Endoplasmic Reticulum Stress Signaling Comprises a G9a Inhibitor Tolerance Pathway and PERK Inhibition Increases Anti-Leukemia Activity of G9a Inhibitor in Leukemia Cells and Leukemia Stem-like Cells

Abstract Background: Histone methyltransferase (HMTase) G9a regulates the transcription of multiple genes by primarily catalyzing dimethylation of histone H3 lysine 9 (H3K9me2), as well as several non-histone lysine sites. Recently, pharmacological and genetic targeting of the G9a was shown to be efficient in slowing down acute myeloid leukemia (AML) cell proliferation in a mouse model and human AML cell lines thus making this HMTase potential target for epigenetic therapy of AML. Activation of adaptive mechanisms to drug plays a crucial role in drug resistance and relapse by allowing cell survival under stressful conditions. Therefore, inhibition of the adaptive response is considered as a prospective therapeutic strategy. The tolerance mechanism to HMTase regulation in leukemia cell is unclear yet. The PERK-eIF2α phosphorylation pathway is an important arm of the unfolded protein response (UPR), which is induced under conditions of endoplasmic reticulum (ER) stress. Recent previous studies showed that pro-survival ER stress is induced in cancer cells and contributes to development of drug resistance. Methods: We investigated the levels of apoptosis and ER stress by G9a inhibitor BIX-01294 in leukemia cell lines. U937, cytarabine-resistant U937 (U937/AR) and KG1 were used. U937/AR cell line was established in our laboratory by exposing parental U937 cells to stepwise increasing concentrations of cytarabine. Results: We initially examined the expression of G9a in leukemia cell lines and the primary AML cells obtained from a patient at the different time point. In U937/AR cells and primary AML cells obtained at relapse, G9a expression was increased compare to that in U937 cells and primary AML cells obtained at diagnosis, respectively. G9a expression was also increased in KG1 cells. In both of U937 and U937/AR, apoptotic cell death was induced by BIX-01294 in a dose-dependent manner. In contrast, apoptotic cell death was minimal in KG1 cells which are enriched in cells expressing a leukemia stem cell phenotype (CD34+CD38-). To address the activation of ER stress response by BIX-01294 in leukemia cells, we examined the effect of BIX-01294 treatment on PERK and eIF2α protein expression and phosphorylation levels. We found that treatment of U937, U937/AR, KG1 cells with 3μM of BIX-01294 for 24h caused an upregulation of phosphorylated PERK and eIF2α. The upregulation of PERK phosphorylation was associated with a decrease in PERK protein levels after treatment. To further address the role of the PERK-eIF2α phosphorylation in BIX-01294 sensitivity, we examined whether PERK inhibition using small interfering RNA (siRNA) or specific inhibitor could sensitize cells to BIX-01294-mediated death. The siRNA against PERK effectively inhibited BIX-01294-mediated phosphorylation of PERK and eIF2α in U937 and U937/AR cells. The addition of PERK siRNA led to a significant increase in the extent of BIX-01294-induced apoptotic cell death in U937 (P = 0.0003) and U937/AR (P < 0.0001) as compared with that of BIX-01294 treatment alone. PERK inhibitor GSK260641 significantly increased BIX-01294-induced apoptotic cell death in U937 (P < 0.0001) and U937/AR (P = 0.006) cells. To our surprise, addition of PERK siRNA or GSK260641 increased the sensitivity of KG1 cells to BIX-01294-mediated death in a dose-dependent manner (P = 0.0003 for siRNA, P = 0.0053 for GSK260641). Conclusion: These data demonstrated that PERK-eIF2α activation has a pro-survival function to G9a inhibitor in leukemia cells and mediates resistance of AML stem cells to G9a inhibitor treatment. The PERK-eIF2α phosphorylation arm may represent a suitable target for combating resistance to G9a inhibitor in AML. The mechanisms underlying the increased sensitivity of AML cells with PERK inhibition to G9a inhibitor are unclear at present and are needed to define in further studies. Disclosures No relevant conflicts of interest to declare.

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NADPH Oxidase Regulates Cytarabine-Induced Apoptotic Death in Acute Myeloid Leukemia Cells

Blood ◽

10.1182/blood.v118.21.4258.4258 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4258-4258

Author(s):

Nazmul H Khan ◽

Kevin J Sexton ◽

Melissa J Grimm ◽

Brahm H Segal ◽

Carlos E Vigil

Keyword(s):

Cell Death ◽

Nadph Oxidase ◽

Myeloid Leukemia ◽

Apoptotic Cell ◽

Leukemia Cell ◽

Apoptotic Cell Death ◽

Leukemia Cell Line ◽

Leukemia Cells ◽

Myelomonocytic Leukemia

Abstract Abstract 4258 Background: Cellular metabolism and oxidative stress are important in the biology and pathophysiology of malignancies. Both increased reactive oxygen species [ROS] levels and induction of anti-oxidative pathways have been described in several malignancies, and may be modulate tumor biology and susceptibility to chemotherapy. Limited studies point to metabolic pathways, including ROS production, influencing pathogenesis and chemo-sensitivity of leukemia. NADPH oxidase is a critical enzyme in antimicrobial host defense and its activation results in ROS generation in myeloid leukemia cells. Our prior studies show that NADPH oxidase can activate Nrf2, a transcriptional factor that induces anti-oxidant and cytoprotective pathways. However the role of NADPH oxidase in chemotherapy-mediated apoptosis induction in leukemic cells is not well-known. Hypothesis: NADPH oxidase-derived ROS will increase sensitivity of AML cells to chemotherapy, whereas Nrf2 will be associated with chemotherapy resistance Methods: We evaluated the role of NADPH oxidase and Nrf2 in regulating cytarabine-induced cell death in wild-type [WT] and engineered PLB-985 cells, a human acute myelomonocytic leukemia cell line derivative. NADPH oxidase-deficient PLB-985 cells were generated by recombination with mutant gp91phox, a necessary component of NADPH oxidase. Nrf2-deficient cells were generated by shRNA (Nrf2shRNA) and depletion (>70%) of Nrf2 mRNA was confirmed by quantitative-PCR. WT and engineered PLB-985 cells were treated with cytarabine (12.5 to 750ng/ml for 24 – 48 hours) and cell death was determined by trypan blue exclusion and Annexin V/7-AAD staining. Results: NADPH oxidase-deficient PLB-985 cells were significantly more resistant to cytarabine compared to WT cells. Cytarabine (500 ng/ml for 48h) induced apoptotic cell death in 25% of NADPH oxidase-deficient vs. 53% of WT PLB-985 cells. Additional dose-response studies confirmed a significant effect of NADPH oxidase in potentiating cytarabine-induced cell death. Nrf2shRNA PLB-985 cells had either similar or modestly increased susceptibility to cytarabine-induced cell death compared to WT PLB-985 cells with empty vectors. NADPH-deficient/Nrf2shRNA PLB-985 cells had similar susceptibility to cytarabine as NADPH-deficient cells with empty vector. Conclusions: Our results show that NADPH oxidase potentiates apoptotic cell death by cytarabine in a myelomonocytic leukemia cell line. However, we did not observe a consistent effect of Nrf2 depletion on apoptotic cell death by cytarabine. These studies suggest that modulation of redox-stress may be a potential therapeutic approach in AML that merits further study. Disclosures: No relevant conflicts of interest to declare.

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Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential

Cancers ◽

10.3390/cancers14010076 ◽

2021 ◽

Vol 14 (1) ◽

pp. 76

Author(s):

Giulia Greco ◽

Michael Schnekenburger ◽

Elena Catanzaro ◽

Eleonora Turrini ◽

Fabio Ferrini ◽

...

Keyword(s):

Cell Death ◽

Apoptotic Cell ◽

Leukemia Cell ◽

Kinase Domain ◽

Apoptotic Cell Death ◽

Dependent Manner ◽

Interacting Protein ◽

Leukemia Cell Lines ◽

Cell Death Mechanisms ◽

Apoptotic Activity

In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities.

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Apoptosis Induced by Extracts of Helleborus Niger in Different Lymphoma and Leukemia Cell Lines and Primary Lymphoblasts of Children with ALL Is Independent of Smac-Overexpression and Executed Via the Mitochondrial Pathway.

Blood ◽

10.1182/blood.v110.11.4215.4215 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4215-4215

Author(s):

Patrick Jesse ◽

Gritt Mottke ◽

Georg Seifert ◽

Simone Fulda ◽

Guenter Henze ◽

...

Keyword(s):

Cell Death ◽

Cell Lines ◽

Apoptotic Cell ◽

Leukemia Cell ◽

Mitochondrial Pathway ◽

Leukemia Cells ◽

Root Extract ◽

Apoptosis Induction ◽

Helleborus Niger ◽

Primary Leukemia

Abstract Helleborus niger, also known as Christmas Rose, belongs to the family of Ranunculaceae, a family of flowering plants with about 2500 different species. In complementary medicine Helleborus niger is used as adjuvant drug in the treatment of non-metastasised and metastasised forms of bronchial cancer, abdominal tumours and prostate cancer. It is also applied in myeloproliferative diseases like Hodgkin and Non-Hodgkin lymphoma, leukaemic disorders and AIDS- related diseases like the Kaposi sarcoma. Until now, there is no clinical or preclinical data regarding the effects of Helleborus niger in vivo, ex vivo or in vitro. For this purpose, we investigated the cytotoxic effects of four different standardized aqueous Helleborus niger extracts from the companies Hiscia and Helixor on various cancer cell lines. We used one whole plant extract, one root extract, one leave extract and one containing only the blossom of Helleborus niger. After 4h of treatment with the extracts no significant LDH release was measured, thus excluding an unspecific, necrotic damage of the cell membrane. After 24h a dose dependent inhibition of proliferation up to 69% could be found and after 48h a distinction into early (45,2%) and late apoptotic (45,5%) cells was detected via Annexin/PI staining. The cell cycle analysis revealed characteristic hypodiploid DNA fragments after 72h, once more identifying apoptosis as cause of the cell death. In the Western Blot analysis a processing of Caspase-3 could be found after 36 h incubation with the extract. Apoptotic cell death was detected in the Burkitt-like lymphoma cell line BJAB, the three human acute lymphoblastic leukemia cell lines NALM-6, Sup-B-15 and REH and the melanoma cell line MEL-HO. The apoptosis induction caused by the root extract was higher than the apoptotic cell death in the other extracts. There are two major pathways of apoptosis, the extrinsic pathway via death receptors like FADD and the intrinsic pathway via the mitochondria. In BJAB cells a breakdown of the mitochondrial membrane potential and dose-dependent mitochondrial permeability transition was detected after 48h, revealing that apoptosis is executed via the mitochondrial pathway. Furthermore, we found a decreased apoptosis induction in BCL-2 overexpressing melanoma cells. The dependency of Bcl-2 expression is another sign of apoptosis via the mitochondrial pathway. In contrast, apoptosis induction by Helleborus niger seems to be independent of Smac overexpression, which could be shown in Jurkat cells. In combination with the vinca alkaloid vincristine, which is used in the treatment of ALL, a synergistic effect could be detected. The apoptosis induction was up to 16% higher in combination than in the single treatment. Finally, we evaluated the effect on primary leukemia cells ex vivo. Interestingly, we could show a significant apoptosis induction in primary leukemia cells from 2 patients with ALL or AML in childhood, which were resistant to the treatment with the anthracycline doxorubicin. For the first time, we were able to show that extracts of Helleborus niger induce apoptosis in different cancer cell lines and primary leukemia cells. Apoptosis is executed via the intrinsic pathway and is independent of Smac overexpression. Thus, we present an interesting baseline for the design of upcoming in vivo experiments or clinical trials.

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Curcumin-induced Apoptotic Cell Death Mediated by ER Stress in Lung Carcinoma Cell Lines

Yakhak Hoeji ◽

10.17480/psk.2017.61.1.12 ◽

2016 ◽

Vol 61 (1) ◽

pp. 12-17

Author(s):

Ji Youn Oh ◽

◽

Sou Hyun Kim ◽

Jae-Hwan Kwak ◽

Young-Suk Jung ◽

...

Keyword(s):

Cell Death ◽

Er Stress ◽

Cell Lines ◽

Lung Carcinoma ◽

Carcinoma Cell ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Carcinoma Cell Lines ◽

Lung Carcinoma Cell

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A Novel SAHA-Bendamustine Hybrid Induces Apoptosis of Leukemia Cells

Blood ◽

10.1182/blood.v124.21.2227.2227 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2227-2227

Author(s):

Jing Yu ◽

Shaowei Qiu ◽

Qiufu Ge ◽

Ying Wang ◽

Hui Wei ◽

...

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Western Blot ◽

Cell Lines ◽

Apoptotic Cell ◽

Leukemia Cell ◽

Leukemia Cells ◽

Nb4 Cells ◽

Leukemia Cell Lines ◽

Primary Leukemia

Abstract Introduction Hybrid anticancer drugs are of great therapeutic interests as they can potentially overcome the flaws of conventional chemotherapy drugs and improve their efficacy. Histone deacetylase inhibitors (HDACi) and DNA damaging agents have showed synergistic effects in recent studies. In this study, we reported a novel hybrid NL-101 that combines chemo-active groups from suberoylanilide hydroxamic acid (SAHA) and bendamustine, the typical HDACi and alkylating agent respectively.The anticancer effect of NL-101 and its possible mechanisms were investigated in human leukemia cell lines and primary leukemia cells. Methods MTT assay was performed to determine the proliferation of Kasumi-1 and NB4 cells treated with NL-101. Cell cycle distribution and apoptosis rate were detected by flow cytometry. Western-blot analysis was used to analyze the level of acetylated H3 as well as apoptotic-related proteins including γ-H2AX, PARP, caspase-3, Bax, Bcl-2 and Bcl-xL. Bone marrow mononuclear cells of AML patients were isolated by density gradient centrifugation. Wright staining and Western blot were performed to determine the inducing apoptosis effect. Results NL-101 inhibited the proliferation of leukemia cell lines Kasumi-1 and NB4 cells with similar IC50 to that of SAHA. Cell cycle analysis indicated that NL-101 induced S phase arrest. As expected, apoptotic cell death was observed in response to NL-101 treatment. After treatment with 2 µmol/L NL-101 for 48 hours, the apoptosis rate of Kasumi-1 and NB4 cells were (60.19±12.01)% and (49.43±11.61)%, respectively. Western blot analysis showed that NL-101 exposure could induce the accumulation of acetylated Histone H3 and γ-H2AX as the biomarker of DNA double-strand breaks. Anti-apoptotic protein Bcl-xL involved in mitochondrial death pathway was also decreased. Moreover, NL-101 induced apoptosis with a low micromolar IC50 in various leukemia cell lines but not in nonmalignant cell line HEK293. The efficacy of NL-101 was also tested in human primary leukemia cells and all the treated samples exhibited apoptosis confirmed by the morphological examination and expression of apoptotic markers. Conclusions The novel SAHA-bendamustine hybrid NL-101 inhibited the proliferation and induced apoptotic cell death of leukemia cell lines and primary leukemia cells. It presented the properties of both HDAC inhibition and DNA damaging. Down-regulation of Bcl-xL was also involved in the apoptosis induction. These results indicated that NL-101 might be a potential compound for the treatment of leukemia. Disclosures Wang: Bristol Myers Squibb: Consultancy; Novartis: Consultancy.

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D-carvone induced ROS mediated apoptotic cell death in human leukemic cell lines (Molt-4)

Bioinformation ◽

10.6026/97320630017171 ◽

2021 ◽

Vol 17 (1) ◽

pp. 171-180

Author(s):

Petchi Iyappan ◽

Keyword(s):

Cell Death ◽

Cell Lines ◽

Mtt Assay ◽

Apoptotic Cell ◽

Biological Activities ◽

Lymphoblastic Leukemia ◽

Apoptotic Cell Death ◽

Lymphoid Cells ◽

Dependent Manner ◽

Intracellular Ros

The immature lymphoid cells with chromosomal structural and numerical abnormalities cause the acute lymphoblastic leukemia (ALL). This hematologic disorder constitutes about 25% of cancer prognosis among children and adolescents. D-Carvone, a monocyclic monoterpene obtained from the essential oils extracted from plants is reported to possess the various biological activities. The present study was aimed to investigate the anticancer potential of D-Carvone against the human leukemic Molt-4 cells. The cytotoxicity of DCarvone was analyzed by MTT assay. The level of lipid peroxidation and antioxidants were determined. The intracellular ROS, MMP and apoptosis were demonstrated by fluorescent staining techniques. The MTT assay revealed that the D-Carvone treatment suppressed the viability of Molt-4 cells and the IC50 was determined at 20 μM/ml. The D-Carvone treatment was increased the oxidative stress and reduced the level of antioxidants in the Molt-4 cell lines. The increased intracellular ROS, apoptotic cell death, and diminished MMP was noted in the D-Carvone treatment. In the Molt-4 cells, D-carvone induced the apoptosis in a time and dose dependent manner by the activation of caspases-8, -9 and -3. Thus, data provide insights for the clinical application of D-Carvone in the treatment of blood cancer Molt-4 cells. Our study suggests the therapeutic potential D-Carvone for the treatment of leukemia in future.

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Britannin, a Sesquiterpene Lactone Induces ROS-Dependent Apoptosis in NALM-6, REH, and JURKAT Cell Lines And Produces a Synergistic Effect With Vincristine

10.21203/rs.3.rs-369748/v1 ◽

2021 ◽

Author(s):

Hassan Mohammadlou ◽

Maryam Hamzeloo-Moghadam ◽

Mohammad Hossein Mohammadi ◽

Amir Yami ◽

Ahmad Gharehbaghian

Keyword(s):

Cell Death ◽

Sesquiterpene Lactone ◽

Cell Lines ◽

Cytotoxic Effect ◽

Apoptotic Cell ◽

Lymphoblastic Leukemia ◽

Single Agent ◽

Apoptotic Cell Death ◽

Dependent Manner ◽

Normal Peripheral Blood

Abstract Britannin, a Sesquiterpene Lactone isolated from Inula aucheriana, has recently gained attractions in the therapeutic fields due to its vast cytotoxic properties in different types of cancers. This study was designed to evaluate the cytotoxic effect of this agent on Acute Lymphoblastic Leukemia (ALL) cell lines, either as a monotherapy or in combination with Vincristine (VCR). The results obtained in this study showed that while Britannin reduced the viability of ALL cell lines such as NALM-6, REH, and JURKAT cells, it did not exert cytotoxicity against normal Peripheral Blood Mononuclear Cells (PBMCs) and L929 cells. Among tested cells, pre-B ALL-derived NALM-6 cells had the highest sensitivity to Britannin. Moreover, we found that Britannin induced p21/p27-mediated G1 cell cycle arrest cells and Reactive Oxygen Specious (ROS)-mediated apoptotic cell death in NALM-6 cells. When NALM-6 cells were treated with N-acetyl-L-Cysteine (NAC), a scavenger of ROS, we found that Britannin could induce neither apoptosis nor reduce the survival of the cells, suggesting that the cytotoxic effect of Britannin is induced through ROS-dependent manner. The cytotoxic effect of Britannin also was potentiated by autophagy suppression using Chloroquine (CQ). Moreover, we found that a low dose of Britannin enhanced the effect of Vincristine in NALM-6 cells by inducing apoptotic cell death via altering the expression of apoptotic-related genes. Overall, our results proposed a mechanism for the cytotoxic effect of Britannin, either as a single agent or in combination with Vincristine, in NALM-6 cells.

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Investigation of the anti-cancer and apoptotic properties of aqueous extract from fermented African locust bean seeds

Food Research ◽

10.26656/fr.2017.5(1).295 ◽

2020 ◽

Vol 5 (1) ◽

pp. 203-210

Author(s):

R.A. Ayo-Lawal ◽

N.R. Sibuyi ◽

O. Ekpo ◽

M. Meyer ◽

O. Osoniyi

Keyword(s):

Cell Death ◽

Cell Lines ◽

Aqueous Extract ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Dependent Manner ◽

Hep G2 ◽

Anti Cancer ◽

Locust Bean ◽

African Locust Bean

Some fermented foods are reported to possess anti-cancer properties. Fermented African locust bean seeds is a condiment prepared from fermentation of Parkia biglobosa. It has been reportedly functional for various medicinal activities but not anti-cancer. The cytotoxic and apoptosis-inducing properties of the aqueous extract of the condiment were investigated in human cancer - hepatocellular (Hep-G2) and cervical (HeLa) and noncancer cell lines. Cytotoxicity was evaluated using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl tetrazolium bromide (MTT) and clonogenic cell survival assays. Apoptotic cell death and DNA fragmentation were also investigated. The results revealed cytotoxicity to both cell lines in a dose-dependent manner (P < 0.05) and selective activities between cancer and non-cancer cells. The IC50 values were 1.3 and 0.5 mg/mL for Hep-G2 and HeLa cells respectively. Furthermore, the extract induced apoptotic cell death in only Hep -G2 (73.03±0.73) cells. The morphologic photomicrographs correlated well with other findings, indicating the cell-specific cytotoxicity of the condiment

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Cytoplasmic vacuolation with endoplasmic reticulum stress directs sorafenib induced non-apoptotic cell death in hepatic stellate cells

Scientific Reports ◽

10.1038/s41598-021-82381-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sachin Sharma ◽

Shaikh Maryam Ghufran ◽

Sampa Ghose ◽

Subhrajit Biswas

Keyword(s):

Cell Death ◽

Cell Viability ◽

Er Stress ◽

Hepatic Stellate Cells ◽

Apoptotic Cell ◽

Stellate Cells ◽

Apoptotic Cell Death ◽

Dependent Manner ◽

Sorafenib Treatment ◽

Cytoplasmic Vacuolation

AbstractThe activated hepatic stellate cells (HSCs) are the major cells that secrete the ECM proteins and drive the pathogenesis of fibrosis in chronic liver disease. Targeting of HSCs by modulating their activation and proliferation has emerged as a promising approach in the development of anti-fibrotic therapy. Sorafenib, a multi-kinase inhibitor has shown anti-fibrotic properties by inhibiting the survival and proliferation of HSCs. In present study we investigated sorafenib induced cytoplasmic vacuolation mediated decreased cell viability of HSCs in dose and time dependent manner. In this circumstance, sorafenib induces ROS and ER stress in HSCs without involvement of autophagic signals. The protein synthesis inhibitor cycloheximide treatment significantly decreased the sorafenib-induced cytoplasmic vacuolation with increasing cell viability. Antioxidant human serum albumin influences the viability of HSCs by reducing sorafenib induced vacuolation and cell death. However, neither caspase inhibitor Z-VAD-FMK nor autophagy inhibitor chloroquine could rescue the HSCs from sorafenib-induced cytoplasmic vacuolation and cell death. Using TEM and ER organelle tracker, we conclude that the cytoplasmic vacuoles are due to ER dilation. Sorafenib treatment induces calreticulin and GPR78, and activates IRE1α-XBP1s axis of UPR pathway, which eventually trigger the non-apoptotic cell death in HSCs. This study provides a notable mechanistic insight into the ER stress directed non-apoptotic cell death with future directions for the development of efficient anti-fibrotic therapeutic strategies.

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