Wogonoside Exerts Anti-Leukemia of AML Cells Via Restricting Phospholipid Scramblase 1 Gene Expression and Promoting Its Translocation Into Nuclear

Abstract Abstract 4282 Objective: To evaluate the antileukemic effect of wogonoside and reveal the underlying mechanism. Method: In this study trypan blue dye exclusion assay, MTT assay, and soft agar colony formation assay were used to analysis growth inhibition of wogonoside the on AML (acute human promyelocytic) cell lines. Propidium iodide (PI)-staining and cell cycle-regulatory proteins detecting by western blots were applied to exam whether wogonoside could induce cell cycle arrest. Then a series of experiment were used to assess the ability of wogonoside to overcome the AML associated differentiation block, by using Giemsa staining, Nitroblue tetrazolium (NBT) reduction assay, and cell-surface differentiation antigens expression analysis. Real time PCR, western blots, cycloheximide inhibition test and RNA interference, nuclear and cytoplasmic fractionation, immunofluorescent staining were used to investigate the underlying mechanism. In this point we mainly focus that wogonoside exerts antileukemic by modulating of PLSCR1 gene expression, as well as influence its subcellular localization to play a role in regulating gene transcription. Result: It was demonstrated that wogonoside have the capacity to decrease the growth of myeloid cell lines by induction of G0/1 phase cell cycle arrest and differentiation. This effect is mediated by the increasing in mRNA and up-regulating protein expression of phospholipids scramblase 1 (PLSCR1). Meanwhile wogonoside promoted PLSCR1 traffic into the nucleus, which let PLSCR1 to play a role in regulating cell cycle and differentiation-related genes transcription including p21, p27, c-myc and IP3R1. Conclusion: Wogonoside induced AML cell lines to undergo differentiation and G1 phase arrest by restricting phospholipid scramblase 1 gene expression and promoting its translocation into nuclear. Disclosures: No relevant conflicts of interest to declare.

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The role of HNF4A in GATA4-deficiency phenotypes of hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.284 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 284-284

Author(s):

Yu Bin Tan ◽

Timothy Shuen ◽

Han Chong Toh

Keyword(s):

Gene Expression ◽

Hepatocellular Carcinoma ◽

Cell Cycle ◽

Correlation Analysis ◽

Cell Cycle Arrest ◽

Cell Line ◽

Transgenic Mouse ◽

Cell Lines ◽

Downstream Target ◽

Cycle Arrest

284 Background: Hepatocellular carcinoma (HCC) is the 2nd leading global cause of cancer death. Recently, we have discovered previously undescribed deletion and germline mutation of GATA4 and showed that GATA4 is a key differentiation driver and metabolic regulator in HCC. However, as GATA4 is mostly deleted in HCC, targeting GATA4-downstream molecules is ideal. In this study, proof-of-concept experiments were conducted to show that introduction of HNF4A, which is a GATA4-regulated downstream target, could partially rescue the impaired phenotypes in GATA4-deficient HCC cell line. Methods: Correlation analysis using gene expression microarray of human HCC samples was conducted to identify the genes that are positively correlated with GATA4. A transgenic mouse model with a liver-specific conditional GATA4 knockout was designed to identify liver morphology and gene expression changes which are correlated with the loss of Gata4 in the mouse liver. CRISPR-mediated knockout of GATA4 and lentiviral HNF4A overexpression was carried out in a GATA4-deficient HCC cell lines, PLC/PRF/5 and Hep3B, followed by proliferation, apoptosis, cell cycle and senescence functional assays. Results: Pearson correlation analysis from human HCC samples showed that expression of HNF4A is positively correlated with that of GATA4. Livers from conditional Gata4 knockout mice had lower Hnf4a gene expression when compared to age-matched control mice. Loss of function analysis by CRISPR-mediated GATA4 knockout further showed downregulation of HNF4A in GATA4-deficient PLC/PRF/5 cell line. Lentiviral HNF4A overexpression in PLC/PRF/5 and Hep3B demonstrated reduced proliferation and increased apoptosis while PLC/PRF/5 also showed cell cycle arrest at G2/M phase when compared to control. However, no senescence induction was detected in HNF4A-overexpressing cells. Conclusions: Transgenic mouse data, CRISPR-mediated knockout and analysis of HCC samples showed that HNF4A is a key GATA4-downstream target. HNF4A overexpression decreases proliferation, increases apoptosis and cell cycle arrest in GATA4-deficient HCC cell lines, thus representing a possible therapeutic target for HCC.

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Peptide SA12 inhibits proliferation of breast cancer cell lines MCF-7 and MDA-MB-231 through G0/G1 phase cell-cycle arrest

OncoTargets and Therapy ◽

10.2147/ott.s154337 ◽

2018 ◽

Vol Volume 11 ◽

pp. 2409-2417 ◽

Cited By ~ 3

Author(s):

Longfei Yang ◽

Huanran Liu ◽

Min Long ◽

Xi Wang ◽

Fang Lin ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Breast Cancer Cell ◽

Phase Cell ◽

G1 Phase ◽

Breast Cancer Cell Lines ◽

Cycle Arrest ◽

Mcf 7

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Coptidis Rhizome inhibits cell growth in HONE-1 cell line by inducing cell cycle arrest and apoptosis

10.21203/rs.3.rs-27848/v1 ◽

2020 ◽

Author(s):

Kim Fey Leu ◽

Menaga Subramaniam ◽

Xinghua Wang ◽

Zao Yang ◽

Lee Fah Yap ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Line ◽

Cell Lines ◽

Cancer Cell ◽

Cytotoxic Effect ◽

Global Gene Expression ◽

Chinese Herbal ◽

Cycle Arrest

Abstract Background Nasopharyngeal carcinoma (NPC) is among the most common head and neck malignancies seen among adults in Malaysia. Therefore, discovery of novel anti-cancer herbal drugs is of importance. In this study, the cytotoxic effect was conducted on a traditional Chinese herbal prescription (Xiao Xian Xiong Decoction (XXXD) that is made up of 3 Chinese herbal medicines, namely Huanglian (Coptidis Rhizome), Banxia (Pinellia Rhizome), Gualuo (Fructus Trichosanthis).Methods The cytotoxic effect of the individual herb and in combination of two and three herbs was studied on 8 nasopharyngeal cancer cell lines. Global gene expression analysis was carried on extracted RNA using nCounter XT Gene Expression Assay.Results TWO-1, TWO-4, HONE-1, SUNE-1, CNE-2, HK-1, CNE-1 and C666-1 treated with Huanglian, the IC50 values obtained were 24.48, 11.77, 4.48, 10.72 6.32, 11.10, 6.77 and 27.30 µg/ml, respectively. For combination of Huanglian and Banxia, the IC50 values obtained were 74.09 µg/ml (TWO-1), 25.80 µg/ml (TWO-4), 38.10 µg/ml (HONE-1), 29.46 µg/ml (SUNE-1), 19.0 µg/ml (CNE-2) and 20.12 µg/ml (HK-1) but did not exert 50% cell killing in CNE-1 and C666-1 cell lines. The IC50 value attained for the combination of Huanglian and Gualuo was 40.70 µg/ml in HONE-1 cell line. The IC50 values obtained for XXXD (triple combination of Huanglian, Banxia and Gualuo)-treated in HONE-1 and CNE-2 cell lines were 88.55 and 92.42 µg/ml, respectively. Out of all these 7 groups of herbal samples, Huanglian showed the highest cytotoxicity against 8 NPC cell lines with the lowest IC50 value of 4.48 µg/ml recorded in HONE-1. Global gene expression showed Huanglian significantly downregulated genes associated with cell cycle arrest and apoptosis, and thus inhibit HONE-1 cell growth.Conclusions This study suggest that Huanglian could be a potent anticancer herb targeting HONE-1 cancer cell line.

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Curcumin Reverses NNMT-Induced 5-Fluorouracil Resistance via Increasing ROS and Cell Cycle Arrest in Colorectal Cancer Cells

Biomolecules ◽

10.3390/biom11091295 ◽

2021 ◽

Vol 11 (9) ◽

pp. 1295

Author(s):

Guoli Li ◽

Sining Fang ◽

Xiao Shao ◽

Yejia Li ◽

Qingchao Tong ◽

...

Keyword(s):

Colorectal Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Induced Resistance ◽

Phase Cell ◽

Ros Generation ◽

Antitumor Effects ◽

Cycle Arrest

Nicotinamide N-methyltransferase (NNMT) plays multiple roles in improving the aggressiveness of colorectal cancer (CRC) and enhancing resistance to 5-Fluorouracil (5-FU), making it an attractive therapeutic target. Curcumin (Cur) is a promising natural compound, exhibiting multiple antitumor effects and potentiating the effect of 5-FU. The aim of the present study is to explore the effect of Cur on attenuating NNMT-induced resistance to 5-FU in CRC. A panel of CRC cell lines with different NNMT expressions are used to characterize the effect of Cur. Herein, it is observed that Cur can depress the expression of NNMT and p-STAT3 in CRC cells. Furthermore, Cur can induce inhibition of cell proliferation, G2/M phase cell cycle arrest, and reactive oxygen species (ROS) generation, especially in high-NNMT-expression CRC cell lines. Cur can also re-sensitize high-NNMT-expression CRC cells to 5-FU both in vitro and in vivo. In summary, it is proposed that Cur can reverse NNMT-induced cell proliferation and 5-FU resistance through ROS generation and cell cycle arrest. Given that Cur has long been used, we suppose that Cur is a promising anticancer drug candidate with minimal side effects for human CRC therapy and can attenuate NNMT-induced resistance to 5-FU.

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PI3KCA and PIM Inhibitors in Peripheral T-Cell Lymphomas

Blood ◽

10.1182/blood.v116.21.4917.4917 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4917-4917

Author(s):

Esperanza Martin-Sanchez ◽

Socorro M. Rodriguez-Pinilla ◽

Luis Lombardia ◽

Margarita Sanchez-Beato ◽

Beatriz Dominguez-Gonzalez ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

T Cell ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Gene Expression Signature ◽

Dependent Manner ◽

Expression Signature ◽

Cycle Arrest ◽

T Cell Lymphomas

Abstract Abstract 4917 T-cell lymphomas (TCL) are a heterogeneous group of aggressive malignancies lacking specific and efficient therapy. Unfortunately, there are neither animal models nor representative cell lines for most TCL types, making functional and pharmacogenomics studies even more difficult. PI3K and PIM are kinases involved in cell proliferation, frequently altered in human cancer that seems to play a critical role in T-cell development and activation. Genomic studies have identified PIK3CD subunit to be significantly associated with in activation of CD40, NF-kB and TCR-pathways. The aim of this project is to determine the efficiency of PI3K inhibitors (PI3Ki) and PIM inhibitors (PIMi) in TCL, looking for biomarkers of their mechanism of action and to identify markers that could identify responders from non-responders. Twenty PTCL and seven reactive lymph nodes were studied using gene expression microarrays. We performed an in silico analysis using the Connectivity Map program to identify drugs that could potentially reverse PTCL gene expression signature. Among them, several PI3K/mTOR inhibitors were found. A panel of 6 TCL cell lines belonging to different TCL subgroups were treated with 3 PI3Ki (LY294002, ETP-45658, GDC-0941) and one PIMi (ETP-39010). Functional studies were also done to establish the role of each of the targeted genes. In vitro studies showed that PI3Ki induced G1 cell cycle arrest in all cell lines, and apoptosis in a portion of them, in a time/dose-dependent manner. We also observed a decrease in the levels of pAKT(S473), pGSK3B(S9) and p-p70S6K(T389) after treatment. In addition, both the analysis of the PTCL gene expression signature as well as western blot studies on TCL cell lines has shown overexpression of PIM family genes, A decrease in cell viability, and a strong induction of apoptosis in all cell lines was seen after PIM inhibition, without cell cycle arrest. Several diagnostic and pharmacodynamic biomarkers of PIMi have been identified at the mRNA and protein level in both cell lines In conclusion, our results indicate that PI3Ki and PIMi are effective therapeutic approaches for TCLs, identifying potential markers for patient's stratification and pharmacodynamic assessment. Disclosures: No relevant conflicts of interest to declare.

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Optimized anti–tumor effects of anthracyclines plus Vinca alkaloids using a novel, mechanism-based application schedule

Blood ◽

10.1182/blood-2010-02-269811 ◽

2011 ◽

Vol 118 (23) ◽

pp. 6123-6131 ◽

Cited By ~ 18

Author(s):

Harald Ehrhardt ◽

David Schrembs ◽

Christian Moritz ◽

Franziska Wachter ◽

Subrata Haldar ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Childhood Leukemia ◽

Underlying Mechanism ◽

Dependent Manner ◽

Vinca Alkaloids ◽

Cycle Arrest ◽

Induced Apoptosis

Abstract Application of anthracyclines and Vinca alkaloids on the same day represents a hallmark of polychemotherapy protocols for hematopoietic malignancies. Here we show, for the first time, that both drugs might act most efficiently if they are applied on different days. Proof-of-concept studies in 18 cell lines revealed that anthracyclines inhibited cell death by Vinca alkaloids in 83% of cell lines. Importantly, in a preclinical mouse model, doxorubicin reduced the anti–tumor effect of vincristine. Both drugs acted in a sequence-dependent manner and the strongest anti–tumor effect was obtained if both drugs were applied on different days. Most notably for clinical relevance, in 34% of 35 fresh primary childhood leukemia cells tested in vitro, doxorubicin reduced the anti–tumor effect of vincristine. As underlying mechanism, doxorubicin activated p53, p53 induced cell-cycle arrest, and cell-cycle arrest disabled inactivation of antiapoptotic Bcl-2 family members by vincristine; therefore, vincristine was unable to activate downstream apoptosis signaling. As molecular proof, antagonism was rescued by knockdown of p53, whereas knockdown of cyclin A inhibited vincristine-induced apoptosis. Our data suggest evaluating anthracyclines and Vinca alkaloids on different days in future trials. Selecting drug combinations based on mechanistic understanding represents a novel conceptional strategy for potent polychemotherapy protocols.

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Gene Expression Alterations Associated with Oleuropein-Induced Antiproliferative Effects and S-Phase Cell Cycle Arrest in Triple-Negative Breast Cancer Cells

Nutrients ◽

10.3390/nu12123755 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3755

Author(s):

Samia S. Messeha ◽

Najla O. Zarmouh ◽

Abrar Asiri ◽

Karam F. A. Soliman

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

Cell Cycle ◽

Cell Lines ◽

Triple Negative ◽

S Phase ◽

Phase Cell ◽

Tnf Receptor ◽

Interacting Protein ◽

Cycle Arrest

It is known that the Mediterranean diet is effective in reducing the risk of several chronic diseases, including cancer. A critical component of the Mediterranean diet is olive oil, and the relationship between olive oil consumption and the reduced risk of cancer has been established. Oleuropein (OL) is the most prominent polyphenol component of olive fruits and leaves. This compound has been shown to have potent properties in various types of cancers, including breast cancer. In the present study, the molecular mechanism of OL was examined in two racially different triple-negative breast cancer (TNBC) cell lines—African American (AA, MDA-MB-468) and Caucasian American (CA, MDA-MB-231). The data obtained showed that OL effectively inhibits cell growth in both cell lines, concomitant with S-phase cell cycle arrest-mediated apoptosis. The results also showed that OL-treated MDA-MB-468 cells were two-fold more sensitive to OL antiproliferative effect than MDA-MB-231 cells were. At lower concentrations, OL modified the expression of many apoptosis-involved genes. OL was more effective in MDA-MB-468, compared to MDA-MB-231 cells, in terms of the number and the fold-change of the altered genes. In MDA-MB-468 cells, OL induced a noticeable transcription activation in fourteen genes, including two members of the caspase family: caspase 1 (CASP1) and caspase 14 (CASP14); two members of the TNF receptor superfamily: Fas-associated via death domain (FADD) and TNF receptor superfamily 21 (TNFRSF21); six other proapoptotic genes: growth arrest and DNA damage-inducible 45 alpha (GADD45A), cytochrome c somatic (CYCS), BCL-2 interacting protein 2 (BNIP2), BCL-2 interacting protein 3 (BNIP3), BH3 interacting domain death agonist (BID), and B-cell lymphoma/leukemia 10 (BCL10); and the CASP8 and FADD-like apoptosis regulator (CFLAR) gene. Moreover, in MDA-MB-468 cells, OL induced a significant upregulation in two antiapoptotic genes: bifunctional apoptosis regulator (BFAR) and B-Raf proto-oncogene (BRAF) and a baculoviral inhibitor of apoptosis (IAP) repeat-containing 3 (BIRC3). On the contrary, in MDA-MB-231 cells, OL showed mixed impacts on gene expression. OL significantly upregulated the mRNA expression of four genes: BIRC3, receptor-interacting serine/threonine kinase 2 (RIPK2), TNF receptor superfamily 10A (TNFRSF10A), and caspase 4 (CASP4). Additionally, another four genes were repressed, including caspase 6 (CASP6), pyrin domain (PYD), and caspase recruitment domain (CARD)-containing (PAYCARD), baculoviral IAP repeat-containing 5 (BIRC5), and the most downregulated TNF receptor superfamily member 11B (TNFRSF11B, 16.34-fold). In conclusion, the data obtained indicate that the two cell lines were markedly different in the anticancer effect and mechanisms of oleuropein’s ability to alter apoptosis-related gene expressions. The results obtained from this study should also guide the potential utilization of oleuropein as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.

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Involvement of p53 and nuclear factor-[kappa]B signaling pathway for the induction of G1-phase cell cycle arrest of cholangiocarcinoma cell lines by isomorellin

Biological and Pharmaceutical Bulletin ◽

10.1248/bpb.b12-00118 ◽

2012 ◽

Cited By ~ 1

Author(s):

Chariya Hahnvajanawong ◽

Supaluk Ketnimit ◽

Kovit Pattanapanyasat ◽

Natthinee Anantachoke ◽

Banchob Sripa ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Signaling Pathway ◽

Cell Lines ◽

Nuclear Factor Kappa B ◽

Phase Cell ◽

G1 Phase ◽

Nuclear Factor ◽

Cycle Arrest ◽

Cholangiocarcinoma Cell

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Immunomodulatory Effect and an Intervention of TNF Signalling Leading to Apoptotic and Cell Cycle Arrest on ORL-204 Oral Cancer Cells by Tiger Milk Mushroom, Lignosus rhinocerus

Food Technology and Biotechnology ◽

10.17113/ftb.60.01.22.7296 ◽

2021 ◽

Vol 60 (1) ◽

Author(s):

Hui Yeng Yeannie Yap ◽

Boon Hong Kong ◽

Chee Sum Alvin Yap ◽

Kien Chai Ong ◽

Rosnah Binti Zain ◽

...

Keyword(s):

Cell Cycle ◽

Oral Cancer ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Cancer Cell ◽

Water Extract ◽

Cancer Cell Lines ◽

Phase Cell ◽

Cycle Arrest ◽

Oral Cancer Cell

Research background. Tiger milk mushroom (Lignosus rhinocerus) is a medicinal mushroom that is geographically distributed in the region of South China, Thailand, Malaysia, Indonesia, Philippines and Papua New Guinea. Consumption of its sclerotium has been reported to treat various ailments. However, its anticancer potential towards oral cancer cell lines is yet to be discovered considering its traditional method of consumption by biting/chewing of the sclerotium. Experimental approach. Mushroom sclerotial powder of cultivar TM02® was extracted and fractionated by a Sephadex G-50 chromatographic column prior to cytotoxicity testing against a panel of human oral cancer cell lines. The capability of the identified bioactive fraction in regulating several molecules associated with its TNF pathway was investigated. Results and conclusions. MTT proliferation assay indicated that ORL-48 (derived from gingiva), ORL-188 (derived from the tongue), and ORL-204 (derived from buccal mucosa) were inhibited by L. rhinocerus sclerotial cold water extract and its high-molecular-mass fraction (HMM) in varying degree with ORL-204 being most affected. Hence, HMM treatment on ORL-204 was further investigated. HMM induced apoptosis and G0/G1-phase cell cycle arrest through caspase-3/7 cleavage. Activities of MIP2 and COX-2 were downregulated by 0.2- and 4.6-fold respectively in the HMM-treated ORL-204 cells. Novelty and scientific contribution. Using ORL-204, it revealed that HMM may have intervened via the TNF pathway at various network sites in its manifestation as a potential dietary compound for cancer prevention and natural adjunct therapeutic to conventional cancer treatment.

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