Molecular Consequences of Depression Treatment: A Potential In Vitro Mechanism for Antidepressants-Induced Reprotoxic Side Effects

The incidence of depression among humans is growing worldwide, and so is the use of antidepressants. However, our fundamental understanding regarding the mechanisms by which these drugs function and their off-target effects against human sexuality remains poorly defined. The present study aimed to determine their differential toxicity on mouse spermatogenic cells and provide mechanistic data of cell-specific response to antidepressant and neuroleptic drug treatment. To directly test reprotoxicity, the spermatogenic cells (GC-1 spg and GC-2 spd cells) were incubated for 48 and 96 h with amitriptyline (hydrochloride) (AMI), escitalopram (ESC), fluoxetine (hydrochloride) (FLU), imipramine (hydrochloride) (IMI), mirtazapine (MIR), olanzapine (OLZ), reboxetine (mesylate) (REB), and venlafaxine (hydrochloride) (VEN), and several cellular and biochemical features were assessed. Obtained results reveal that all investigated substances showed considerable reprotoxic potency leading to micronuclei formation, which, in turn, resulted in upregulation of telomeric binding factor (TRF1/TRF2) protein expression. The TRF-based response was strictly dependent on p53/p21 signaling and was followed by irreversible G2/M cell cycle arrest and finally initiation of apoptotic cell death. In conclusion, our findings suggest that antidepressants promote a telomere-focused DNA damage response in germ cell lines, which broadens the established view of antidepressants’ and neuroleptic drugs’ toxicity and points to the need for further research in this topic with the use of in vivo models and human samples.

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W436, a novel SMART derivative, exhibits anti‐hepatocarcinoma activity by inducing apoptosis and G2/M cell cycle arrest in vitro and in vivo and induces protective autophagy

Journal of Biochemical and Molecular Toxicology ◽

10.1002/jbt.22831 ◽

2021 ◽

Author(s):

Shuai Man ◽

Zhuzhu Wu ◽

Rui Sun ◽

Qi Guan ◽

Zengqiang Li ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

M Cell ◽

Cycle Arrest

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Inhibition of histone methyltransferase DOT1L silences ERα gene and blocks proliferation of antiestrogen-resistant breast cancer cells

Science Advances ◽

10.1126/sciadv.aav5590 ◽

2019 ◽

Vol 5 (2) ◽

pp. eaav5590 ◽

Cited By ~ 21

Author(s):

Giovanni Nassa ◽

Annamaria Salvati ◽

Roberta Tarallo ◽

Valerio Gigantino ◽

Elena Alexandrova ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Gene Transcription ◽

Apoptotic Cell ◽

Estrogen Receptor Α ◽

Cycle Arrest ◽

H3k79 Methylation ◽

Target Gene Transcription

Breast cancer (BC) resistance to endocrine therapy results from constitutively active or aberrant estrogen receptor α (ERα) signaling, and ways to block ERα pathway in these tumors are sought after. We identified the H3K79 methyltransferase DOT1L as a novel cofactor of ERα in BC cell chromatin, where the two proteins colocalize to regulate estrogen target gene transcription. DOT1L blockade reduces proliferation of hormone-responsive BC cells in vivo and in vitro, consequent to cell cycle arrest and apoptotic cell death, with widespread effects on ER-dependent gene transcription, including ERα and FOXA1 gene silencing. Antiestrogen-resistant BC cells respond to DOT1L inhibition also in mouse xenografts, with reduction in ERα levels, H3K79 methylation, and tumor growth. These results indicate that DOT1L is an exploitable epigenetic target for treatment of endocrine therapy–resistant ERα-positive BCs.

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Effect of Marsdenia tenacissima extract on G2/M cell cycle arrest by upregulating 14-3-3σ and downregulating c-myc in vitro and in vivo

Chinese Herbal Medicines ◽

10.1016/j.chmed.2019.03.002 ◽

2019 ◽

Vol 11 (2) ◽

pp. 169-176 ◽

Cited By ~ 1

Author(s):

Li Sun ◽

Qurat UI Ain ◽

Ying-sheng Gao ◽

Ghulam Jilany Khan ◽

Sheng-tao Yuan ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

M Cell ◽

Cycle Arrest ◽

Marsdenia Tenacissima

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Romidepsin Induces G2/M Phase Arrest and Apoptosis in Cholangiocarcinoma Cells

Technology in Cancer Research & Treatment ◽

10.1177/1533033820960754 ◽

2020 ◽

Vol 19 ◽

pp. 153303382096075

Author(s):

Pihong Li ◽

Luguang Liu ◽

Xiangguo Dang ◽

Xingsong Tian

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Antitumor Effect ◽

Caspase 3 ◽

M Cell ◽

Cycle Arrest ◽

Phase Arrest ◽

M Phase

Background: Cholangiocarcinoma (CCA) is an extremely intractable malignancy since most patients are already in an advanced stage when firstly discovered. CCA needs more effective treatment, especially for advanced cases. Our study aimed to evaluate the effect of romidepsin on CCA cells in vitro and in vivo and explore the underlying mechanisms. Methods: The antitumor effect was determined by cell viability, cell cycle and apoptosis assays. A CCK-8 assay was performed to measure the cytotoxicity of romidepsin on CCA cells, and flow cytometry was used to evaluate the effects of romidepsin on the cell cycle and apoptosis. Moreover, the in vivo effects of romidepsin were measured in a CCA xenograft model. Results: Romidepsin could reduce the viability of CCA cells and induce G2/M cell cycle arrest and apoptosis, indicating that romidepsin has a significant antitumor effect on CCA cells in vitro. Mechanistically, the antitumor effect of romidepsin on the CCA cell lines was mediated by the induction of G2/M cell cycle arrest and promotion of cell apoptosis. The G2/M phase arrest of the CCA cells was associated with the downregulation of cyclinB and upregulation of the p-cdc2 protein, resulting in cell cycle arrest. The apoptosis of the CCA cells induced by romidepsin was attributed to the activation of caspase-3. Furthermore, romidepsin significantly inhibited the growth of the tumor volume of the CCLP-1 xenograft, indicating that romidepsin significantly inhibited the proliferation of CCA cells in vivo. Conclusions: Romidepsin suppressed the proliferation of CCA cells by inducing cell cycle arrest through cdc2/cyclinB and cell apoptosis by targeting caspase-3/PARP both in vitro and in vivo, indicating that romidepsin is a potential therapeutic agent for CCA.

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Ethanolic Extract of Senna velutina Roots: Chemical Composition, In Vitro and In Vivo Antitumor Effects, and B16F10-Nex2 Melanoma Cell Death Mechanisms

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/5719483 ◽

2019 ◽

Vol 2019 ◽

pp. 1-14 ◽

Cited By ~ 3

Author(s):

David Tsuyoshi Hiramatsu Castro ◽

Jaqueline Ferreira Campos ◽

Marcio José Damião ◽

Heron Fernandes Vieira Torquato ◽

Edgar Julian Paredes-Gamero ◽

...

Keyword(s):

Cell Cycle ◽

Chemical Composition ◽

Caspase 3 ◽

Tumor Volume ◽

Apoptotic Cell ◽

Ethanolic Extract ◽

Antitumor Effects ◽

Cycle Arrest

Cutaneous melanoma is among the most aggressive types of cancer, and its rate of occurrence increases every year. Current pharmacological treatments for melanoma are not completely effective, requiring the identification of new drugs. As an alternative, plant-derived natural compounds are described as promising sources of new anticancer drugs. In this context, the objectives of this study were to identify the chemical composition of the ethanolic extract of Senna velutina roots (ESVR), to assess its in vitro and in vivo antitumor effects on melanoma cells, and to characterize its mechanisms of action. For these purposes, the chemical constituents were identified by liquid chromatography coupled to high-resolution mass spectrometry. The in vitro activity of the extract was assessed in the B16F10-Nex2 melanoma cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and based on the apoptotic cell count; DNA fragmentation; necrostatin-1 inhibition; intracellular calcium, pan-caspase, and caspase-3 activation; reactive oxygen species (ROS) levels; and cell cycle arrest. The in vivo activity of the extract was assessed in models of tumor volume progression and pulmonary nodule formation in C57Bl/6 mice. The chemical composition results showed that ESVR contains flavonoid derivatives of the catechin, anthraquinone, and piceatannol groups. The extract reduced B16F10-Nex2 cell viability and promoted apoptotic cell death as well as caspase-3 activation, with increased intracellular calcium and ROS levels as well as cell cycle arrest at the sub-G0/G1 phase. In vivo, the tumor volume progression and pulmonary metastasis of ESVR-treated mice decreased over 50%. Combined, these results show that ESVR had in vitro and in vivo antitumor effects, predominantly by apoptosis, thus demonstrating its potential as a therapeutic agent in the treatment of melanoma and other types of cancer.

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Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1811432115 ◽

2018 ◽

Vol 115 (50) ◽

pp. E11721-E11730 ◽

Cited By ~ 32

Author(s):

Soo Jeong Park ◽

Jeong Mi Kim ◽

Jihyo Kim ◽

Jaehark Hur ◽

Sun Park ◽

...

Keyword(s):

Inflammatory Mediators ◽

Molecular Mechanisms ◽

Apoptotic Cell ◽

Inflammatory Factors ◽

In Vivo Models ◽

Marker Proteins ◽

Sphingosine 1 Phosphate ◽

Molecular Patterns

Recent research has led to contradictory notions regarding the conventional theory that apoptotic cell death can evoke inflammatory or immunogenic responses orchestrated by released damage-associated patterns (DAMPs). By inducing IL-1β from bone marrow-derived macrophages in an effort to determine the inflammatory mediators released from apoptotic cells, we found that exosomal fractions called “apoptotic exosome-like vesicles” (AEVs) prepared from apoptotic-conditioned medium were the main inflammatory factors. These AEVs showed characteristics of exosomes in their size, density, morphology, and protein expression but had unique marker proteins, sphingosine-1-phosphate receptors 1 and 3 (S1PR1 and 3). Their biogenesis was completely dependent on cellular sphingosine-1-phosphate (S1P)/S1PRs signaling from multiple fine spindles of plasma membrane accompanied by F-actin, S1PR1, S1PR3, and CD63 at the early apoptotic phase and progressing to the maturation of F-actin–guided multivesicular endosomes mediated by Gβγ subunits of S1PRs downstream. S1P-loaded S1PRs on AEVs were critical factors for inducing IL-1β via NF-κB transcriptional factor and p38 MAPK, possibly through the RHOA/NOD2 axis, in differentiating macrophages. The AEVs induced genes of proinflammatory cytokines, chemokines, and mediators in both in vitro and in vivo models. In conclusion, AEVs could be key inflammatory mediators, acting as DAMPs that could explain the pathogeneses of various chronic inflammations, autoimmune diseases, or cancers in the future.

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The Cytoprotective and Anti-cancer Potential of Bisbenzylisoquinoline Alkaloids from Nelumbo nucifera

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666191116160908 ◽

2020 ◽

Vol 19 (32) ◽

pp. 2940-2957 ◽

Cited By ~ 5

Author(s):

Prasath Manogaran ◽

Narasimha Murthy Beeraka ◽

Viswanadha Vijaya Padma

Keyword(s):

Map Kinases ◽

Apoptotic Cell ◽

Neurological Diseases ◽

Nelumbo Nucifera ◽

Ros Generation ◽

In Vivo Models ◽

Bisbenzylisoquinoline Alkaloids ◽

Cerebrovascular Stroke

: Natural product therapy has been gaining therapeutic importance against various diseases, including cancer. The failure of chemotherapy due to its associated adverse effects promoted adjunct therapy with natural products. Phytochemicals exert anti-carcinogenic activities through the regulation of various cell signaling pathways such as cell survival, inflammation, apoptosis, autophagy and metastasis. The ‘small molecule-chemosensitizing agents’ from plants induce apoptosis in drug-resistant and host-immune resistant cancer cells in in vitro as well as in vivo models. For example, alkaloids from Nelumbo nucifera, liensinine, isoliensinine and neferine exert the anticancer activity through enhanced ROS generation, activation of MAP kinases, followed by induction of autophagy and apoptotic cell death. Likewise, these alkaloids also exert their cytoprotective action against cerebrovascular stroke/ischemic stroke, diabetes, and chemotherapy-induced cytotoxicity. Therefore, the present review elucidates the pharmacological activities of these bisbenzylisoquinoline alkaloids which include the cytoprotective, anticancer and chemosensitizing abilities against various diseases such as cardiovascular diseases, neurological diseases and cancer.

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Antitumour effect of polyoxomolybdates: induction of apoptotic cell death and autophagy in in vitro and in vivo models

British Journal of Cancer ◽

10.1038/sj.bjc.6604133 ◽

2007 ◽

Vol 98 (2) ◽

pp. 399-409 ◽

Cited By ~ 78

Author(s):

A Ogata ◽

H Yanagie ◽

E Ishikawa ◽

Y Morishita ◽

S Mitsui ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Antitumour Effect ◽

In Vivo Models

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Prunellae Spica Extract Suppresses Teratoma Formation of Pluripotent Stem Cells through p53-Mediated Apoptosis

Nutrients ◽

10.3390/nu12030721 ◽

2020 ◽

Vol 12 (3) ◽

pp. 721 ◽

Cited By ~ 2

Author(s):

Aeyung Kim ◽

Seo-Young Lee ◽

Chang-Seob Seo ◽

Sun-Ku Chung

Keyword(s):

Stem Cells ◽

Pluripotent Stem Cells ◽

Apoptotic Cell ◽

Embryonic Stem ◽

M Cell ◽

In Ovo ◽

Differentiated Cells ◽

Teratoma Formation

Induced pluripotent stem cells (iPSCs) have similar properties to embryonic stem cells in terms of indefinite self-renewal and differentiation capacity. After in vitro differentiation of iPSCs, undifferentiated iPSCs (USCs) may exist in cell therapy material and can form teratomas after in vivo transplantation. Selective elimination of residual USCs is, therefore, very important. Prunellae Spica (PS) is a traditional medicinal plant that has been shown to exert anti-cancer, antioxidant, and anti-inflammatory activities; however, its effects on iPSCs have not been previously characterized. In this study, we find that ethanol extract of PS (EPS) effectively induces apoptotic cell death of USCs through G2/M cell cycle arrest, generation of intracellular reactive oxygen species, alteration of mitochondrial membrane potentials, and caspase activation of USCs. In addition, EPS increases p53 accumulation and expression of its downstream targets. In p53 knockout (KO) iPSCs, the EPS did not induce apoptosis, indicating that EPS-mediated apoptosis of USCs was p53-dependent. In addition, EPS was not genotoxic towards iPSCs-derived differentiated cells. EPS treatment before injection efficiently prevented in ovo teratoma formation of p53 wild-type (WT) iPSCs but not p53KO iPSCs. Collectively, these results indicate that EPS has potent anti-teratoma activity and no genotoxicity to differentiated cells. It can, therefore, be used in the development of safe and efficient iPSC-based cell therapies.

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