Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

Liu, Siwei; Liang, Bing; Jia, Huijue; Jiao, Yuhan; Pang, Zhongqiu; Huang, Yongye

doi:10.1002/2211-5463.12223

Cited by 29 publications

(26 citation statements)

References 59 publications

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“…We observe a reduction in mitochondrial content in melatonin treated BeWo cells exposed to H/R, which may indicate heightened levels of mitophagy, and which has been shown to be harmful for cancer cells [44, 45]. Our result showing the decreased mitochondrial content of cancer cells exposed to H/R and treated with melatonin corroborates other studies that have found antiproliferative and pro-apoptotic activity of melatonin, evident in both in vitro and in vivo models as well as in clinical assays for an array of diverse cancers [19, 42, 43].…”

Section: Discussionsupporting

confidence: 89%

“…Consequent to JNK inhibition, autophagy activation has been shown to be decreased in a hepatoma cell line [41]. Other studies indicate that the inhibitory effect of melatonin on autophagy may be mediated by the activation of endoplasmic reticulum (ER)-stress [42, 43]. The lack of variation in the levels of LC3B lipidation in melatonin-treated BeWo cells is not related to the lack of autophagic activity, but rather arises as a consequence of the active destruction of defective mitochondria via mitophagy [39].…”

Section: Discussionmentioning

confidence: 99%

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Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Sagrilo-Fagundes

Bienvenue-Pariseault

Vaillancourt

2018

Preprint

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HighlightsH/R induces autophagy and Nrf2 in tumoral and primary trophoblast cells.Melatonin inhibits autophagy and Nrf2 under H/R, inducing BeWo cell death.Melatonin increases autophagy and Nrf2 under H/R conditions, promoting primary villous trophoblast cells survival.AbstractHypoxia/reoxygenation (H/R) induces oxidative damage and apoptosis. These consequences activate autophagy, which degrades damaged cellular content, as well as inducing the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor, and thereby the expression of protective genes. Melatonin has protective roles in normal cells and cytotoxic actions in cancer cells, with effects involving autophagy and Nrf2 pathways. The current study shows melatonin to differentially modulate autophagy and Nrf2 pathways in tumor and normal placental cells exposed to H/R. BeWo, a human placental choriocarcinoma cell line, and primary villous cytotrophoblasts isolated from normal term placenta, were maintained in normoxia (8% O2) for 24 h or exposed to hypoxia (0.5% of O2 for 4 h) followed by 20 h of normoxia, creating a H/R, in the presence or absence of 1 mM melatonin. Melatonin induced a 7-fold increase in the activation of 5’ adenosine monophosphate-activated protein kinase (AMPK)α, an upstream modulator of autophagy, rising to a 16-fold increase in cells co-exposed to H/R and melatonin, compared to controls. H/R induced autophagosome formation via the increased expression of Beclin-1 (by 94 %) and ATG7 (by 97%). H/R also induced autophagic activity, indicated by the by the 630% increase in P62, and increased Nrf2 by 314%. In H/R conditions, melatonin reduced autophagy by 74% and Nrf2 expression by 66%, leading to BeWo cell apoptosis. In contrast, in human primary villous cytotrophoblasts, H/R induced autophagy and Nrf2, which melatonin further potentiated, thereby affording protection against H/R. This study demonstrates that melatonin differentially modulates autophagy and the Nrf2 pathway in normal vs. tumor trophoblast cells, being cytoprotective in normal cells whilst increasing apoptosis in tumoral trophoblast cells.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Sagrilo-Fagundes

Bienvenue-Pariseault

Vaillancourt

2018

Preprint

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“…Valproic acid (VA) inhibits invasiveness of bladder cancer. When combined with melatonin, VA exhibits enhanced autophagy by triggering several autophagic genes including Beclin1, Atg3 and Atg5 [143]. Collectively, the results support the use of melatonin as a chemotherapeutic in the treatment of these tumors of the gastrointestinal system due to their ability to enhance cancer cell autophagy.…”

Section: Autophagysupporting

confidence: 58%

Advances in Characterizing Recently-Identified Molecular Actions of Melatonin: Clinical Implications

Reíter¹,

Sharma²,

Rosales-Corral³

et al. 2020

Human Perspectives in Health Sciences and Technology

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IntroductionSome system-wide functions/aspects of melatonin were identified decades ago, e.g., regulation of seasonal reproduction [51,200,201], photoperiodic control of pineal melatonin synthesis [122,227], sleep initiation [31,117], antioxidant actions [67, 197], circadian rhythm modulation [208,279], cancer inhibition [27,86,163], etc. These aspects of melatonin are generally well known by the scientists working in the field, although the detailed mechanisms of these actions, in most cases, require further clarification. These functions are not discussed in detail in the current review, but they may be mentioned when they are germane to the discussion. Also, the functions of melatonin in plants [18,61,62,194] are not considered even though

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“…It has been documented that melatonin modulates the signalling of neuronal cell death [47] and bladder cancer cells induced by ERS [48]. Melatonin significantly reverses tunicamycin-induced ERS in human hepatocellular carcinoma cells and improves cytotoxic responses to doxorubicin by increasing the expression of CHOP [49].…”

Section: Discussionmentioning

confidence: 99%

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

Cui

Ren

et al. 2017

Cell Physiol Biochem

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Background/Aims: Busulfan is commonly used for cancer chemotherapy. Although it has the advantage of increasing the survival rate of patients, it can cause male infertility via damaging the testes and reducing sperm counts. Therefore, the underlying mechanism should be explored, and new agents should be developed to protect the male reproductive system from busulfan-induced damage. Endoplasmic reticulum stress (ERS) is considered a key contributor to numerous pathologies. Despite several studies linking ERS to toxicants, studies have yet to determine whether ERS is a contributing factor to busulfan-induced testicular damage. Melatonin is a well-known broad-spectrum antioxidant, anti-inflammatory and antitumour agent, but the effects of melatonin on busulfan-induced ERS in mouse testes damage are less documented. Methods: The effects of melatonin were measured by immunofluorescence staining, Western blot, qRT-PCR analysis and flow cytometry assay. The underlying mechanism was investigated by measuring ERS. Results: We found that ERS was strongly activated in mouse testes (in vivo) and the C18-4 cell line (in vitro) after busulfan administration. ERS-related apoptosis proteins such as caspase-12, CHOP and caspase-3 were activated, and the expression of apoptotic proteins such as P53 and PUMA were upregulated. Furthermore, we investigated whether melatonin reduced the extent of damage to mouse testes and improved the survival rates of busulfan-treated mice. When exploring the underlying mechanisms, we found melatonin could counteract ERS by decreasing the expression levels of the ERS markers GRP78, ATF6, pIRE1 and XBP1 in mouse testes and mouse SSCs (C18-4 cells). Moreover, it blocked the activation of ERS-related apoptosis proteins caspase-12, CHOP and caspase-3 and suppressed P53 and PUMA expression stimulated by busulfan both in vivo and in vitro. Conclusion: Our results demonstrate that ERS is an important mediator for busulfan-induced apoptosis. The attenuation of ERS by melatonin can prevent busulfan-treated SSCs apoptosis and protect busulfan-treated testes from damage. Thus, this study suggests that melatonin may alleviate the side effects of busulfan for male patients during clinical treatment.

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Evaluation of cell death pathways initiated by antitumor drugs melatonin and valproic acid in bladder cancer cells

Cited by 29 publications

References 59 publications

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Melatonin: The smart molecule that differentially modulates autophagy in tumor and normal placental cells

Advances in Characterizing Recently-Identified Molecular Actions of Melatonin: Clinical Implications

Melatonin Relieves Busulfan-Induced Spermatogonial Stem Cell Apoptosis of Mouse Testis by Inhibiting Endoplasmic Reticulum Stress

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