scholarly journals Role for Caspase-Mediated Cleavage of Rad51 in Induction of Apoptosis by DNA Damage

1999 ◽  
Vol 19 (4) ◽  
pp. 2986-2997 ◽  
Author(s):  
YinYin Huang ◽  
Shuji Nakada ◽  
Takatoshi Ishiko ◽  
Taiju Utsugisawa ◽  
Rakesh Datta ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Mammalian Cells ◽  
Caspase 3 ◽  
Apoptotic Response ◽  
Cell Death Response ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis ◽  
Dependent Mechanism

ABSTRACT We report here that the Rad51 recombinase is cleaved in mammalian cells during the induction of apoptosis by ionizing radiation (IR) exposure. The results demonstrate that IR induces Rad51 cleavage by a caspase-dependent mechanism. Further support for involvement of caspases is provided by the finding that IR-induced proteolysis of Rad51 is inhibited by Ac-DEVD-CHO. In vitro studies show that Rad51 is cleaved by caspase 3 at a DVLD/N site. Stable expression of a Rad51 mutant in which the aspartic acid residues were mutated to alanines (AVLA/N) confirmed that the DVLD/N site is responsible for the cleavage of Rad51 in IR-induced apoptosis. The functional significance of Rad51 proteolysis is supported by the finding that, unlike intact Rad51, the N- and C-terminal cleavage products fail to exhibit recombinase activity. In cells, overexpression of the Rad51(D-A) mutant had no effect on activation of caspase 3 but did abrogate in part the apoptotic response to IR exposure. We conclude that proteolytic inactivation of Rad51 by a caspase-mediated mechanism contributes to the cell death response induced by DNA damage.

The P-MAPA immunomodulator partially prevents apoptosis induced by Zika virus infection in THP-1 cells

2020 ◽  
Vol 21 ◽  
Author(s):  
Morganna C. Lima ◽  
Elisa A. N. Azevedo ◽  
Clarice N. L. de Morais ◽  
Larissa I. O. de Sousa ◽  
Bruno M. Carvalho ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Virus Infection ◽  
Virus Replication ◽  
Zika Virus ◽  
Mammalian Cells ◽  
Caspase 3 ◽  
Neurological Complications ◽  
Zika Virus Infection

Background: Zika virus is an emerging arbovirus of global importance. ZIKV infection is associated with a range of neurological complications such as the Congenital Zika Syndrome and Guillain Barré Syndrome. Despite the magnitude of recent outbreaks, there is no specific therapy to prevent or to alleviate disease pathology. Objective: To investigate the role of P-MAPA immunomodulator in Zika-infected THP-1 cells. Methods: THP-1 cells were subjected at Zika virus infection (Multiplicity of Infection = 0.5) followed by treatment with P-MAPA for until 96 hours post-infection. After that, the cell death was analyzed by annexin+/ PI+ and caspase 3/ 7+ staining by flow cytometry. In addition, the virus replication and cell proliferation were accessed by RT-qPCR and Ki67 staining, respectively. Results: We demonstrate that P-MAPA in vitro treatment significantly reduces Zika virus-induced cell death and caspase-3/7 activation on THP-1 infected cells, albeit it has no role in virus replication and cell proliferation. Conclusions: Our study reveals that P-MAPA seems to be a satisfactory alternative to inhibits the effects of Zika virus infection in mammalian cells.

4-Acetyl-12,13-Epoxyl-9-Trichothecene-3,15-Diol from Isaria japonica Mediates Apoptosis of Rat Bladder Carcinoma NBT-II Cells by Decreasing Anti-apoptotic Bcl-2 Expression and Increasing Pro-apoptotic Bax Expression

2004 ◽  
Vol 32 (03) ◽  
pp. 377-387 ◽  
Author(s):  
Hyung-Jin Kim ◽  
Seon Il Jang ◽  
Young-Jun Kim ◽  
Hyun-Ock Pae ◽  
Hae-Young Won ◽  
...  
Keyword(s):  
Cell Death ◽  
Bladder Carcinoma ◽  
Cytotoxic Effect ◽  
Caspase 3 ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Rat Bladder ◽  
Apoptotic Protein ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

We studied the effect of 4-acetyl-12,13-epoxyl-9-trichothecene-3,15-diol (AETD) isolated from Isaria japonica, one of the most popular Chinese fungal medicines, on the induction of apoptosis in rat bladder carcinoma NBT-II cells. AETD was cytotoxic to NBT-II cells, and this cytotoxic effect appears to be attributed to its induction of apoptotic cell death, as AETD induced nuclear morphological changes and internucleosomal DNA fragmentation, and increased the proportion of hypodiploid cells and activity of caspase-3. AETD treatment also decreased the expression of the anti-apoptotic protein Bcl-2 and increased the expression of the pro-apoptotic protein Bax. These results provide important information in understanding the mechanism(s) of AETD-induced apoptosis.

scholarly journals Salmonella-Induced Caspase-2 Activation in Macrophages

2000 ◽  
Vol 192 (7) ◽  
pp. 1035-1046 ◽  
Author(s):  
Veronika Jesenberger ◽  
Katarzyna J. Procyk ◽  
Junying Yuan ◽  
Siegfried Reipert ◽  
Manuela Baccarini
Keyword(s):  
Type Iii Secretion ◽  
Caspase 3 ◽  
Secretion System ◽  
Caspase 1 ◽  
Chemical Inhibition ◽  
Induction Of Apoptosis ◽  
Caspase 2 ◽  
Induced Apoptosis

The enterobacterial pathogen Salmonella induces phagocyte apoptosis in vitro and in vivo. These bacteria use a specialized type III secretion system to export a virulence factor, SipB, which directly activates the host's apoptotic machinery by targeting caspase-1. Caspase-1 is not involved in most apoptotic processes but plays a major role in cytokine maturation. We show that caspase-1–deficient macrophages undergo apoptosis within 4–6 h of infection with invasive bacteria. This process requires SipB, implying that this protein can initiate the apoptotic machinery by regulating components distinct from caspase-1. Invasive Salmonella typhimurium targets caspase-2 simultaneously with, but independently of, caspase-1. Besides caspase-2, the caspase-1–independent pathway involves the activation of caspase-3, -6, and -8 and the release of cytochrome c from mitochondria, none of which occurs during caspase-1–dependent apoptosis. By using caspase-2 knockout macrophages and chemical inhibition, we establish a role for caspase-2 in both caspase-1–dependent and –independent apoptosis. Particularly, activation of caspase-1 during fast Salmonella-induced apoptosis partially relies on caspase-2. The ability of Salmonella to induce caspase-1–independent macrophage apoptosis may play a role in situations in which activation of this protease is either prevented or uncoupled from the induction of apoptosis.

Honokiol Induces Autophagic Apoptosis in Neuroblastoma Cells through a P53-Dependent Pathway

2019 ◽  
Vol 47 (04) ◽  
pp. 895-912 ◽  
Author(s):  
Ming-Chung Lin ◽  
Yuan-Wen Lee ◽  
Yuan-Yun Tseng ◽  
Yung-Wei Lin ◽  
Jui-Tai Chen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Therapeutic Option ◽  
Neuroblastoma Cells ◽  
Cytochrome C Release ◽  
Dependent Pathway ◽  
Dependent Mechanism ◽  
Stimulation Of

In children, neuroblastomas are the most common and deadly solid tumor. Our previous studies showed that honokiol can cross the blood–brain barrier and kill neuroblastoma cells. In this study, we further evaluated if exposure to honokiol for short periods could induce autophagy and subsequent apoptosis of neuroblastoma cells and possible mechanisms. Exposure of neuroblastoma neuro-2a cells to honokiol for 24[Formula: see text]h induced morphological shrinkage and cell death. As to the mechanisms, honokiol consecutively induced cytochrome c release from mitochondria, caspase-3 activation, DNA fragmentation and cell apoptosis. Separately, honokiol time-dependently augmented the proportion of autophagic cells and the ratio of light chain 3 (LC3)-II/LC3-I. Pretreatment of neuro-2a cells with 3-methyladenine, an inhibitor of autophagy, attenuated honokiol-induced cell autophagy, caspase-3 activation, DNA damage and cell apoptosis. In contrast, stimulation of autophagy by rapamycin, an inducer of autophagy, significantly enhanced honokiol-induced cell apoptosis. Furthermore, honokiol-induced autophagic apoptosis was confirmed in neuroblastoma NB41A3 cells. Knocking down translation of p53 using RNA interference attenuated honokiol-induced autophagy and apoptosis in neuro-2a and NB41A3 cells. Taken together, this study showed that at early periods, honokiol can induce autophagic apoptosis of neuroblastoma cells through activating a p53-dependent mechanism. Consequently, honokiol has the potential to be a therapeutic option for neuroblastomas.

The mTOR Inhibitor Everolimus Overcomes CXCR4-Mediated Resistance to HDAC Inhibitor Panobinostat through Inhibition of p21 and Mitosis Regulators, Sensitizing MM Cells to DNA-Damaged Induced Apoptosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 891-891
Author(s):  
Katia Beider ◽  
Valeria Voevoda ◽  
Hanna Bitner ◽  
Evgenia Rosenberg ◽  
Hila Magen ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Cell Lines ◽  
Hdac Inhibitor ◽  
Mtor Inhibitor ◽  
Mtor Inhibition ◽  
Induced Apoptosis

Abstract Introduction: Multiple myeloma (MM) is a neoplastic disorder that is characterized by clonal proliferation of plasma cells in the bone marrow (BM). Despite the initial efficacious treatment, MM patients often become refractory to common anti-MM drugs, therefore novel therapies are in need. Pan-histone deacetylase (HDAC) inhibitor panobinostat exerts multiple cytotoxic actions in MM cells in vitro, and was approved for the treatment of relapsed/refractory MM in combination with bortezomib and dexamethasone. Although having promising anti-MM properties, panobinostat lacks therapeutic activity as monotherapy. The aim of the current study was to elucidate the mechanisms underlying MM resistance to panobinostat and to define strategies to overcome it. Results: Panobinostat at the low concentrations (IC50 5-30 nM) suppressed the viability in MM cell lines (n=7) and primary CD138+ cells from MM patients (n=8) in vitro. Sensitivity to panobinostat correlated with reduced expression of chemokine receptor CXCR4, while overexpression of CXCR4 or its ligand CXCL12 in RPMI8226 and CAG MM cell lines significantly (p<0.001) increased their resistance to panobinostat, pointing to the role of the CXCR4 axis in HDACi response. Notably, similar expression levels of class I HDACs (HDAC1-3) were detected in MM cells with either low or high CXCR4. Interaction with BM stromal cells that represent the source of CXCL12 also protected MM cells from panobinostat-induced apoptosis, further strengthening a role for CXCR4 downstream pathway. Decreased sensitivity to cytotoxic effect was concomitant with reduced histone (H3K9 and H4K8) acetylation in response to panobinostat treatment. In addition, resistance to HDACi was associated with the reversible G0/G1 cell growth arrest, whereas sensitivity was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators involved in CXCR4-mediated HDACi resistance revealed the pro-survival AKT/mTOR pathway to be regulated by both CXCR4 over-expression and interaction with BMSCs. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance and induced synergistic cell death of MM cell lines and primary MM cells, but not of normal mononuclear cells (CI<0.4). This effect was concurrent with the increase in DNA double strand breaks, histone H2AX phosphorylation, loss of Dψm, cytochrome c release, caspase 3 activation and PARP cleavage. The increase in DNA damage upon combinational treatment was not secondary to the apoptotic DNA fragmentation, as it occurred similarly when apoptosis onset was blocked by caspase inhibitor z-VAD-fmk. Kinetics studies also confirmed that panobinostat-induced DNA damage preceded apoptosis induction. Strikingly, combined panobinostat/everolimus treatment resulted in sustained DNA damage and irreversible suppression of MM cell proliferation accompanied by robust apoptosis, in contrast to the modest effects induced by single agent. Gene expression analysis revealed distinct genetic profiles of single versus combined exposures. Whereas panobinostat increased the expression of cell cycle inhibitors GADD45G and p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated DNA repair genes, including RAD21, Ku70, Ku80 and DNA-PKcs. Furthermore, combined treatment markedly decreased both mRNA and protein expression of anti-apoptotic factors survivin and BCL-XL, checkpoint regulator CHK1, and G2/M-specific factors PLK1, CDK1 and cyclin B1, therefore suppressing the DNA damage repair and inhibiting mitotic progression. Given the anti-apoptotic role of p21, the synergistic lethal effect of everolimus could be attributed to its ability to suppress p21 induction by panobinostat ensuing the shift in the DNA damage response toward apoptosis. Conclusions: Collectively, our findings indicate that CXCR4/CXCL12 activity promotes the resistance of MM cells to HDACi with panobinostat through mTOR activation. Inhibition of mTOR by everolimus synergizes with panobinostat by simultaneous suppression of p21, G2/M mitotic factors and DNA repair machinery, rendering MM cells incapable of repairing accumulated DNA damage and promoting their apoptosis. Our results unravel the mechanism responsible for strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel therapeutic strategy to eradicate MM. Disclosures No relevant conflicts of interest to declare.

scholarly journals ASAP, a Novel Protein Complex Involved in RNA Processing and Apoptosis

2003 ◽  
Vol 23 (8) ◽  
pp. 2981-2990 ◽  
Author(s):  
Christian Schwerk ◽  
Jayendra Prasad ◽  
Kurt Degenhardt ◽  
Hediye Erdjument-Bromage ◽  
Eileen White ◽  
...  
Keyword(s):  
Cell Death ◽  
Rna Processing ◽  
Protein Complex ◽  
Mammalian Cells ◽  
Cell Extract ◽  
Hela Cell Extract ◽  
In Vitro Splicing ◽  
Induction Of Apoptosis ◽  
Novel Protein

ABSTRACT Different isoforms of a protein complex termed the apoptosis- and splicing-associated protein (ASAP) were isolated from HeLa cell extract. ASAP complexes are composed of the polypeptides SAP18 and RNPS1 and different isoforms of the Acinus protein. While Acinus had previously been implicated in apoptosis and was recently identified as a component of the spliceosome, RNPS1 has been described as a general activator of RNA processing. Addition of ASAP isoforms to in vitro splicing reactions inhibits RNA processing mediated by ASF/SF2, by SC35, or by RNPS1. Additionally, microinjection of ASAP complexes into mammalian cells resulted in acceleration of cell death. Importantly, after induction of apoptosis the ASAP complex disassembles. Taken together, our results suggest an important role for the ASAP complexes in linking RNA processing and apoptosis.

scholarly journals Voruciclib, an Oral, Selective CDK9 Inhibitor, Enhances Cell Death Induced By the Bcl-2 Selective Inhibitor Venetoclax in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1361-1361 ◽  
Author(s):  
Daniel A Luedtke ◽  
Yongwei Su ◽  
Holly Edwards ◽  
Lisa Polin ◽  
Juiwanna Kushner ◽  
...  
Keyword(s):  
Cell Lines ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Combination Index ◽  
Survival Rates ◽  
Annexin V ◽  
Antileukemic Activity ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis

Abstract Introduction: Patients with acute myeloid leukemia (AML) face overall 5-year survival rates of 65% and 27% for children and adults, respectively, leaving significant room for improvement. Relapse remains a major contributor to such low overall survival rates, and leukemic stem cells (LSCs) that survive treatment are believed to be responsible for AML relapse. The anti-apoptotic protein Bcl-2 is overexpressed in bulk AML cells and LSCs and is associated with poor clinical outcomes. Thus, Bcl-2 represents a promising therapeutic target for the treatment of AML. Venetoclax (ABT-199) is a selective Bcl-2 inhibitor that has shown great potential for treating a number of malignancies, including AML. Venetoclax inhibits Bcl-2, preventing it from sequestering pro-apoptotic Bcl-2 family protein Bim, leading to Bim activated Bax/Bak, resulting in apoptosis. However, Mcl-1 can also sequester Bim and prevent apoptosis. We previously showed that directly targeting Mcl-1 can enhance the antileukemic activity of venetoclax (Luedtke DA, et al. Signal Transduct Target Ther. Apr 2017). Alternatively, we proposed that indirect targeting of Mcl-1 may preserve or enhance the antileukemic activity of venetoclax, and prevent resistance resulting from Mcl-1. It has been reported that inhibition of CDK9 can downregulate cell survival genes regulated by superenhancers, including Mcl-1, MYC, and Cyclin D1. One CDK9 inhibitor in clinical development, flavopiridol (alvocidib), has progressed to phase II clinical trials in AML. However, off target effects and dose-limiting toxicities remain a concern. Voruciclib is an oral, selective CDK inhibitor differentiated by its potent inhibition of CDK9 as compared to other CDK inhibitors. This selectivity may potentially circumvent toxicities resulting from inhibition of non-CDK targets like MAK and ICK that are inhibited by flavopiridol. Voruciclib has been shown in vitro to promote apoptosis and decrease Mcl-1 expression levels in chronic lymphocytic leukemia (CLL) cells (Paiva C, et al. PLOS One. Nov 2015) and inhibit tumor growth in mouse xenograft models of diffuse large B-cell lymphoma (DLBCL) in combination with venetoclax (Dey J. et al Scientific Reports. Dec 2017). Based on these data, voruciclib may downregulate Mcl-1 in AML cells and therefore synergistically enhance the antileukemic activity of venetoclax. Methods/Results: Culturing AML cell lines (THP-1, U937, MOLM-13, MV4-11, and OCI-AML3) and primary patient samples with various concentrations of voruciclib resulted in a concentration-dependent increase in Annexin V+ cells (2 μM voruciclib induced 13.8-55.8% Annexin V+ cells) along with increased levels of cleaved caspase 3 and PARP, demonstrating that voruciclib induces apoptosis in AML cells. Next, we tested the combination of voruciclib and venetoclax in AML cell lines and primary AML patient samples at clinically achievable concentrations. Annexin V/PI staining, flow cytometry analysis, and combination index calculation (using CalcuSyn software) revealed synergistic induction of apoptosis by voruciclib and venetoclax combination (combination index values for MV4-11, U937, THP-1, and MOLM-13 cells were <0.73; treatment with 2 µM voruciclib and venetoclax for 24 h resulted in >80% apoptosis). Importantly, synergy was observed in both venetoclax sensitive and resistant cell lines. This was accompanied by increased cleavage of caspase 3 and PARP. Lentiviral shRNA knockdown of Bak and Bax partially rescued AML cells from voruciclib-induced apoptosis, showing that voruciclib induces apoptosis at least partially through the intrinsic apoptosis pathway. However, Bak and Bax knockdown had little to no effect on induction of apoptosis by the combination treatment, indicating that there might be other molecular mechanisms underlying the synergistic interaction between the two agents. Treatment with the pan-caspase inhibitor Z-VAD-FMK partially rescued cells from combination treatment induced-apoptosis. Discussion: Collectively, these results demonstrate that voruciclib and venetoclax synergistically induce apoptosis in AML cells in vitro and reverse venetoclax resistance. Further studies to determine the mechanism of action and in vivo efficacy of this promising combination in AML xenografts and PDX models are underway. Disclosures Ge: MEI Pharma: Research Funding.

Abstract 1950: Role of Superoxide, Nitric Oxide and Peroxynitrite in Doxorubicin-induced Cell Death in vitro and in vivo

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Partha Mukhopadhyay ◽  
Mohanraj Rajesh ◽  
Sandor Bátkai ◽  
György Haskó ◽  
Csaba Szabo ◽  
...  
Keyword(s):  
Cell Death ◽  
Caspase 3 ◽  
Superoxide Generation ◽  
Cytochrome C Release ◽  
Mitochondrial Superoxide ◽  
Induced Apoptosis ◽  
Peroxynitrite Scavengers

Although doxorubicin (DOX) is one of the most potent antitumor agents available, its clinical use is limited because of the risk of severe cardiotoxicity often leading to irreversible congestive heart failure. Apoptotic cell death is a key component in DOX-induced cardiotoxicity, but its trigger(s) and mechanisms are poorly understood. Here, we explore the role of peroxynitrite (a reactive oxidant produced from the diffusion-controlled reaction between nitric oxide and superoxide anion) in DOX-induced cell death. Using a well-established in vivo mouse model of DOX-induced acute heart failure, we demonstrate marked increases in myocardial apoptosis (caspase-3 and 9 gene expression, caspase 3 activity, cytochrome-c release, and TUNEL), iNOS but not eNOS and nNOS expression, 3-nitrotyrosine formation and a decrease in myocardial contractility following DOX treatment. Pre-treatment of mice with peroxynitrite scavengers markedly attenuated DOX-induced myocardial cell death and dysfunction without affecting iNOS expression. DOX induced increased superoxide generation and nitrotyrosine formation in the mitochondria, dissipation of mitochondrial membrane potential, apoptosis (cytochrome-C release, annexin V staining, caspase activation, nuclear fragmentation), and disruption of actin cytoskeleton structure in cardiac-derived H9c2 cells. Selective iNOS inhibitors attenuated DOX-induced apoptosis, without affecting increased mitochondrial superoxide generation, whereas NO donors increased DOX-induced cell death in vitro . The peroxynitrite scavengers FeTMPyP and MnTMPyP markedly reduced both DOX- or peroxynitrite-induced nitrotyrosine formation and cell death in vitro , without affecting DOX-induced increased mitochondrial superoxide formation. Thus, peroxynitrite is a major trigger of DOX-induced apoptosis, and its effective neutralization can be of significant therapeutic benefit.

scholarly journals The Chicken Anemia Virus-Derived Protein Apoptin Requires Activation of Caspases for Induction of Apoptosis in Human Tumor Cells

2000 ◽  
Vol 74 (15) ◽  
pp. 7072-7078 ◽  
Author(s):  
A. A. A. M. Danen-van Oorschot ◽  
A. J. van der Eb ◽  
M. H. M. Noteborn
Keyword(s):  
Mammalian Cells ◽  
Caspase 3 ◽  
Human Tumor ◽  
Chemotherapeutic Agents ◽  
Chicken Anemia Virus ◽  
Virus Protein ◽  
Nuclear Morphology ◽  
Induction Of Apoptosis ◽  
Induced Apoptosis ◽  
Anemia Virus

ABSTRACT The chicken anemia virus protein Apoptin has been shown to induce apoptosis in a large number of transformed and tumor cell lines, but not in primary cells. Whereas many other apoptotic stimuli (e.g., many chemotherapeutic agents and radiation) require functional p53 and are inhibited by Bcl-2, Apoptin acts independently of p53, and its activity is enhanced by Bcl-2. Here we study the involvement of caspases, an important component of the apoptotic machinery present in mammalian cells. Using a specific antibody, active caspase-3 was detected in cells expressing Apoptin and undergoing apoptosis. Although Apoptin activity was not affected by CrmA, p35 did inhibit Apoptin-induced apoptosis, as determined by nuclear morphology. Cells expressing both Apoptin and p35 showed only a slight change in nuclear morphology. However, in most of these cells, cytochrome c is still released and the mitochondria are not stained by CMX-Ros, indicating a drop in mitochondrial membrane potential. These results imply that although the final apoptotic events are blocked by p35, parts of the upstream apoptotic pathway that affect mitochondria are already activated by Apoptin. Taken together, these data show that the viral protein Apoptin employs cellular apoptotic factors for induction of apoptosis. Although activation of upstream caspases is not required, activation of caspase-3 and possibly also other downstream caspases is essential for rapid Apoptin-induced apoptosis.

scholarly journals Antidepressant Sertraline Hydrochloride Inhibits the Growth of HER2+ AU565 Breast Cancer Cell Line through Induction of Apoptosis, and Arrest of Cell Cycle

2021 ◽  
Author(s):  
Atia-tul- Wahab ◽  
Sharmeen Fayyaz ◽  
Rimsha Irshad ◽  
Rafat A. Siddiqui ◽  
Atta-ur- Rahman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Death ◽  
Cell Line ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Caspase 3 ◽  
Potential Candidate ◽  
Sertraline Hydrochloride ◽  
Induction Of Apoptosis

AbstractBreast cancer is one the most aggressive cancer worldwide, especially Pakistan due to limited therapeutic options. This study was conducted to repurpose the use of selective serotonin reuptake inhibitors (SSRIs), in the treatment of breast cancers, and merit to pursue drug re-positioning in oncology. Anti-proliferative activity of SSRIs, such as fluoxetine, paroxetine, and sertraline hydrochloride on the growth of AU-565, MCF-7, MDA-MB-231, and BT-474 breast cancer cell lines, along with human fibroblast BJ cells was determined in vitro. Changes in nuclear morphology (DAPI staining), and induction of apoptosis (flow cytometry, and caspase-3 activation) were also studied. Sertraline hydrochloride most effectively inhibited the growth of breast cancer cells in vitro. Therefore, pharmacological mechanism involved in sertraline mediated cell death was investigated in HER2+ AU565 cell line. Enhanced nuclear fragmentation, increased Annexin (+) cells, and caspase-3/7 activation indicated that sertraline-mediated cell death could be a result of BCl2-independent apoptosis as evidenced by expression of Bax, and BCl2 genes. Taken together, our results identified sertraline hydrochloride, as a potential candidate for the treatment of HER2-positive breast cancer. Even though these are in vitro results, this study opens great opportunity in the field of drug repurposing for the development of chemotherapeutic agents.

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