Full extract of Euphorbia esula reversed chemoresistance, inhibited cell migration/invasion, and induced apoptosis of multidrug-resistant SGC7901/VCR cells

Objective Previous studies suggested that sevoflurane exerts anti-proliferative, anti-migratory, and anti-invasive effects on cancer cells. To determine the role of sevoflurane on gastric cancer (GC) progression, we evaluated its effects on the proliferation, migration, and invasion of SGC7901, AGS, and MGC803 GC cells. Methods GC cells were exposed to different concentrations of sevoflurane (1.7, 3.4, or 5.1% v/v). Cell viability, migration, and invasion were evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Transwell assays. Immunohistochemical staining and immunoblotting were performed to analyze forkhead box protein 3 (FOXP3) protein expression in tissue specimens and cell lines, respectively. Results FOXP3 was downregulated in human GC specimens and cell lines. Functionally, FOXP3 overexpression significantly inhibited the proliferation, migration, and invasion of GC cells and accelerated their apoptosis. Moreover, sevoflurane significantly blocked GC cell migration and invasion compared with the findings in the control group. However, FOXP3 silencing neutralized sevoflurane-induced apoptosis and the inhibition of GC cell migration and invasion. Sevoflurane-induced apoptosis and the suppression of migration and invasion might be associated with FOXP3 overactivation in GC cells. Conclusions Sevoflurane activated FOXP3 and prevented GC progression via inhibiting cell migration and invasion in vitro.

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Fiber density and matrix stiffness modulate distinct cell migration modes in a 3D stroma mimetic composite hydrogel

10.1101/2021.02.27.433190 ◽

2021 ◽

Author(s):

Harrison L. Hiraki ◽

Daniel L. Matera ◽

William Y. Wang ◽

Alexander A. Zarouk ◽

Anna E. Argento ◽

...

Keyword(s):

Cell Migration ◽

Epithelial Mesenchymal Transition ◽

Cancer Therapeutics ◽

Therapy Resistance ◽

Metastatic Spread ◽

Tumor Escape ◽

Fiber Density ◽

Mesenchymal Transition ◽

Stromal Microenvironment ◽

Induced Apoptosis

ABSTRACTThe peritumoral stroma is a complex 3D tissue that provides cells with myriad biophysical and biochemical cues. Histologic observations suggest that during metastatic spread of carcinomas, these cues influence transformed epithelial cells, prompting a diversity of migration modes spanning single cell and multicellular phenotypes. Purported consequences of these variations in tumor escape strategies include differential metastatic capability and therapy resistance. Therefore, understanding how cues from the peritumoral stromal microenvironment regulate migration mode phenotypes has prognostic and therapeutic value. Here, we utilize a synthetic stromal mimetic in which matrix fiber density and bulk hydrogel stiffness can be orthogonally tuned to investigate the contribution of these two key matrix attributes on MCF10A migration mode phenotypes, epithelial-mesenchymal transition (EMT), and invasive potential. We developed an automated computational image analysis framework to extract migratory phenotypes from fluorescent images and determine 3D migration metrics relevant to metastatic spread. Using this analysis, we find that matrix fiber density and bulk hydrogel stiffness distinctly contribute to a variety of MCF10A migration modes including amoeboid, single mesenchymal, multicellular clusters, and collective strands. Taking advantage of the tunability of this material platform, we identify a combination of physical and soluble cues that induces distinct heterogeneous migration modes originating from the same MCF10A spheroid and use this setting to examine a functional consequence of migration mode – apoptotic resistance. We find that cells migrating as part of collective strands are more resistant to staurosporine-induced apoptosis than either disconnected multicellular clusters or individual invading cells. Improved models of the peritumoral stromal microenvironment that help elucidate relationships between matrix attributes and cell migration mode can contribute to ongoing efforts to identify efficacious cancer therapeutics that address migration plasticity-based therapy resistances.

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Cytotoxic Constituents of the Bark of Hypericum roeperianum towards Multidrug-Resistant Cancer Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/4314807 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Michel-Gael F. Guefack ◽

Francois Damen ◽

Armelle T. Mbaveng ◽

Simplice Beaudelaire Tankeo ◽

Gabin T. M. Bitchagno ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Colon Adenocarcinoma ◽

Cancer Cell Lines ◽

Multidrug Resistant ◽

Leukemia Cells ◽

Ros Production ◽

Cytotoxic Effects ◽

Induced Apoptosis

The global cancer burden remains a serious concern with the alarming incidence of one in eight men and one in eleven women dying in developing countries. This situation is aggravated by the multidrug resistance (MDR) of cancer cells that hampers chemotherapy. In this study, the cytotoxicity of the methanol extract (HRB), fractions (HRBa, HRBb, and HRBa1-5), and compounds from the bark of Hypericum roeperianum (HRB) was evaluated towards a panel of 9 cancer cell lines. The mode of action of the HRB and trichadonic acid (1) was also studied. Column chromatography was applied to isolate the constituents of HRB. The cytotoxicity of botanicals and phytochemicals was evaluated by the resazurin reduction assay (RRA). Caspase-Glo assay was used to evaluate the activity of caspases, and reactive oxygen species (ROS) (H2DCFH-DA) were assessed by flow cytometry. Phytochemicals isolated from HRB were trichadonic acid (1), fridelan-3-one (2), 2-hydroxy-5-methoxyxanthone (3), norathyriol (4), 1,3,5,6-tetrahydroxyxanthone (5), betulinic acid (6), 3′-hydroxymethyl-2′-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5′,6′:5,6-(6,8-dihydroxyxanthone)-1′,4′-dioxane (7), and 3′-hydroxymethyl-2′-(4″-hydroxy-3″,5″-dimethoxyphenyl)-5′,6′:5,6-(xanthone)-1′,4′-dioxane (8). Botanicals HRB, HRBa, HRBa2-4, HRBb, and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines. The recorded IC50 values ranged from 11.43 µg/mL (against the P-glycoprotein (gp)-overexpressing CEM/ADR5000 leukemia cells) to 26.75 µg/mL (against HCT116 (p53+/+) colon adenocarcinoma cells) for the crude extract HRB. Compounds 1, 5, and doxorubicin displayed cytotoxic effects towards the 9 tested cancer cell lines with IC50 values varying from 14.44 µM (against CCRF-CEM leukemia cells) to 44.20 µM (against the resistant HCT116 (p53−/−) cells) for 1 and from 38.46 µM (against CEM/ADR5000 cells) to 112.27 µM (against the resistant HCT116 (p53−/−) cells) for 5. HRB and compound 1 induced apoptosis in CCRF-CEM cells. The apoptotic process was mediated by enhanced ROS production for HRB or via caspases activation and enhanced ROS production for compound 1. This study demonstrated that Hypericum roeperianum is a potential source of cytotoxic phytochemicals such as trichadonic acid and could be further exploited in cancer chemotherapy.

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Clinical Isolates ofMycobacterium tuberculosisDiffer in Their Ability to Induce Respiratory Burst and Apoptosis in Neutrophils as a Possible Mechanism of Immune Escape

Clinical and Developmental Immunology ◽

10.1155/2012/152546 ◽

2012 ◽

Vol 2012 ◽

pp. 1-11 ◽

Cited By ~ 18

Author(s):

María M. Romero ◽

Luciana Balboa ◽

Juan I. Basile ◽

Beatriz López ◽

Viviana Ritacco ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Reference Strain ◽

Immune Escape ◽

Multidrug Resistant ◽

Polymorphonuclear Neutrophils ◽

Ros Production ◽

Oxygen Species ◽

Phenotypic Differences ◽

Induced Apoptosis ◽

P38 Pathway

Tuberculosis pathogenesis was earlier thought to be mainly related to the host but now it appears to be clear that bacterial factors are also involved. Genetic variability ofMycobacterium tuberculosis(Mtb) could be slight but it may lead to sharp phenotypic differences. We have previously reported that nonopsonizedMtbH37Rv induce apoptosis of polymorphonuclear neutrophils (PMNs) by a mechanism that involves the p38 pathway. Here we evaluated the capability to induce PMN apoptosis of two prevalentMtblineages in Argentina, the Latin America and Mediterranean (LAM), and Haarlem, using the H37Rv as a reference strain. Results showed that LAM strains strongly induced apoptosis of PMN which correlated with the induction of reactive oxygen species (ROS) production and p38 activation. Interestingly, the highly prosperous multidrug-resistant M strain, belonging to the Haarlem lineage, lacked the ability to activate and to induce PMN apoptosis as a consequence of (1) a weak ROS production and (2) the contribution of antiapoptotic mechanisms mediated at least by ERK. Although with less skill, M is able to enter the PMN so that phenotypic differences could lead PMN to be a reservoir allowing some pathogens to prevail and persist over other strains in the community.

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Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress MDR, MRP, Bcl-2, or Bcl-xL

Blood ◽

10.1182/blood.v95.3.1014.003k04_1014_1022 ◽

2000 ◽

Vol 95 (3) ◽

pp. 1014-1022 ◽

Cited By ~ 162

Author(s):

Charles Perkins ◽

Caryn N. Kim ◽

Guofu Fang ◽

Kapil N. Bhalla

Keyword(s):

Myeloid Leukemia ◽

Blast Crisis ◽

K562 Cells ◽

Cell Types ◽

Multidrug Resistant ◽

Leukemia Cells ◽

Protein Levels ◽

Growth Inhibitory ◽

Induced Apoptosis

We investigated the in vitro growth inhibitory and apoptotic effects of clinically achievable concentrations of As2O3 (0.5 to 2.0 μmol/L) against human myeloid leukemia cells known to be resistant to a number of apoptotic stimuli. These included chronic myelocytic leukemia (CML) blast crisis K562 and HL-60/Bcr-Abl cells, which contain p210 and p185 Bcr-Abl, respectively, and HL-60 cell types that overexpress Bcl-2 (HL-60/Bcl-2), Bcl-xL(HL-60/Bcl-xL), MDR (HL-60/VCR), or MRP (HL-60/AR) protein. The growth-inhibitory IC50 values for As2O3 treatment for 7 days against all these cell types ranged from 0.8 to 1.5 μmol/L. Exposure to 2 μmol/L As2O3 for 7 days induced apoptosis of all cell types, including HL-60/Bcr-Abl and K562 cells. This was associated with the cytosolic accumulation of cyt c and preapoptotic mitochondrial events, such as the loss of inner membrane potential (▵Ψm) and the increase in reactive oxygen species (ROS). Treatment with As2O3 (2 μmol/L) generated the activities of caspases, which produced the cleavage of the BH3 domain containing proapoptotic Bid protein and poly (ADP-ribose) polymerase. Significantly, As2O3-induced apoptosis of HL-60/Bcr-Abl and K562 cells was associated with a decline in Bcr-Abl protein levels, without any significant alterations in the levels of Bcl-xL, Bax, Apaf-1, Fas, and FasL. Although As2O3 treatment caused a marked increase in the expression of the myeloid differentiation marker CD11b, it did not affect Hb levels in HL-60/Bcr-Abl, K562, or HL-60/neo cells. However, in these cells, As2O3 potently induced hyper-acetylation of the histones H3 and H4. These findings characterize As2O3 as a growth inhibiting and apoptosis-inducing agent against a variety of myeloid leukemia cells resistant to multiple apoptotic stimuli.

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Bullatacin Triggered ABCB1-Overexpressing Cell Apoptosis via the Mitochondrial-Dependent Pathway

Journal of Biomedicine and Biotechnology ◽

10.1155/2009/867123 ◽

2009 ◽

Vol 2009 ◽

pp. 1-9 ◽

Cited By ~ 3

Author(s):

Yong-Ju Liang ◽

Xu Zhang ◽

Chun-Ling Dai ◽

Jian-Ye Zhang ◽

Yan-Yan Yan ◽

...

Keyword(s):

Cell Apoptosis ◽

Multidrug Resistant ◽

Resistant Cell ◽

Ros Generation ◽

Caspase 8 ◽

Dependent Manner ◽

Caspase 9 ◽

Concentration Dependent Manner ◽

Induced Apoptosis ◽

Dependent Pathway

This paper was to explore bullatacin-mediated multidrug-resistant cell apoptosis at extremely low concentration. To investigate its precise mechanisms, the pathway of cell apoptosis induced by bullatacin was examined. Bullatacin causes an upregulation of ROS and a downregulation ofΔΨmin a concentration-dependent manner in ABCB1-overexpressing KBv200 cells. In addition, cleavers of caspase-9, caspase-3, and PARP were observed following the release of cytochrome c from mitochondria after bullatacin treatment. However, neither cleavage of caspase-8 nor change of expression level of bcl-2, bax and Fas was observed by the same treatment. Pretreating KBv200 cells with N-acetylcysteine, an antioxidant modulator, resulted in a significant reduction of ROS generation and cell apoptosis induced by bullatacin. Bullatacin-induced apoptosis was antagonized by z-LEHD-fmk, a caspase-9 inhibitor, but not by z-IETD-fmk, a caspase-8 inhibitor. These implied that apoptosis of KBv200 cells induced by bullatacin was associated with the mitochondria-dependent pathway that was limited to activation of apical caspase-9.

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The role of cyclooxygenase‐2 in berberine induced apoptosis and inhibited cell migration of human gastric adenocarcinoma RF‐1 and RF‐48 cell lines

The FASEB Journal ◽

10.1096/fasebj.20.5.a1131-d ◽

2006 ◽

Vol 20 (5) ◽

Author(s):

CHUN‐SHU YU ◽

Hsiu‐Maan Kuo ◽

Jing‐Gung Chung

Keyword(s):

Cell Migration ◽

Gastric Adenocarcinoma ◽

Cell Lines ◽

Cyclooxygenase 2 ◽

Human Gastric Adenocarcinoma ◽

Induced Apoptosis

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Chemopreventive Property of Sencha Tea Extracts towards Sensitive and Multidrug-Resistant Leukemia and Multiple Myeloma Cells

Biomolecules ◽

10.3390/biom10071000 ◽

2020 ◽

Vol 10 (7) ◽

pp. 1000

Author(s):

Xiaohua Lu ◽

Mohamed E. M. Saeed ◽

Mohamed-Elamir F. Hegazy ◽

Christopher J. Kampf ◽

Thomas Efferth

Keyword(s):

Cell Cycle ◽

Cell Lines ◽

Green Tea ◽

Cell Cycle Progression ◽

Multidrug Resistant ◽

Cellular Growth ◽

Leukemic Cells ◽

Multiple Myelomas ◽

Induced Apoptosis ◽

Chemopreventive Activity

The popular beverage green tea possesses chemopreventive activity against various types of tumors. However, the effects of its chemopreventive effect on hematological malignancies have not been defined. In the present study, we evaluated antitumor efficacies of a specific green tea, sencha tea, on sensitive and multidrug-resistant leukemia and a panel of nine multiple myelomas (MM) cell lines. We found that sencha extracts induced cytotoxicity in leukemic cells and MM cells to different extents, yet its effect on normal cells was limited. Furthermore, sencha extracts caused G2/M and G0/G1 phase arrest during cell cycle progression in CCRF/CEM and KMS-12-BM cells, respectively. Specifically, sencha-MeOH/H2O extracts induced apoptosis, ROS, and MMP collapse on both CCRF/CEM and KMS-12-BM cells. The analysis with microarray and COMPARE in 53 cell lines of the NCI panel revealed diverse functional groups, including cell morphology, cellular growth and proliferation, cell cycle, cell death, and survival, which were closely associated with anti-tumor effects of sencha tea. It is important to note that PI3K/Akt and NF-κB pathways were the top two dominant networks by ingenuity pathway analysis. We demonstrate here the multifactorial modes of action of sencha tea leading to chemopreventive effects of sencha tea against cancer.

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