Inhibition of autophagy and induction of breast cancer cell death by mefloquine, an antimalarial agent

Sharma, Natasha; Thomas, Simmy; Golden, Encouse B.; Hofman, Florence M.; Chen, Thomas C.; Petasis, Nicos A.; Schönthal, Axel H.; Louie, Stan G.

doi:10.1016/j.canlet.2012.07.029

Cited by 101 publications

(79 citation statements)

References 53 publications

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“…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. 13,24,34 Now that we have established a novel class of autophagy inhibitors, it will be a matter of further characterizing the unique secondary qualities of each compound as a strategy for optimizing the activation of ER stress in combination with other clinically useful chemotherapies, such as proteasome and SERCA inhibitors, as a means of reducing the tumor burden while minimizing systemic side effects.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, we have recently examined the use of MFQ in breast cancer. 35 Since QBAs possess the unique ability to accumulate in the AFVs of P. falciparum in various clinical conditions, we set out to determine whether these compounds have antitumor properties similar to those of CQ, including the ability to accumulate in lysosomes and block autophagy. Our data here showed that QBAs induced higher levels of CHOP/GADD-153 (an endoplasmic reticulum [ER] stress proapoptotic protein) as well as apoptosis in vitro and in vivo in U87MG subcutaneous implants.…”

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confidence: 99%

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

Golden

Cho²,

Hofman³

et al. 2015

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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.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Golden

Cho²,

Hofman³

et al. 2015

FOC

Self Cite

150

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“…Coincidentally, like DHA, CQ is another classical antimalarial agent, and several clinical trials have shown CQ exerts well anticancer effects. 34 CQ exerts its effects mainly through blunting the activivty of lysosomal enzymes, 35 to arrest degradation of the autolysosome, the latter step of autophagy, Figure 6. The combination of dihydroartemisinin and chloroquine exerted synergistic anti-tumor efficacy both in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

Chen

Zeng

et al. 2015

Cancer Biology & Therapy

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Dihydroartemisinin (DHA) exhibits anticancer activities in a variety of cancer cells, but DHA alone are not effective enough for cancer therapy. In this study we found the stress-regulated protein p8 was obviously increased after DHA treatment in several cancer cells, which further to induce autophagy by the upregulation of endoplasmic reticulum stress-related protein ATF4 and CHOP. Furthermore, when we silenced p8 by siRNA in cancer cells, the apoptosis induced by DHA were notably increased, whereas the overexpression of p8 in cancer cells leaded to the resistance to DHA-induced apoptosis. Moreover, we found the inhibition of autophagy with chloroquine (CQ) can enhance the anticancer effect of DHA both in vitro and in vivo. In conclusion, we found that p8-mediated autophagy attenuates DHA-induced apoptosis in cancer cells, which provides evidence to support the use p8 as a cancer therapeutic target, and suggests that the combination treatment with DHA and autophagy inhibitor might be an effective cancer therapeutic strategy.

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“…Clearly, autophagy plays an important role in tumor cell survival under extreme stress, thus inhibition of autophagy may become a novel therapeutic strategy for cancer treatment (23,24). It has been reported that chemical inhibitors of autophagy induce the death of cancer cells and sensitize the antitumor activity of a broad array of anticancer agents (25). CQ, an autophagic inhibitor, is being used as a chemosensitizer in clinical trials (11).…”

Section: Discussionmentioning

confidence: 99%

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

Liu

Shang

et al. 2015

Oncology Reports

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Abstract. Honokiol (HNK), a potential antitumor compound, has been widely studied in recent years. It induces apoptosis and affects autophagy in cancer cells, yet the mechanism of its antitumor efficacy remains obscure. Chloroquine (CQ), an autophagy inhibitor, is often applied to sensitize antitumor drugs in clinical trials. Here, we investigated the antitumor effect of HNK or CQ alone or in combination in non-small cell lung cancer (NSCLC) cells. Using an experimental approach, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) or sulforhodamine B (SRB) was used to determine the cytotoxicity of the agents. The expression levels of proteins were detected by western blotting. Apoptosis was examined via Annexin V-FITC and PI staining. H460 cell xenografts in nude mice were used to study the effects of HNK and/or CQ in vivo. Transfection with siRNA was applied to knock down cathepsin D. The results demonstrated the enhanced effects of HNK combined with CQ on the inhibition of proliferation, induction of apoptosis in vitro and the reduction in growth in vivo. It was confirmed that HNK and/or CQ triggered apoptosis via a caspase-dependent manner. Furthermore, HNK significantly increased the expression of p62 and LC3-Ⅱ in the A549 and H460 cells and inhibited autophagy and induced apoptosis in a cathepsin D-involved manner. In conclusion, an enhanced antitumor effect was demonstrated following treatment with HNK combined with CQ by inhibiting autophagy and inducing apoptosis via a caspase-dependent and cathepsin D-involved manner. This combination may be a novel and useful antitumor approach for chemotherapy in NSCLC. IntroductionHonokiol (HNK) (Fig. 1A), a biphenolic compound isolated from the leaves, bark, and root of Magnolia officinalis is used in traditional Chinese and Japanese medicine (1). It was reported that HNK effectively reduces the growth of cancer in vitro and in vivo in cell and animal xenograft models (2). It also induces caspase-dependent apoptosis of cancer cells through downregulation of survivin, c-FLIP, Bcl-xL and upregulation of . Recent studies have demonstrated that HNK increases the expression levels of the two hallmarks of autophagy, Beclin-1 and LC3-II, and induces autophagy in glioblastoma multiforme (GBM) DBTRG-05MG cells, yet the role of autophagy in the anti-GBM effects requires further research (6). In addition, HNK was found to induce autophagy in prostate cancer cells (7). However, another study indicated that w007B, a newly synthesized derivative of honokiol, exerted neuroprotective effects through inhibition of autophagy (8). As suggested above, the role of autophagy in the antitumor effects of HNK requires further research and combined treatment of HNK with an autophagy inhibitor or activator may result in enhanced antitumor effects.Autophagy is a conserved, lysosomal-dependent membrane process to maintain cellular homeostasis under metabolic stress. During this process, autophagosomes engulf damaged proteins and defective organelles and then fuse with lysosomes f...

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Inhibition of autophagy and induction of breast cancer cell death by mefloquine, an antimalarial agent

Cited by 101 publications

References 53 publications

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

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

p8 attenuates the apoptosis induced by dihydroartemisinin in cancer cells through promoting autophagy

Honokiol exhibits enhanced antitumor effects with chloroquine by inducing cell death and inhibiting autophagy in human non-small cell lung cancer cells

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