Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling

Yan, Kun; Yao, Chun-Han; Hsiao, Chi Hao; Lin, Ke; Lin, Yung Wei; Wen, Yu‐Ching; Liu, Chung Chi; Yan, Ming; Chuang, Shuang‐En; Lai, Gi Ming; Lee, Liang Ming

doi:10.3892/ol.2013.1211

Cited by 26 publications

(20 citation statements)

References 25 publications

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“…Indeed, our data suggest that ROS generation has a key role in the induction of cell death in response to mefloquine. Intriguingly, the lipophilic ROS scavenger a-tocopherol did not rescue mast cells from mefloquine-induced cell death whereas essentially complete blockade of cell death was seen when administering the hydrophilic ROS scavenger NAC, a finding that is in agreement with a recent report showing that mefloquine-induced cell death of prostate cancer PC3 cells is inhibited by NAC (Yan et al 2013). Although the implication of this observation is not entirely clear, it is notable that a-tocopherol is typically an effective inhibitor of mitochondrial ROS generation (Majima et al 2011;Cesen et al 2013;Quast et al 2013).…”

Section: Discussionsupporting

confidence: 90%

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Paivandy

Calounova

Zarnegar

et al. 2014

Pharmacology Res & Perspec

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Mast cells are known to have a detrimental impact on a variety of pathological conditions. There is therefore an urgent need of developing strategies that limit their harmful effects. The aim of this study was to accomplish this by developing a means of inducing mast cell apoptosis. The strategy was to identify novel compounds that induce mast cell apoptosis by permeabilization of their secretory lysosomes (granules). As a candidate, we assessed mefloquine, an anti-malarial drug that has been proposed to have lysosome-permeabilizing activity. Mefloquine was added to mast cells and administered in vivo, followed by assessment of the extent and mechanisms of mast cell death. Mefloquine was cytotoxic to murine and human mast cells. Mefloquine induced apoptotic cell death of wild-type mast cells whereas cells lacking the granule compounds serglycin proteoglycan or tryptase were shown to undergo necrotic cell death, the latter finding indicating a role of the mast cell granules in mefloquine-induced cell death. In support of this, mefloquine was shown to cause compromised granule integrity and to induce leakage of granule components into the cytosol. Mefloquine-induced cell death was refractory to caspase inhibitors but was completely abrogated by reactive oxygen species inhibition. These findings identify mefloquine as a novel anti-mast cell agent, which induces mast cell death through a granule-mediated pathway. Mefloquine may thus become useful in therapy aiming at limiting harmful effects of mast cells.

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Section: Discussionsupporting

confidence: 90%

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Paivandy

Calounova

Zarnegar

et al. 2014

Pharmacology Res & Perspec

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“…Thus, it is conceivable that the drug widely used for malaria prevention and treatment might be tried for CRC that are addicted to activated NF‐κB. Interestingly, it has been found that mefloquine induced breast cancer cell death by inhibiting autophagy, killed prostate cancer cells by reactive oxygen species (ROS)‐mediated mechanisms, and inhibited the proliferation of gastric cancer cells through blocking the PI3K/Akt/mTOR signaling pathway . Therefore, mefloquine appears to be an effective agent for many types of cancers, although it remains to be determined whether there is a common mechanism responsible for its action in different cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Antimalarial drug mefloquine inhibits nuclear factor kappa B signaling and induces apoptosis in colorectal cancer cells

Wang

Han³

et al. 2018

Cancer Science

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Nuclear factor kappa B (NF‐κB) signaling pathway is activated in many colorectal cancer (CRC) cells and in the tumor microenvironment, which plays a critical role in cancer initiation, development, and response to therapies. In the present study, we found that the widely used antimalarial drug mefloquine was a NF‐κB inhibitor that blocked the activation of IκBα kinase, leading to reduction of IκBα degradation, decrease of p65 phosphorylation, and suppressed expression of NF‐κB target genes in CRC cells. We also found that mefloquine induced growth arrest and apoptosis of CRC cells harboring phosphorylated p65 in culture and in mice. Furthermore, expression of constitutive active IKKβ kinase significantly attenuated the cytotoxic effect of the compound. These results showed that mefloquine could exert antitumor action through inhibiting the NF‐κB signaling pathway, and indicated that the antimalarial drug might be repurposed for anti‐CRC therapy in the clinic as a single agent or in combination with other anticancer drugs.

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“…In Plasmodium species as well as various other cell types a number of hypotheses have been proposed. These hypotheses range from the inhibition of plasma membrane dynamics to the induction of reactive oxygen species stress [32–36]. One particular hypothesis raised by two papers from the past decade proposed that mefloquine might act against Plasmodium parasites through inhibition of the cytosolic ribosome and resultant suppression of protein translation [37, 38].…”

Section: Discussionmentioning

confidence: 99%

Antimalarial drug mefloquine kills both trophozoite and cyst stages of Entamoeba

Sauvey

Ehrenkaufer

Debnath

et al. 2018

Preprint

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Entamoeba histolytica is a protozoan parasite which infects approximately 50 million people worldwide, resulting in an estimated 70,000 deaths every year. Since the 1960s E. histolytica infection has been successfully treated with metronidazole. However, drawbacks to metronidazole therapy exist, including adverse effects, length of treatment, and the need for additional drugs to prevent transmission. All of these may decrease patient compliance and hence increase disease severity and spread of infection. In this study we identified the antimalarial drug mefloquine as possessing more potent, rapid, amoebicidal in vitro activity against E. histolytica trophozoites than metronidazole. We also showed that mefloquine could kill the cysts of a closely related reptilian parasite Entamoeba invadens unlike metronidazole. Additionally, mefloquine is known to possess a much longer half-life in human patients than metronidazole. This property, along with mefloquine's rapid and broad action against E. histolytica position it as a promising new drug candidate against this widespread and devastating disease.

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Mefloquine exerts anticancer activity in prostate cancer cells via ROS-mediated modulation of Akt, ERK, JNK and AMPK signaling

Cited by 26 publications

References 25 publications

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Mefloquine, an anti‐malaria agent, causes reactive oxygen species‐dependent cell death in mast cells via a secretory granule‐mediated pathway

Antimalarial drug mefloquine inhibits nuclear factor kappa B signaling and induces apoptosis in colorectal cancer cells

Antimalarial drug mefloquine kills both trophozoite and cyst stages of Entamoeba

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