Molecular Mechanisms Involved in UV-Induced Apoptotic Cell Death

2002 ◽  
Vol 15 (5) ◽  
pp. 342-347 ◽  
Author(s):  
Dagmar Kulms ◽  
Thomas Schwarz
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death

Artocarpus communis Induces Autophagic Instead of Apoptotic Cell Death in Human Hepatocellular Carcinoma Cells

2015 ◽  
Vol 43 (03) ◽  
pp. 559-579 ◽  
Author(s):  
Cheng-Wei Tzeng ◽  
Wen-Sheng Tzeng ◽  
Liang-Tzung Lin ◽  
Chiang-Wen Lee ◽  
Ming-Hong Yen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Death ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Hepatoma Cell ◽  
Apoptotic Cell Death ◽  
Human Hepatocellular Carcinoma ◽  
Acridine Orange Staining ◽  
Hepatoma Cell Lines

For centuries, natural plant extracts have played an important role in traditional medicine for curing and preventing diseases. Studies have revealed that Artocarpus communis possess various bioactivities, such as anti-inflammation, anti-oxidant, and anticancer activities. A. communis offers economic value as a source of edible fruit, yields timber, and is widely used in folk medicines. However, little is known about its molecular mechanisms of anticancer activity. Here, we demonstrate the antiproliferative activity of A. communis methanol extract (AM) and its dichloromethane fraction (AD) in two human hepatocellular carcinoma (HCC) cell lines, HepG2 and PLC/PRF/5. Colony assay showed the long-term inhibitory effect of both extracts on cell growth. DNA laddering and immunoblotting analyses revealed that both extracts did not induce apoptosis in the hepatoma cell lines. AM and AD-treated cells demonstrated different cell cycle distribution compared to UV-treated cells, which presented apoptotic cell death with high sub-G1 ratio. Instead, acridine orange staining revealed that AM and AD triggered autophagosome accumulation. Immunoblotting showed a significant expression of autophagy-related proteins, which indicated the autophagic cell death (ACD) of hepatoma cell lines. This study therefore demonstrates that A. communis AM and its dichloromethane fraction can induce ACD in HCC cells and elucidates the potential of A. communis extracts for development as anti tumor therapeutic agents that utilize autophagy as mechanism in mediating cancer cell death.

Cell Death Mechanisms Induced by INNO-406, a Novel Tyrosine Kinase Inhibitor for Imatinib-Resistant Ph+ Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2177-2177
Author(s):  
Yuri Kamitsuji ◽  
Souichi Adachi ◽  
Motonobu Watanabe ◽  
Hiroshi Matsubara ◽  
Yasuhiro Mizushima ◽  
...  
Keyword(s):  
Cell Death ◽  
Dna Fragmentation ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Cellular Growth ◽  
Caspase Activity ◽  
Apoptosis Pathway ◽  
Cell Death Mechanisms

Abstract The blockade of Bcr-Abl signaling suppresses cellular growth and induces cell death in Bcr-Abl-positive (Bcr-Abl+) cells. We herein assessed the cell death mechanisms induced by INNO-406 (formerly NS-187; Kimura et al, Blood 2005), in four CML-derived Bcr-Abl+ cell lines (K562, KT-1, BV173 and MYL), and Ba/F3 harboring wild type bcr-abl (Ba/F3/wt bcr-abl). When cells are treated by INNO-406, the accumulation of subG1 fraction was seen in all five cell lines. This cell death was accompanied by loss of mitochondrial membrane potential and was inhibited by over-expression of Bcl-2, indicating that INNO-406-induced cell death is mainly mediated by mitochondria-dependent apoptosis. Caspase-3 activation in INNO-406-treated cell was also common among all cell lines. However, the inhibition of caspase activity by ZVAD-fmk (ZVAD), a pan-caspase inhibitor, was variable in the cell lines tested. In K562, KT-1 and BV173 cells treated with INNO-406, ZVAD almost completely prevented apoptosis (i.e. showing atypical feature for apoptosis, no DNA fragmentation and no accumulation of subG1 fraction), with cell death resulting from morphologically non-apoptotic cell death. The percentages of non-apoptotic cells under ZVAD co-treated with INNO-406 varied among the three cell lines, suggesting that the dependence on non-apoptotic cell death is variable. While, in MYL and Ba/F3/wt bcr-abl cells, despite the sufficient inhibition of caspases’ activity, the inhibition of the cell death by ZVAD was only partial and these cell lines still underwent apoptosis (i.e. showing DNA fragmentation and the accumulation of subG1 population), suggesting the presence of caspase-independent apoptotic machineries. In addition, assay data for apoptosome activities (complex of Apaf-1, cytochrome c and caspase-9 that initiates and drives cysteine protease activities of caspase in mitochondrial-mediated pathway) suggested that cell types could be largely subdivided into two groups, namely those cells with high apoptosome activity (K562, KT-1 and BV173) that undergo non-apoptotic, and, those cells with low apoptosome activity (MYL and Ba/F3/wt bcr-abl.) that undergo caspase-independent apoptosis when caspase activity was blocked by ZVAD. These data indicate that there is a common initial pathway for cell death due to INNO-406, while the pathway for cell death commitment (i.e. dependence on apoptosome/caspases-mediated apoptosis pathway that has been commonly believed to be central for apoptosis execution) vary among cellular context in Bcr-Abl+ leukemic cells. Moreover, in a mouse model of primary human CML in blast crisis, INNO-406 caused cell death with fragmented nuclei typical to apoptosis and “necklace-like” nuclei not typical of apoptosis, further implicating the significance of involvement of caspase-independent, non-apoptotic cell death in vivo. Further studies of the role of caspase-independent cell death in patient-derived Bcr-Abl+ cells and the molecular mechanisms that lead to mitochondrial-depolarization and caspase-independent apoptotic and/or non-apoptotic cell death may help the development of novel therapeutic strategies against Bcr-Abl+ leukemias.

scholarly journals Cell Death and Ageing – A Question of Cell Type

2002 ◽  
Vol 2 ◽  
pp. 943-948 ◽  
Author(s):  
Pidder Jansen-Dürr
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Replicative Senescence ◽  
Apoptotic Cell ◽  
Apoptotic Cell Death ◽  
Ageing Process ◽  
Human Ageing

Replicative senescence of human cells in primary culture is a widely accepted model for studying the molecular mechanisms of human ageing. The standard model used for studying human ageing consists of fibroblasts explanted from the skin and grown intoin vitrosenescence. From this model, we have learned much about molecular mechanisms underlying the human ageing process; however, the model presents clear limitations. In particular, a long-standing dogma holds that replicative senescence involves resistance to apoptosis, a belief that has led to considerable confusion concerning the role of apoptosis during human ageing. While there are data suggesting that apoptotic cell death plays a key role for ageingin vitroand in the pathogenesis of various age-associated diseases, this is not reflected in the current literature onin vitrosenescence. In this article, I summarize key findings concerning the relationship between apoptosis and ageingin vivoand also review the literature concerning the role of apoptosis during in vitro senescence. Recent experimental findings, summarized in this article, suggest that apoptotic cell death (and probably other forms of cell death) are important features of the ageing process that can also be recapitulated in tissue culture systems to some extent. Another important lesson to learn from these studies is that mechanisms ofin vivosenescence differ considerably between various histotypes.

scholarly journals Otoprotective Effect of 2,3,4′,5-Tetrahydroxystilbene-2-O-β-d-Glucoside on Gentamicin-Induced Apoptosis in Mouse Cochlear UB/OC-2 Cells

Molecules ◽  
2020 ◽  
Vol 25 (13) ◽  
pp. 3070
Author(s):  
Yu-Hsuan Wen ◽  
Jia-Ni Lin ◽  
Rong-Shuan Wu ◽  
Szu-Hui Yu ◽  
Chuan-Jen Hsu ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Therapeutic Option ◽  
Apoptotic Cell Death ◽  
Ros Generation ◽  
Sod Activity ◽  
Ldh Release ◽  
Induced Apoptosis ◽  
Related Proteins

Excessive levels of reactive oxygen species (ROS) lead to mitochondrial damage and apoptotic cell death in gentamicin-induced ototoxicity. 2,3,4’,5-Tetrahydroxystilbene-2-O-β-d-glucoside (THSG), a bioactive constituent, isolated from Polygonum multiflorum Thunb., exhibits numerous biological benefits in treating aging-related diseases by suppressing oxidative damage. However, its protective effect on gentamicin-induced ototoxicity remains unexplored. Therefore, here, we aimed to investigate the otoprotective effect of THSG on gentamicin-induced apoptosis in mouse cochlear UB/OC-2 cells. We evaluated the effect of gentamicin and THSG on the ROS level, superoxide dismutase (SOD) activity, mitochondrial membrane potential, nuclear condensation, and lactate dehydrogenase (LDH) release, and the expression of apoptosis-related proteins was assessed to understand the molecular mechanisms underlying its preventive effects. The findings demonstrated that gentamicin increased ROS generation, LDH release, and promoted apoptotic cell death in UB/OC-2 cells. However, THSG treatment reversed these effects by suppressing ROS production and downregulating the mitochondrial-dependent apoptotic pathway. Additionally, it increased the SOD activity, decreased the expression of apoptosis-related proteins, alleviated the levels of the apoptotic cells, and impaired cytotoxicity. To the best of our knowledge, this is the first study to demonstrate that THSG could be a potential therapeutic option to attenuate gentamicin-induced ototoxicity.

scholarly journals The Role of Necroptosis in ROS-Mediated Cancer Therapies and Its Promising Applications

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2185
Author(s):  
Sheng-Kai Hsu ◽  
Wen-Tsan Chang ◽  
I-Ling Lin ◽  
Yih-Fung Chen ◽  
Nitin Balkrushna Padalwar ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Biology ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Close Correlation ◽  
Apoptotic Cell Death ◽  
Cancer Therapies ◽  
Independent Form ◽  
Potential Strategy ◽  
Apoptosis And Necrosis

Over the past decades, promising therapies targeting different signaling pathways have emerged. Among these pathways, apoptosis has been well investigated and targeted to design diverse chemotherapies. However, some patients are chemoresistant to these therapies due to compromised apoptotic cell death. Hence, exploring alternative treatments aimed at different mechanisms of cell death seems to be a potential strategy for bypassing impaired apoptotic cell death. Emerging evidence has shown that necroptosis, a caspase-independent form of cell death with features between apoptosis and necrosis, can overcome the predicament of drug resistance. Furthermore, previous studies have also indicated that there is a close correlation between necroptosis and reactive oxygen species (ROS); both necroptosis and ROS play significant roles both under human physiological conditions such as the regulation of inflammation and in cancer biology. Several small molecules used in experiments and clinical practice eliminate cancer cells via the modulation of ROS and necroptosis. The molecular mechanisms of these promising therapies are discussed in detail in this review.

scholarly journals Pancracine, a Montanine-Type Amaryllidaceae Alkaloid, Inhibits Proliferation of A549 Lung Adenocarcinoma Cells and Induces Apoptotic Cell Death in MOLT-4 Leukemic Cells

2021 ◽  
Vol 22 (13) ◽  
pp. 7014
Author(s):  
Darja Koutová ◽  
Radim Havelek ◽  
Eva Peterová ◽  
Darina Muthná ◽  
Karel Královec ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Human Cancer ◽  
A549 Cells ◽  
Apoptotic Cell Death ◽  
Leukemic Cells ◽  
The Impact

Pancracine, a montanine-type Amaryllidaceae alkaloid (AA), is one of the most potent compounds among natural isoquinolines. In previous studies, pancracine exhibited cytotoxic activity against diverse human cancer cell lines in vitro. However, further insight into the molecular mechanisms that underlie the cytotoxic effect of pancracine have not been reported and remain unknown. To fill this void, the cell proliferation and viability of cancer cells was explored using the Trypan Blue assay or by using the xCELLigence system. The impact on the cell cycle was determined by flow cytometry. Apoptosis was evaluated by Annexin V/PI and by quantifying the activity of caspases (-3/7, -8, and -9). Proteins triggering growth arrest or apoptosis were detected by Western blotting. Pancracine has strong antiproliferative activity on A549 cells, lasting up to 96 h, and antiproliferative and cytotoxic effects on MOLT-4 cells. The apoptosis-inducing activity of pancracine in MOLT-4 cells was evidenced by the significantly higher activity of caspases. This was transmitted through the upregulation of p53 phosphorylated on Ser392, p38 MAPK phosphorylated on Thr180/Tyr182, and upregulation of p27. The pancracine treatment negatively altered the proliferation of A549 cells as a consequence of an increase in G1-phase accumulation, associated with the downregulation of Rb phosphorylated on Ser807/811 and with the concomitant upregulation of p27 and downregulation of Akt phosphorylated on Thr308. This was the first study to glean a deeper mechanistic understanding of pancracine activity in vitro. Perturbation of the cell cycle and induction of apoptotic cell death were considered key mechanisms of pancracine action.

scholarly journals EGR1/GADD45α Activation by ROS of Non-Thermal Plasma Mediates Cell Death in Thyroid Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 351
Author(s):  
Seung-Nam Jung ◽  
Chan Oh ◽  
Jae Won Chang ◽  
Lihua Liu ◽  
Mi Ae Lim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Apoptotic Cell Death ◽  
Promising Alternative ◽  
Alternative Treatment Strategy

(1) Background: Nonthermal plasma (NTP) induces cell death in various types of cancer cells, providing a promising alternative treatment strategy. Although recent studies have identified new mechanisms of NTP in several cancers, the molecular mechanisms underlying its therapeutic effect on thyroid cancer (THCA) have not been elucidated. (2) Methods: To investigate the mechanism of NTP-induced cell death, THCA cell lines were treated with NTP-activated medium -(NTPAM), and gene expression profiles were evaluated using RNA sequencing. (3) Results: NTPAM upregulated the gene expression of early growth response 1 (EGR1). NTPAM-induced THCA cell death was enhanced by EGR1 overexpression, whereas EGR1 small interfering RNA had the opposite effect. NTPAM-derived reactive oxygen species (ROS) affected EGR1 expression and apoptotic cell death in THCA. NTPAM also induced the gene expression of growth arrest and regulation of DNA damage-inducible 45α (GADD45A) gene, and EGR1 regulated GADD45A through direct binding to its promoter. In xenograft in vivo tumor models, NTPAM inhibited tumor progression of THCA by increasing EGR1 levels. (4) Conclusions: Our findings suggest that NTPAM induces apoptotic cell death in THCA through a novel mechanism by which NTPAM-induced ROS activates EGR1/GADD45α signaling. Furthermore, our data provide evidence that the regulation of the EGR1/GADD45α axis can be a novel strategy for the treatment of THCA.

scholarly journals MEK1 Inhibitor Selumetinib Sensitizes Precursor B-Cell Acute Lymphoblastic Leukemia Cells (B-ALL) to Dexamethasone through Modulation of mTOR Activity and Stimulation of Autophagy

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4917-4917
Author(s):  
Anna Polak ◽  
Przemyslaw Kiliszek ◽  
Tomasz Sewastianik ◽  
Maciej Szydlowski ◽  
Ewa Jablonska ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Lymphoblastic Leukemia ◽  
Apoptotic Cell Death ◽  
Leukemia Cells ◽  
Erk Pathway ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Glucocorticoids (GC) have been used for decades in the treatment of B-cell acute lymphoblastic leukemia (B-ALL) in children and adults. Induction of apoptosis is thought to be the principal effector mechanism of GC's action, but recent studies highlight the role of autophagy upstream of apoptotic cell death (Laane et al 2009). Resistance to GCs is a major adverse prognostic factor, however the molecular mechanisms leading to GC resistance are not completely understood. Herein, we sought to elucidate the molecular mechanisms driving GC-resistance in precursor B-cell acute lymphoblastic leukemia cells and in vitro characterize the therapeutic potential of targeted intervention in these mechanisms. To identify molecular mechanisms involved in GC resistance, we performed gene set enrichment analysis of gene expression profiles GC-sensitive and -resistant B-ALL blasts using publicly available datasets and GenePattern program. Resistant cells exhibited significantly higher expression of MAPK/ERK pathway components (p<.002, FDR=0.13). To validate these findings, we assessed DEX sensitivity in ALL cells with high (SEMK2) or undetectable (RS4;11) activity of MAPK/ERK pathway. SEMK2 cells were resistant to DEX, whereas RS4;11 were highly sensitive to this drug. In GC-resistant cell line SEMK2, inhibition of MEK1 kinase with SEL completely abrogated ERK and p90RSK phosphorylation and increased sensitivity to GC by 1.8-2.6-fold. Similar pattern was observed in primary ALL blasts from 19 of 23 tested patients. Overexpression of a constitutively active MEK mutant in GC-sensitive cells (RS4;11) reversed sensitivity of these cells to DEX. Since GC in leukemic cells induce autophagic cell death, we assessed LC3 processing, MDC staining (a dye of autophagolysosomes) and GFP-LC3 relocalization in cells incubated with either DEX, SEL or combination of drugs. Either drug alone caused only marginal change in the level of these markers, but their combination markedly increased autophagic flux. Since mTORC1 is the critical regulator of autophagy, we assessed the activity of mTORC1 following DEX/SEL co-treatment and found that the combination resulted in a marked decrease of p4E-BP1, an mTORC1 substrate. Finally, to assess whether induction of autophagy is required for the observed synergy between SEL and DEX we used an shRNA approach to silence beclin-1 (BCN1), a gene required for autophagosome formation, and assessed cellular responses to DEX/SEL co-treatment. In control cells transduced with non-targeting shRNA, SEL sensitized cells to DEX, but in BCN1-deficient cells, the synergy of DEX and SEL was markedly decreased. Taken together, we show that MEK1 inhibitor selumetinib enhances DEX toxicity in GC-resistant B-ALL cells. The underlying mechanism of this interaction involves inhibition of mTORC1 signaling pathway and induction of autophagy that leads to apoptotic cell death. Disclosures No relevant conflicts of interest to declare.

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