi:10.1016/j.ygeno.2005.07.004

Cited by 24 publications

(23 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We cannot rule out the possibility of a non-thapsigargin-like effect of mefloquine on SERCA. The confocal microscopy data and the results of earlier studies are consistent with an effect of mefloquine on this target, although our transcriptional data argue for a reversible, non-thapsigargin-like effect (13). Regardless, CCE is a downstream effect of any of these store-discharging triggers.…”

Section: Discussionsupporting

confidence: 90%

“…The precise mechanisms responsible for these events have not been defined. In a subsequent transcriptional study, we showed that mefloquine induced an ER stress response qualitatively dissimilar to that of thapsigargin, an irreversible inhibitor of SERCA (13). This study appeared to indicate either a reversible effect of mefloquine on SERCA or discharge via other mechanisms.…”

Section: Discussionmentioning

confidence: 79%

“…Initially we suspected that this effect might occur as a consequence of the inhibition of the thapsigargin-sensitive sarcoplasmic reticulum/ER Ca 2ϩ -ATPase (SERCA), followed by subsequent triggering of capacitative calcium entry (CCE). However, in subsequent gene expression studies, we observed that mefloquine failed to induce the downstream stress responses typical of thapsigargininduced ER calcium depletion (13). These observations suggested either that the interaction of mefloquine with the ER calcium pump were transient or that the depletion was mediated via different mechanisms.…”

mentioning

confidence: 87%

See 2 more Smart Citations

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

Caridha

Yourick

Cabezas

et al. 2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

In previous studies, we have shown that mefloquine disrupts calcium homeostasis in neurons by depletion of endoplasmic reticulum (ER) stores, followed by an influx of external calcium across the plasma membrane. In this study, we explore two hypotheses concerning the mechanism(s) of action of mefloquine. First, we investigated the possibility that mefloquine activates non-N-methyl-D-aspartic acid receptors and the inositol phosphate 3 (IP3) signaling cascade leading to ER calcium release. Second, we compared the disruptive effects of mefloquine on calcium homeostasis to those of ionomycin in neuronal and nonneuronal cells. Ionomycin is known to discharge the ER calcium store (through an undefined mechanism), which induces capacitative calcium entry (CCE). In radioligand binding assays, mefloquine showed no affinity for the known binding sites of several glutamate receptor subtypes. The pattern of neuroprotection induced by a panel of glutamate receptor antagonists was dissimilar to that of mefloquine. Both mefloquine and ionomycin exhibited doserelated and qualitatively similar disruptions of calcium homeostasis in both neurons and macrophages. The influx of external calcium was blocked by the inhibitors of CCE in a dose-related fashion. Both mefloquine and ionomycin upregulated the IP3 pathway in a manner that we interpret to be secondary to CCE. Collectively, these data suggest that mefloquine does not activate glutamate receptors and that it disrupts calcium homeostasis in mammalian cells in a manner similar to that of ionomycin.Mefloquine is an antimalarial with utility for chemoprophylaxis and treatment. The drug has been associated with adverse central nervous system (CNS) effects in a dose-related manner (reviewed in reference 14). As a consequence, its continued use in an otherwise healthy population for prophylaxis is controversial. The precise etiology of mefloquine-induced adverse effects is unknown. There is clinical evidence that P glycoprotein polymorphisms are associated with adverse neurological outcomes (1). Numerous putative CNS targets have been proposed (reviewed in reference 12) in either in vitro or ex vivo contexts. Recent studies in our laboratory demonstrated mefloquine induction of brain stem histopathology consistent with direct cellular neurotoxicity in rats (12) and disruption of neuronal calcium homeostasis in vitro (14). The latter effect involves discharge of the endoplasmic reticulum (ER) calcium store and induction of a subsequent influx of calcium into the cell from the extracellular space (14). Initially we suspected that this effect might occur as a consequence of the inhibition of the thapsigargin-sensitive sarcoplasmic reticulum/ER Ca 2ϩ -ATPase (SERCA), followed by subsequent triggering of capacitative calcium entry (CCE). However, in subsequent gene expression studies, we observed that mefloquine failed to induce the downstream stress responses typical of thapsigargininduced ER calcium depletion (13). These observations suggested either that the interaction of mefloquine ...

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 87%

See 1 more Smart Citation

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

Caridha

Yourick

Cabezas

et al. 2008

Antimicrob Agents Chemother

View full text Add to dashboard Cite

show abstract

“…Others have shown that MFQ inhibits sarcoplasmic/ER calcium ATPase (SERCA), thereby causing calcium release from the ER, an increase in misfolded proteins, and induction of the ER stress response. 10,16 Thus, MFQ's multilevel effect of increasing the burden of unfolded ER proteins targeted for lysosomal degradation while blocking autophagy and aggravating ER stress may contribute to greater potency, in comparison with the other QBAs. 35 We previously demonstrated that combinations of chemotherapeutic compounds that manipulate the ER stress response at multiple levels hold clinical promise by synergistically inciting cell death.…”

Section: Discussionmentioning

confidence: 99%

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

Golden

Cho²,

Hofman³

et al. 2015

FOC

152

View full text Add to dashboard Cite

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.

show abstract

“…This assay utilizes primary rat forebrain neurons and is a multi-end-point screen. In this system a large component of the neurotoxicity of mefloquine can be attributed to the disruption of calcium homeostasis via discharge of the endoplasmic reticulum calcium store and activation of ill-defined plasma membrane calcium channels (14,15). Mefloquine may also induce other, uncharacterized effects in these cells.…”

Section: Methodsmentioning

confidence: 99%

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Dow

Heady

Bhattacharjee

et al. 2006

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Mefloquine has been one of the more valuable antimalarial drugs but has never reached its full clinical potential due to concerns about its neurologic side effects, its greater expense than that of other antimalarials, and the emergence of resistance. The commercial development of mefloquine superseded that of another quinolinyl methanol, WR030090, which was used as an experimental antimalarial drug by the U.S. Army in the 1970s. We evaluated a series of related 2-phenyl-substituted alkylaminoquinolinyl methanols (AAQMs) for their potential as mefloquine replacement drugs based on a series of appropriate in vitro and in vivo efficacy and toxicology screens and the theoretical cost of goods. Generally, the AAQMs were less neurotoxic and exhibited greater antimalarial potency, and they are potentially cheaper than mefloquine, but they showed poorer metabolic stability and pharmacokinetics and the potential for phototoxicity. These differences in physiochemical and biological properties are attributable to the "opening" of the piperidine ring of the 4-position side chain. Modification of the most promising compound, WR069878, by substitution of an appropriate N functionality at the 4 position, optimization of quinoline ring substituents at the 6 and 7 positions, and deconjugation of quinoline and phenyl ring systems is anticipated to yield a valuable new antimalarial drug.In the late 1960s to early 1970s, Plasmodium falciparum malaria in Southeast Asia had begun to develop resistance to all of the available antimalarial drugs (6). Cure rates were 11 to 20% and 26 to 50% for chloroquine and quinine, respectively, and had declined to only 90% for the triple combination of quinine/pyrimethamine/dapsone (6). All of these regimens were associated with adverse side effects (6). As a consequence, the U.S. Army began routinely employing two experimental antimalarial drugs, WR030090 and WR033063, for the treatment of recrudescent malaria infections at the Walter Reed Army Medical Center (6). Subsequent field trials demonstrated that WR030090, a quinolinyl methanol, exhibited cure rates of at least 88% and was better tolerated than quinine (6, 21).Shortly thereafter, mefloquine was discovered and was developed commercially by Hoffman La Roche and the U.S. Army. Mefloquine exhibited a long half-life in humans, and this desirable property facilitated its administration as a single dose for malaria treatment and as a once-weekly dosing for prophylaxis (50). In contrast, WR030090 was only partially effective as a prophylactic agent, required a dosing regimen similar to that of quinine to effect cures, and was subsequently abandoned (6,9,21,30). However, it is important to recognize that this occurred because of unfavorable pharmacokinetic characteristics, not as a consequence of unacceptable toxicity.Mefloquine combined with artesunate constitutes one of the most effective combination agents for treatment of malaria (41). Mefloquine is also the only once-weekly drug approved for malaria chemoprophylaxis in the United States that...

show abstract

Transcriptional profiling of mefloquine-induced disruption of calcium homeostasis in neurons in vitro

Cited by 24 publications

References 46 publications

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

Mefloquine-Induced Disruption of Calcium Homeostasis in Mammalian Cells Is Similar to That Induced by Ionomycin

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

Utility of Alkylaminoquinolinyl Methanols as New Antimalarial Drugs

Contact Info

Product

Resources

About