Niclosamide induces mitochondria fragmentation and promotes both apoptotic and autophagic cell death

Park, Soo‐Young; Shin, Ji Hyun; Kang, Hee Eun; Hwang, Jung Jin; Cho, Dong‐Hyung

doi:10.5483/bmbrep.2011.44.8.517

Cited by 67 publications

(49 citation statements)

References 30 publications

(37 reference statements)

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“…Both pathways can be activated with TNF-α treatment. Caspase-8 is mainly involved in the mitochondria-independent pathway and caspase-9 is known to play an important role in the mitochondria-dependent pathway (24,25). Our data shows that both caspase-8 and caspase-9 are activated in Parkin＋ TNF-α cells.…”

Section: Discussionsupporting

confidence: 48%

“…Caspase-8 and caspase-9 are upstream molecules of caspase-3/-7 (23). Caspase-8 is mainly involved in the mitochondria-independent pathway and caspase-9 is involved in the mitochondria-dependent pathway (24,25). To determine which of these pathways are activated in Parkin＋TNF-α cells, we assessed the formation of cleaved caspase-8 and cleaved caspase-9.…”

Section: Parkin Expression Results In Tnf-α-induced Apoptotic Cell Deathmentioning

confidence: 99%

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Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells

Lee¹,

Lee²,

Kang³

et al. 2012

BMB Reports

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Section: Discussionsupporting

confidence: 48%

Section: Parkin Expression Results In Tnf-α-induced Apoptotic Cell Deathmentioning

confidence: 99%

Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells

Lee¹,

Lee²,

Kang³

et al. 2012

BMB Reports

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“…We previously showed some autophagy regulators in cancer cells. 23,24) In the present study, we identified Sertindole as a potent autophagy inducer in neuroblastoma cells. From the screening, we also discovered several known autophagy regulator not only cyclosphorinA, niclosamide but also some dopamine receptor antagonists such as Pimozide.…”

Section: Discussionmentioning

confidence: 94%

Sertindole, a Potent Antagonist at Dopamine D<sub>2</sub> Receptors, Induces Autophagy by Increasing Reactive Oxygen Species in SH-SY5Y Neuroblastoma Cells

Shin

Park

Kim

et al. 2012

Biological & Pharmaceutical Bulletin

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Autophagy is associated with cell survival and cell death. Autophagy is implicated in the pathophysiology of various human diseases. In order to identify autophagy regulatory molecules, we screened a chemical drug library in SH-SY5Y cells and selected Sertindole as a potent autophagy inducer. Sertindole was developed as an antipsychotic drug for Schizophrenia. Sertindole treatment highly induced the formation of autophagosomes as well as LC3 conversion. Subsequently, Sertindole-induced autophagy was efficiently suppressed by down regulation of ATG5. Sertindole also increased reactive oxygen species (ROS) production, which contributes to autophagy-associated cell death in neuroblastoma cells. ROS scavengers such as Nacetylcysteine and Trolox suppressed not only ROS generation but also autophagy activation by Sertindole. These results suggest Sertindole induces autophagy and autophagy-associated cell death by ROS production in neuroblastoma cells.Key words Sertindole; autophagy; ATG5; reactive oxygen species; SH-SY5Y cell Autophagy refers to a highly conserved lysosome-dependent degradation mechanism that involves the removal of cytoplasmic proteins and organelles.1,2) Autophagy plays important role in development, immune defense, and cell death. The fundamental role of autophagy helps cell survival under stressful conditions by enhancing metabolic homeostasis. However, autophagy may also contribute to non-apoptotic cell death processes under some conditions. 3-6) Indeed, autophagy has been implicated in many pathophysiologic conditions such as neurodegenerative diseases such as cancer, type 2 diabetes, infectious diseases, cardiomyopathies, and innate immune diseases.3-6) Therefore, understanding the molecular mechanism of autophagy may help to develop new therapeutic strategies for those diseases. Based on this notion, several groups reported on small molecules that modulate autophagy and can be used as potential therapeutic drugs. 7,8) For example, Rapamycin, an autophagy inducer, enhances clearance of intracellular aggregate proteins associated with Huntington's disease. 9,10) In addition, some autophagy regulators sensitize tumor cells to anticancer therapy. 11) However, the precise mechanisms of autophagy in pathological conditions are not fully understood.Schizophrenia (SZ) is a complex mental disorder often associated with cognitive impairment and depressive symptoms that affects about 1% of the population. SZ is caused by environmental and genetic risk factors or their interactions.12) Although, several genome wide association studies have identified SZ-related genes, the molecular mechanism is still largely unknown. [13][14][15] The primary treatment for SZ is antipsychotic medications.16,17) Sertindole, a phenylindole derivative was developed as an antipsychotic drug. It is a potent antagonist at dopamine D 2 , serotonin 5-HT 2 , and α 1 -adrenergic receptors with high affinity. 18,19) Additionally, Sertindole suppresses potassium channel in the brain and heart. 20,21) In contrast to other antipsychotic...

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“…Niclosamide inhibits multiple signaling pathways that regulate cancer progression such as the mTORC1 (Fonseca et al, 2012), NF-kB (Jin et al, 2010), and Notch pathways (Wang et al, 2009). It also induces cell cycle arrest, growth inhibition and apoptosis by targeting mitochondria (Park et al, 2011). Moreover, niclosamide shows strong inhibitory effects on the growth of cancer stem cells (Jin et al, 2010;Li et al, 2014;Pan et al, 2012).…”

Section: Introductionmentioning

confidence: 98%

Metabolism of the anthelmintic drug niclosamide by cytochrome P450 enzymes and UDP-glucuronosyltransferases: metabolite elucidation and main contributions from CYP1A2 and UGT1A1

Zhang

et al. 2015

Xenobiotica

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1. Niclosamide is an old anthelmintic drug that shows potential in fighting against cancers. Here, we characterized the metabolism of niclosamide by cytochrome P450 enzymes (CYPs) and UDP-glucuronosyltransferases (UGTs) using human liver microsomes (HLM) and expressed enzymes. 2. NADPH-supplemented HLM (and liver microsomes from various animal species) generated one hydroxylated metabolite (M1) from niclosamide; and UDPGA-supplemented liver microsomes generated one mono-O-glucuronide (M2). The chemical structures of M1 (3-hydroxy niclosamide) and M2 (niclosamide-2-O-glucuronide) were determined through LC-MS/MS and/or NMR analyses. 3. Reaction phenotyping revealed that CYP1A2 was the main enzyme responsible for M1 formation. The important role of CYP1A2 in niclosamide metabolism was further confirmed by activity correlation analyses as well as inhibition experiments using specific inhibitors. 4. Although seven UGT enzymes were able to catalyze glucuronidation of niclosamide, UGT1A1 and 1A3 were the enzymes showed the highest metabolic activities. Activity correlation analyses demonstrated that UGT1A1 played a predominant role in hepatic glucuronidation of niclosamide, whereas the role of UGT1A3 was negligible. 5. In conclusion, niclosamide was subjected to efficient metabolic reactions hydroxylation and glucuronidation, wherein CYP1A2 and UGT1A1 were the main contributing enzymes, respectively.

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Niclosamide induces mitochondria fragmentation and promotes both apoptotic and autophagic cell death

Cited by 67 publications

References 30 publications

Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells

Parkin induces apoptotic cell death in TNF-α-treated cervical cancer cells

Sertindole, a Potent Antagonist at Dopamine D<sub>2</sub> Receptors, Induces Autophagy by Increasing Reactive Oxygen Species in SH-SY5Y Neuroblastoma Cells

Metabolism of the anthelmintic drug niclosamide by cytochrome P450 enzymes and UDP-glucuronosyltransferases: metabolite elucidation and main contributions from CYP1A2 and UGT1A1

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