The Molecular Mechanism of ESZM Extract on Treatment ER(-) Breast Cancer in Vivo: Application of “Combat Poison with Poison” Theory

Abstract Background: Extract of Euphorbia fischeriana S. and Ziziphus jujuba M. (ESZM) is a formula preparation, was composed of Euphorbia fischeriana S. (E. fischeriana) and Ziziphus jujuba M. (Z. jujuba). The aim of the current research was to examine for the first time the pharmacological effects and the underlying molecule mechanism of ESZM extract on the growth inhibition and apoptosis in human ER(-) or ER(+) breast cancer in vivo, and enrich and innovate the theory of traditional Chinese medicine of combating poison with poison. Methods: Growth inhibition, cell cycle arrest and apoptosis in tumor tissues were determined by tumor inhibition rates, cycle analysis kit, Annexin V-FITC/PI staining, Hoechst 33342/PI staining, TUNEL test and TEM observation. Related genes and proteins expression levels were identified by qRT-PCR assay, Western Blotting method, immunohistochemistry and immunofluorescence means. Drug toxicity was analysised by serum biochemistry detection and H&E staining.Results: We found that ESZM extract can inhibite growth, block cell cycle at G2/M phase and induce apoptosis of subcutaneously transplanted tumor, especially ER(-) breast cancer transplanted tumor. Furthermore, we demonstrated that the polyjuice can down-regulate or up-regulate the expression of Bcl-2 family and PI3k/Akt pathway -related signaling molecules proteins and genes in vivo. ESZM extract or E. fischeriana extract increased the levels of ALT, AST, Cr and BUN, and increased liver and kidney toxicity in tumor-bearing mice by serum biochemistry detection and H&E staining.Conclusion: The pharmacological detection suggested that ESZM extract had significant anti-breast cancer effect, especially ER(-) breast cancer xenograft, and this process may be implement through the mitochondrion dependent pathway and the PI3k/Akt signaling pathway. Drug toxicity detection proved that ESZM extract because of compatibility with Z. jujuba was lower toxicity than E. fischeriana extract, was no significant difference in hepatorenal toxicity between ER(-) or ER(+) tumor-bearing mice.

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ST09, A Novel Curcumin Derivative, Blocks Cell Migration by Inhibiting Matrix Metalloproteases in Breast Cancer Cells and Inhibits Tumor Progression in EAC Mouse Tumor Models

Molecules ◽

10.3390/molecules25194499 ◽

2020 ◽

Vol 25 (19) ◽

pp. 4499

Author(s):

Snehal Nirgude ◽

Raghunandan Mahadeva ◽

Jinsha Koroth ◽

Sujeet Kumar ◽

Kothanahally S. Sharath Kumar ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Flow Cytometry ◽

Cell Death ◽

Cell Migration ◽

Drug Toxicity ◽

Mouse Tumor ◽

Curcumin Derivative

Purpose: Curcumin is known for its anticancer and migrastatic activity in various cancers, including breast cancer. Newer curcumin derivatives are being explored to overcome limitations of curcumin like low bioavailability, stability, and side effects due to its higher dose. In this study, the synthesis of ST09, a novel curcumin derivative, and its antiproliferative, cytotoxic, and migrastatic properties have been explored both in vitro and in vivo. Methods: After ST09 synthesis, anticancer activity was studied by performing standard cytotoxicity assays namely, lactate dehydrogenase (LDH) release assay, 3-(4, 5-dimethylthiazol-2-yl)-2–5-diphenyletrazolium bromide (MTT), and trypan blue exclusion assay. Annexin-FITC, cell cycle analysis using flow cytometry, and Western blotting were performed to elucidate cell death mechanisms. The effect on the inhibition of cell migration was studied by transwell migration assay. An EAC (Ehrlich Ascites carcinoma) induced mouse tumor model was used to study the effect of ST09 on tumor regression. Drug toxicity was measured using aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and flow-cytometry based lymphocyte count. Histological analysis was performed for assessment of any tissue injury post ST09 treatment. Results: ST09 shows an approximate 100-fold higher potency than curcumin, its parent compound, on breast tumor cell lines MCF-7 and MDA-MB231. ST09 arrests the cell cycle in a cell type-specific manner and induces an intrinsic apoptotic pathway both in vitro and in vivo. ST09 inhibits migration by downregulating matrix metalloprotease 1,2 (MMP1,2) and Vimentin. In vivo, ST09 administration led to decreased tumor volume in a mouse allograft model by boosting immunity with no significant drug toxicity. Conclusion: ST09 exhibits antiproliferative and cytotoxic activity at nanomolar concentrations. It induces cell death by activation of the intrinsic pathway of apoptosis both in vitro and in vivo. It also inhibits migration and invasion. This study provides evidence that ST09 can potentially be developed as a novel antitumor drug candidate for highly metastatic and aggressive breast cancer.

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Synergistic effect of paclitaxel and epigenetic agent phenethyl isothiocyanate on growth inhibition, cell cycle arrest and apoptosis in breast cancer cells

Cancer Cell International ◽

10.1186/1475-2867-13-10 ◽

2013 ◽

Vol 13 (1) ◽

pp. 10 ◽

Cited By ~ 41

Author(s):

Katherine Liu ◽

Shundong Cang ◽

Yuehua Ma ◽

Jen Wei Chiao

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Synergistic Effect ◽

Growth Inhibition ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Phenethyl Isothiocyanate ◽

Cycle Arrest

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Growth inhibition observed following administration of an LHRH agonist to a clonal variant of the MCF-7 breast cancer cell line is accompanied by an accumulation of cells in the G0/G1 phase of the cell cycle

British Journal of Cancer ◽

10.1038/bjc.1991.203 ◽

1991 ◽

Vol 63 (6) ◽

pp. 930-932 ◽

Cited By ~ 23

Author(s):

P Mullen ◽

WN Scott ◽

WR Miller

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Growth Inhibition ◽

Cell Line ◽

Breast Cancer Cell Line ◽

Cancer Cell Line ◽

G1 Phase ◽

Lhrh Agonist ◽

Clonal Variant ◽

Mcf 7

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Mibefradil inhibits the proliferation of triple-negative breast cancer by targeting AURKA to regulate apoptosis signal pathway

10.21203/rs.3.rs-210031/v1 ◽

2021 ◽

Author(s):

Xu Han ◽

Xiujuan Qu ◽

Beixing Liu ◽

Yizhe Wang ◽

Yang Cheng ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Molecular Docking ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Therapeutic Drug ◽

Specific Gene ◽

In Vivo Models

Abstract Background: Triple negative breast cancer (TNBC) is a tumor characterized by high recurrence and mortality, but without effective targeted therapy. It is urgent to explore new treatment strategy to improve the efficacy of TNBC therapy. Methods: Transcriptomic profiling datasets of TNBC were used for screening TNBC specific gene sets. Drug prediction was performed in Connectivity map (CMap) database. Molecular docking method was used for analyzing drug targets. In vitro and in vivo models of TNBC were constructed to examine the drug efficacy. Results: We screened out Mibefradil, a T-type Ca2+ channel blocker, might be a potential therapeutic drug for TNBC by transcriptomics and bioinformatics analysis, and verified that Mibefradil could inhibit the proliferation of TNBC cells by inducing apoptosis and cell cycle arrest. Furthermore, by network pharmacology and molecular docking analysis, AURKA was predicted as the most possible drug target of Mibefradil. Finally, it was proved that Mibefradil treatment could induce apoptosis by decreasing protein expression and phosphorylation level of AURKA in vitro and in vivo. Conclusions: Mibefradil played anti-cancer role in TNBC cells by targeting to AURKA to induce cell cycle and apoptosis. Our results repurposed Mibefradil as a potential targeted drug of TNBC and provided a fundamental research for a novel strategy TNBC treatment.

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Roquin1 Suppresses Breast Cancer Growth by Inducing Cell Cycle Arrest via Selectively Destabilizing Cell Cycle–Promoting Gene mRNAs

10.21203/rs.3.rs-53499/v1 ◽

2020 ◽

Author(s):

Wenbao Lu ◽

Meicen Zhou ◽

Bing Wang ◽

Xueting Liu ◽

Bingwei Li

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Proliferation ◽

Cell Cycle Arrest ◽

Breast Cancer Cell ◽

Breast Tumor ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Cycle Arrest

Abstract Background: Dysregulation of cell cycle progression is one of the common features of human cancer cells, however, its mechanism remains unclear. This study aims to clarify the role and the underlying mechanisms of Roquin1 in cell cycle arrest induction in breast cancer.Methods: Public cancer databases were analyzed to identify the expression pattern of Roquin1 in human breast cancers and the significant association with patient survival. Quantitative real-time PCR and western blots were performed to detect the expression of Roquin1 in breast cancer samples and cell lines. Cell counting, MTT assay, flow cytometry, and in vivo study were conducted to investigate the effects of Roquin1 on cell proliferation, cell cycle progression and tumor progression. RNA-sequencing was applied to identify the differential genes and pathways regulated by Roquin1. RNA immunoprecipitation assay, luciferase reporter assay, mRNA half-life detection, RNA affinity binding assay, and RIP-ChIP were used to explore the molecular mechanisms of Roquin1.Results: We showed that Roquin1 expression in breast cancer tissues and cell lines was inhibited, and the reduction in Roquin1 expression was associated with poor overall survival and relapse free survival of patients with breast cancer. Roquin1 overexpression inhibited breast cancer cell proliferation and induced G1/S cell cycle arrest without causing significant apoptosis. In contrast, knockdown of Roquin1 promoted breast cancer cell growth and cycle progression. Moreover, in vivo induction of Roquin1 by adenovirus significantly suppressed breast tumor growth and metastasis. Mechanistically, Roquin1 selectively destabilizing cell cycle–promoting genes, including Cyclin D1, Cyclin E1, cyclin dependent kinase 6 (CDK6) and minichromosome maintenance 2 (MCM2) through targeting the stem–loop structure in the 3’untranslated region (3’UTR) of mRNAs via its ROQ domain, leading to the downregulation of cell cycle–promoting mRNAs.Conclusions: Our findings demonstrated that Roquin1 was a novel breast tumor suppressor and could induce G1/S cell cycle arrest by selectively downregulating the expression of cell cycle–promoting genes, which might as a potential molecular target for breast cancer treatment.

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Regulation of Parathyroid Hormone-Related Peptide by Estradiol: Effect on Tumor Growth and Metastasis in Vitro and in Vivo

Endocrinology ◽

10.1210/en.2005-0062 ◽

2005 ◽

Vol 146 (7) ◽

pp. 2885-2894 ◽

Cited By ~ 22

Author(s):

S. A. Rabbani ◽

P. Khalili ◽

A. Arakelian ◽

H. Pizzi ◽

G. Chen ◽

...

Keyword(s):

Breast Cancer ◽

Cell Growth ◽

Tumor Growth ◽

Tumor Volume ◽

In Vivo Studies ◽

Promoting Effect ◽

X Ray ◽

Tumor Bearing ◽

Tumor Growth And Metastasis

Abstract We evaluated the capacity of estradiol (E2) to regulate PTHrP production, cell growth, tumor growth, and metastasis to the skeleton in breast cancer. In estrogen receptor (ER)-negative human breast cancer cells, MDA-MB-231, and cells transfected with full-length cDNA encoding ER (S-30), E2 caused a marked decrease in cell growth and PTHrP production, effects that were abrogated by anti-E2 tamoxifen. E2 also inhibited PTHrP promoter activity in S-30 cells. For in vivo studies, MDA-MB-231 and S-30 cells were inoculated into the mammary fat pad of female BALB/c nu.nu mice. Animals receiving S-30 cells developed tumors of significantly smaller volume compared with MDA-MB-231 tumor-bearing animals. This change in tumor volume was reversed when S-30 cells were inoculated into ovariectomized (OVX) hosts. Inoculation of MDA-MB-231 cells into the left ventricle resulted in the development of lesions in femora and tibia as determined by x-ray analysis. In contrast, these lesions were significantly smaller in volume and number in animals inoculated with S-30, and this lower incidence was reversed in OVX animals. Bone histological analysis showed that the tumor volume to tissue volume ratio was comparable with that seen by x-ray. Immunohistochemical analysis showed that PTHrP production was inhibited in S-30 group and restored to levels comparable to that seen in MDA-MB-231 tumor-bearing animals when S-30 cells were inoculated in OVX animals. Collectively these studies show that E2 production is inversely correlated with PTHrP production and that the growth-promoting effect of PTHrP has a direct impact on tumor growth at both nonskeletal and skeletal sites.

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PTEN insufficiency modulates ER+ breast cancer cell cycle progression and increases cell growth in vitro and in vivo

Drug Design Development and Therapy ◽

10.2147/dddt.s86184 ◽

2015 ◽

pp. 4631 ◽

Cited By ~ 2

Author(s):

Kun-Chun Chiang ◽

Chun-Nan Yeh ◽

Huang-Yang Chen ◽

Jong-Hwei S.Pang ◽

Shang-Yu Wang ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cell Growth ◽

Cancer Cell ◽

Breast Cancer Cell ◽

Cell Cycle Progression ◽

Cycle Progression

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A novel form of Deleted in breast cancer 1 (DBC1) lacking the N-terminal domain does not bind SIRT1 and is dynamically regulated in vivo

Scientific Reports ◽

10.1038/s41598-019-50789-7 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 1

Author(s):

Leonardo Santos ◽

Laura Colman ◽

Paola Contreras ◽

Claudia C. Chini ◽

Adriana Carlomagno ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Normal Cell ◽

Cell Cycle Progression ◽

Cycle Progression ◽

Quiescent Cells ◽

Normal Cell Cycle

Abstract The protein Deleted in Breast Cancer-1 is a regulator of several transcription factors and epigenetic regulators, including HDAC3, Rev-erb-alpha, PARP1 and SIRT1. It is well known that DBC1 regulates its targets, including SIRT1, by protein-protein interaction. However, little is known about how DBC1 biological activity is regulated. In this work, we show that in quiescent cells DBC1 is proteolytically cleaved, producing a protein (DN-DBC1) that misses the S1-like domain and no longer binds to SIRT1. DN-DBC1 is also found in vivo in mouse and human tissues. Interestingly, DN-DBC1 is cleared once quiescent cells re-enter to the cell cycle. Using a model of liver regeneration after partial hepatectomy, we found that DN-DBC1 is down-regulated in vivo during regeneration. In fact, WT mice show a decrease in SIRT1 activity during liver regeneration, coincidentally with DN-DBC1 downregulation and the appearance of full length DBC1. This effect on SIRT1 activity was not observed in DBC1 KO mice. Finally, we found that DBC1 KO mice have altered cell cycle progression and liver regeneration after partial hepatectomy, suggesting that DBC1/DN-DBC1 transitions play a role in normal cell cycle progression in vivo after cells leave quiescence. We propose that quiescent cells express DN-DBC1, which either replaces or coexist with the full-length protein, and that restoring of DBC1 is required for normal cell cycle progression in vitro and in vivo. Our results describe for the first time in vivo a naturally occurring form of DBC1, which does not bind SIRT1 and is dynamically regulated, thus contributing to redefine the knowledge about its function.

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