scholarly journals Diallyl thiosulfinate enhanced the anti-cancer activity of dexamethasone in the side population cells of multiple myeloma by promoting miR-127-3p and deactivating the PI3K/AKT signaling pathway

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wenfeng He ◽  
Yonghui Fu ◽  
Yongliang Zheng ◽  
Xiaoping Wang ◽  
Bin Liu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Signaling Pathway ◽  
Cell Lines ◽  
Colony Formation ◽  
Side Population ◽  
Mtor Signaling Pathway ◽  
Cycle Arrest

Abstract Background Side population (SP) cells, which have similar features to those of cancer stem cells, show resistance to dexamethasone (Dex) treatment. Thus, new drugs that can be used in combination with Dex to reduce the population of SP cells in multiple myeloma (MM) are required. Diallyl thiosulfinate (DATS, allicin), a natural organosulfur compound derived from garlic, has been shown to inhibit the proliferation of SP cells in MM cell lines. Therefore, we investigated the effect of a combination of DATS and Dex (DAT + Dex) on MM SP cells. Methods SP cells were sorted from MM RPMI-8226 and NCI-H929 cell lines using Hoechst 33342-labeled fluorescence-activated cell sorting. The growth of SP cells was evaluated using the cell counting kit-8 assay. Cell cycle and apoptosis assays were conducted using a BD Calibur flow cytometer. miRNA expression was measured using quantitative reverse transcription-polymerase chain reaction. Phosphoinositide 3-kinase (PI3K), phosphorylated AKT (p-AKT), AKT, p-mechanistic target of rapamycin (mTOR), and mTOR levels were measured using western blot analysis. Results Our results showed that the combination of DATS+Dex inhibited sphere formation, colony formation, and proliferation of MM SP cells by inducing apoptosis and cell cycle arrest in the G1/S phase. In addition, the combination of DATS+Dex promoted miR-127-3p expression and inhibited PI3K, p-AKT, and p-mTOR expression in SP cells. Knockdown of miR-127-3p expression weakened the effect of DATS+Dex on cell proliferation, colony formation, apoptosis, and cell cycle of MM SP cells. Additionally, knockdown of miR-127-3p activated the PI3K/AKT/mTOR signaling pathway in MM SP cells cotreated with DATS+Dex. Conclusion We demonstrated that cotreatment with DATS+Dex reduced cell proliferation, promoted apoptosis, and caused cell cycle arrest of MM SP cells by promoting miR-127-3p expression and deactivating the PI3K/AKT/mTOR signaling pathway.

scholarly journals Induction of Apoptosis, Autophagy and Ferroptosis by Thymus vulgaris and Arctium lappa Extract in Leukemia and Multiple Myeloma Cell Lines

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5016
Author(s):  
Aveen N. Adham ◽  
Mohamed Elamir F. Hegazy ◽  
Alaadin M. Naqishbandi ◽  
Thomas Efferth
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Death ◽  
Ethyl Acetate ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Thymus Vulgaris ◽  
Arctium Lappa ◽  
Cycle Arrest ◽  
Induction Of Apoptosis

Thymus vulgaris and Arctium lappa have been used as a folk remedy in the Iraqi Kurdistan region to deal with different health problems. The aim of the current study is to investigate the cytotoxicity of T. vulgaris and A. lappa in leukemia and multiple myeloma (MM) cell lines and determine the mode of cell death triggered by the most potent cytotoxic fractions of both plants in MM. Resazurin assay was used to evaluate cytotoxic and ferroptosis activity, apoptosis, and modulation in the cell cycle phase were investigated via Annexin V-FITC/PI dual stain and cell-cycle arrest assays. Furthermore, we used western blotting assay for the determination of autophagy cell death. n-Hexane, chloroform, ethyl acetate, and butanol fractions of T. vulgaris and A. lappa exhibited cytotoxicity in CCRF-CEM and CEM/ADR 5000 cell lines at concentration range 0.001–100 μg/mL with potential activity revealed by chloroform and ethyl acetate fractions. NCI-H929 displayed pronounced sensitivity towards T. vulgaris (TCF) and A. lappa (ACF) chloroform fractions with IC50 values of 6.49 ± 1.48 and 21.9 ± 0.69 μg/mL, respectively. TCF induced apoptosis in NCI-H929 cells with a higher ratio (71%), compared to ACF (50%) at 4 × IC50. ACF demonstrated more potent autophagy activity than TCF. TCF and ACF induced cell cycle arrest and ferroptosis. Apigenin and nobiletin were identified in TCF, while nobiletin, ursolic acid, and lupeol were the main compounds identified in ACF. T. vulgaris and A. lappa could be considered as potential herbal drug candidates, which arrest cancer cell proliferation by induction of apoptosis, autophagic, and ferroptosis.

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

Biomolecules ◽  
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.

scholarly journals Cell Cycle Arrest of Extract from Artemisia annua Linné. Via Akt-mTOR Signaling Pathway in HCT116 Colon Cancer Cells

KSBB Journal ◽  
2015 ◽  
Vol 30 (5) ◽  
pp. 223-229 ◽  
Author(s):  
Bo Min Kim ◽  
Guen Tae Kim ◽  
Eun Gyeong Lim ◽  
Eun Ji Kim ◽  
Sang Yong Kim ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Colon Cancer ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Artemisia Annua ◽  
Mtor Signaling ◽  
Colon Cancer Cells ◽  
Mtor Signaling Pathway ◽  
Cycle Arrest

β1 Integrin Adhesion Enhances IL-6 Mediated STAT3 Signaling in Multiple Myeloma Cells: Implications for Microenvironment Influence on Tumor Cell Survival and Proliferation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1706-1706
Author(s):  
Kenneth H Shain ◽  
Danielle Yarde ◽  
Mark Mead ◽  
Lori Hazlehurst ◽  
William S Dalton
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Genetic Alterations ◽  
Β1 Integrin ◽  
Cycle Arrest ◽  
Stat3 Signaling ◽  
Stat3 Phosphorylation ◽  
In Cells

Abstract Multiple Myeloma (MM) is a B cell malignancy characterized by the monoclonal expansion of plasma cells. Although numerous genetic alterations have been implicated in MM pathogenesis, it is widely hypothesized that the bone marrow (BM) microenvironment contributes to MM cell pathogenesis. The BM microenvironmental components, interleukin (IL)-6 and fibronectin (FN), have individually been shown to influence the proliferation and survival of MM cells; however, in vivo these effectors most likely work together. We examined signaling events, cell cycle progression, and levels of drug response in MM cells either adhered to FN via β1 integrins, stimulated with IL-6, or with the two combined. IL-6 and FN adhesion have been demonstrated to protect cells from a host of cytotoxic stimuli suggesting co-stimulation of MM cell lines with IL-6 and FN-adhesion may confer a greater protection against chemotherapeutics than either effector alone. However, MTT cytotoxicity assays demonstrate that although adhesion to FN provides significant protection against treatment with mitoxantrone or doxorubicin (p=0.0002 and p=<0.0001 respectively), the addition of IL-6 provides no further protection. These findings were corroborated by analysis of drug-mediated apoptosis using FCM by Annexin-V/7-AAD. In regards to cell cycle kinetics, our laboratory has previously demonstrated that adhesion of the 8226 MM cell line to FN mediated a p27Kip1 dependent G0/G1 cell cycle arrest. As predicted, BrdU/PI analysis of 8226 cells adhered to FN for 24 hours results in an increased number of cells in G0/G1 relative to cells maintained in suspension (p=0.0028). In contrast, when cells were adhered to FN in the presence of IL-6 no accumulation of cells in G0/G1 was observed, with levels similar to that observed in cells maintained in suspension with or without stimulation by IL-6. Our studies demonstrated that the G1/S cell cycle arrest associated with FN adhesion of MM cell lines was overcome when IL-6 was added; however, the cell adhesion mediated drug resistance (CAM-DR) was maintained in the presence of IL-6. Investigation of the biochemical signaling following concomitant exposure of MM cells to IL-6 and FN adhesion revealed a synergistic increase in STAT3 phosphorylation, nuclear translocation and DNA-binding as compared to either IL-6 or FN-adhesion alone in four MM cell lines. STAT3 phosphorylation was increased in cells adhered to FN in an IL-6 dose dependent manner. Electrophoretic mobility shift assay demonstrated a parallel 3-fold increase in STAT3/DNA complexes in cells adhered to FN relative to cells in suspension. To further characterize the receptor proximal affects of FN adhesion on IL-6 signaling we immunoprecipitated the IL-6R complex with antisera to gp130. Immunoprecipitation of gp130 revealed enhanced tyrosine phosphorylation of the gp130/Jak family complexes following stimulation FN-adhered RPMI 8226 MM cells with IL-6. Consistent with increased phosphorylation of the receptor complex, increased levels of phospho-STAT3 were identified associated with gp130 under co-stimulatory conditions relative to IL-6 or FN adhesion alone. Interestingly, immunoprecipitation with gp130 antibodies also revealed an association between STAT3 (non-phosphorylated) and gp130 in the absence of IL-6 stimulation in cells adhered to FN. These results suggest that adhesion to FN facilitates an IL-6-independent association between gp130 and STAT3, resulting in enhanced STAT3 signaling. Taken together, these data demonstrate a novel mechanism by which collaborative signaling by β1 integrin and gp130 confer an increased survival advantage to MM cells.

ANP32A Dysregulation Involves Histone Modifications and Contributes to Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2456-2456
Author(s):  
Bin Lu ◽  
Xueqin Sun ◽  
John Crispino ◽  
Zan Huang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Cycle Arrest ◽  
Histone Modifications ◽  
Colony Formation ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Genetic Alterations ◽  
Leukemic Cells ◽  
Cycle Arrest

Abstract Genetic alterations as the initiator inducing leukemia also cause disorder of gene expression. Cooperation of these factors is known to be essential for leukemia development and remains to be further elucidated. In this study, we discovered that ANP32A dysregulation might contribute to myeloid leukemia. ANP32A expression was unanimously elevated in multiple online leukemia datasets and its upregulation was confirmed in human primary myeloid leukemia cells. Although ectopic expression of ANP32A did not promote leukemic cell proliferation, it did increase cell resistance to drug treatment such as TPA, Ara-C, VP16, and BCL2 inhibitor. Interestingly, ANP32A knockdown reduced cell proliferation and impaired colony formation in soft agar in various leukemic cells. ANP32A knockdown did so by inducing apoptosis and cell cycle arrest at G1 phase evidenced by upregulation of pro-apoptosis genes (BAK, BAD, cleaved caspase 3 and PARP) and downregulation of pro-survival or cell cycle progress genes (BCL2, CDK4, CCND1). The function of ANP32A knockdown to induce apoptosis and reduce colony formation was verified in human primary acute myeloid leukemia (AML) cells (Figure 1). However, re-introduction of BCL2, CDK4, or CCND1 failed to restore the impaired ability of colony formation by ANP32A knockdown, suggesting that apoptosis and cell cycle arrest may not be the direct effect of ANP32A knockdown. To probe how ANP32A would affect cell proliferation, we performed microarray analysis to identify potential ANP32A target genes including APOC1 and CCL26. Indeed, reintroduction of APOC1 or CCL26 significantly rescued colony formation ability while knockdown of APOC1 or CCL26 alone was sufficient to reduce colony formation. Further gene set enrichment analysis (GSEA) also revealed Notch signaling and histone modification signatures in ANP32A knockdown cells. To support this, ANP32A knockdown reduced intracellular Notch and NOTCH1 ovexpression significantly recovered the ability of colony formation. Furthermore, ANP32A knockdown also led to a global alteration of histone modifications including decrease of H3K9-acetylation (H3K9ac), H3K27-trimethylation (H3K27me3), and H3K4-trimethylation (H3K4me3) and increase of H3K9-trimethylation (H3K9me3). In fact, ChIP-PCR demonstrated that ANP32A bound to the promoter region of multiple target genes identified in microarray analysis and ANP32A downregulation caused decreased H3K27me3 and H3K4me3 at the same sites (Figure 2). These findings suggest that ANP32A may bind to the chromosome and involve histone modifications. To further test the potential function of ANP32A in leukemogenesis, we took advantage of MLL-AF9 fusion gene to immortalize bone marrow cells in vitro and compared wild-type (WT) cells to Anp32a knockout (Anp32a-/-) cells. We found that MLL-AF9-transduced Anp32a-/- bone marrow cells reproduced all phenotypes of leukemic cells with ANP32A knockdown: Anp32a-/- cells proliferated less, formed less colonies, exhibited more apoptosis, and showed cell cycle arrest at G1 phase compared to WT cells (Figure 3). These observations suggest a potential role of ANP32A in MLL-AF9-induced acute myeloid leukemia. Taken together, our studies have revealed ANP32A as a potential novel player to cooperate with other genetic alterations to induce leukemia. ANP32A upregulation may somehow involve histone modifications at genomic level that ultimately alter the expression of multiple genes and facilitate leukemic cell proliferation and survival. Thus ANP32A may serve as a potential target for developing novel therapy or biomarker for diagnosis and prognosis. Disclosures No relevant conflicts of interest to declare.

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