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

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.

New docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12556-e12556
Author(s):  
Michel Demeule ◽  
Borhane Annabi ◽  
Jean-Christophe Currie ◽  
Alain Larocque ◽  
Cyndia Charfi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Tumor Regression ◽  
Cell Model ◽  
Molecular Signature ◽  
Specific Gene ◽  
Real Time System

e12556 Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease which still lacks defined molecular biomarkers. In the last decade, targeting of specific gene/protein molecular signature of tumors emerged among the best anticancer strategies. Recently, increased expression of the Sortilin (SORT1) receptor has been reported in TNBC patients. Given SORT1 functions in protein internalization, sorting and trafficking, we developed a new peptide-anticancer drug conjugation platform to target SORT1-positive breast cancer by linking Docetaxel to a peptide (KA-peptide) that specifically targets SORT1. Methods: MDA-MB-231 cells were used as a TNBC cell model for in vitro and in vivo xenograft (CD1 nude mice) assays. Cell migration was assessed using the xCELLigence real-time system, whereas MTT assay was used for cell proliferation analysis. Apoptosis biomarkers expression was assessed by immunoblotting. Results: In MDA-MB-231, the Docetaxel-KA-peptide conjugate (DoceKA) exerted potent anti-proliferative and anti-migratory activities in vitro. DoceKA triggered faster and higher cell death mechanisms than did free Docetaxel alone. The apoptotic and anti-migratory effects were reversed by the SORT1 ligands Neurotensin and Progranulin, and upon siRNA-mediated silencing of SORT1. DoceKA altered microtubules polymerization and triggered the down-regulation of IL-6, Survivin, Bcl-xL and mutant p53 pro-survival biomarkers. In vivo, DoceKA exhibited a greater tumor regression capacity with a prolonged survival in a murine MDA-MB-231 xenograft tumor model than did Docetaxel. Conclusions: Collectively, we demonstrate that DoceKA is specifically internalized through a receptor-mediated mechanism. Such property allows for targeting SORT1-positive breast cancers, and makes DoceKA a promising novel therapy for the treatment of TNBC.

scholarly journals Correction: Prosopis juliflora (Sw.), DC induces apoptosis and cell cycle arrest in triple negative breast cancer cells: in vitro and in vivo investigations

Oncotarget ◽  
2018 ◽  
Vol 9 (68) ◽  
pp. 33050-33050 ◽  
Author(s):  
Bhimashankar Gurushidhappa Utage ◽  
Milind Shivajirao Patole ◽  
Punam Vasudeo Nagvenkar ◽  
Sonali Shankar Kamble ◽  
Rajesh Nivarti Gacche
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Prosopis Juliflora ◽  
Cycle Arrest

scholarly journals Prosopis juliflora (Sw.), DC induces apoptosis and cell cycle arrest in triple negative breast cancer cells: in vitro and in vivo investigations

Oncotarget ◽  
2018 ◽  
Vol 9 (54) ◽  
pp. 30304-30323 ◽  
Author(s):  
Bhimashankar Gurushidhappa Utage ◽  
Milind Shivajirao Patole ◽  
Punam Vasudeo Nagvenkar ◽  
Sonali Shankar Kamble ◽  
Rajesh Nivarti Gacche
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cancer Cells ◽  
Triple Negative Breast Cancer ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
Prosopis Juliflora ◽  
Cycle Arrest

scholarly journals Novel sequential treatment with palbociclib enhances the effect of cisplatin in RB-proficient triple-negative breast cancer

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yajing Huang ◽  
Hao Wu ◽  
Xingrui Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Endocrine Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sequential Treatment ◽  
Phase Cell

Abstract Background Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks sensitivity to chemotherapy, endocrine therapy or targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been shown to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Therefore, we investigated whether the CDK4/6 inhibitor palbociclib (PD) could enhance the effects of cisplatin (CDDP) on TNBC. Methods The effects of different drug regimens consisting of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and in vivo. MDA-MB-468 and RB-overexpressing MDA-MB-468 cells were used to assess the effect of the PD-CDDP regimens in vitro. Immunoblotting illustrated the role of the cyclin D1/RB/E2F axis signalling pathway. Results PD induced G1 phase cell cycle arrest in the MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24 h, treatment with PD for 24 h followed by CDDP and treatment with CDDP for 24 h followed by PD had no influence on MDA-MB-231 cell apoptosis. We further investigated the effect of PD or CDDP withdrawal on the effects of sequential treatment and found that PD treatment for 48 h followed by withdrawal for 48 h and subsequent CDDP treatment (PD-CDDP) significantly increased apoptosis and inhibited the cell viability and colony formation of MDA-MB-231 cells, while with other regimens, PD and CDDP had an additive or antagonistic response. The preferential use of PD increased DNA damage induced by CDDP, as measured through γH2AX immunofluorescence. These findings were not observed in sh-MDA-MB-231 cells, and experiments to assess cell function in MDA-MB-468 and RB-overexpressing MDA-MB-468 cells yielded similar results, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in an RB-dependent manner. In vivo, compared with single drug treatment, combination treatment inhibited tumour growth and Ki-67 expression in MDA-MB-231 xenograft models. Western blot analysis revealed that PD enhanced sensitivity to CDDP through the CDK4/6-cyclin D1-RB-E2F pathway. Conclusions Pre-treatment with PD synchronized the tumour cell cycle through the CDK4/6-cyclin D1-RB-E2F pathway, which increased the antitumour effect of CDDP. Thus, PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

scholarly journals Cyclin B2 (CCNB2) Stimulates the Proliferation of Triple-Negative Breast Cancer (TNBC) Cells In Vitro and In Vivo

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Shuai Wu ◽  
Rui Su ◽  
Hongyan Jia
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Triple Negative Breast Cancer ◽  
Potential Role ◽  
Triple Negative ◽  
Targeting Therapy ◽  
A Cell

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer. Currently, targeting therapy makes great advances for the treatment of TNBC, whereas more effective therapeutic targets are urgently needed. Cyclin B2 (CCNB2), which belongs to B-type cyclins, is known as a cell cycle regulator. CCNB2 is synthesized at G1 phase in cancer cells and downregulated at anaphase. The defects of CCNB2 led to the abnormal cell cycle and tumorigenesis. Though there are wide effects of CCNB2 on multiple types of tumors, the potential role of CCNB2 in TNBC progression is still unclear. Herein, we found that CCNB2 was highly expressed in human TNBC tissues and correlated with the prognosis and clinical pathological features including tumor size ( p = 0.022 ∗ ) and pTNM stage ( p = 0.021 ∗ ) of patients with TNBC. CCNB2 could promote the proliferation of TNBC cells in vitro and in mice. Our findings therefore confirmed the involvement of CCNB2 in TNBC progression and provided the evidence that CCNB2 could serve as a promising molecular target of TNBC.

scholarly journals Novel sequential treatment with palbociclib enhances the effect of cisplatin in RB-proficient triple-negative breast cancer

2020 ◽  
Author(s):  
Yajing Huang ◽  
Hao Wu ◽  
Xingrui Li
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Endocrine Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sequential Treatment ◽  
Phase Cell

Abstract Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks sensitivity to chemotherapy, endocrine therapy or targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been shown to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. Therefore, we investigated whether the CDK4/6 inhibitor palbociclib (PD) could enhance the effects of cisplatin (CDDP) on TNBC.Methods: The effects of different drug regimens consisting of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and in vivo. MDA-MB-468 and RB-overexpressing MDA-MB-468 cells were used to assess the effect of the PD-CDDP regimens in vitro. Immunoblotting illustrated the role of the cyclin D1/RB/E2F axis signalling pathway.Results: PD induced G1 phase cell cycle arrest in the MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24 h, treatment with PD for 24 h followed by CDDP and treatment with CDDP for 24 h followed by PD had no influence on MDA-MB-231 cell apoptosis. We further investigated the effect of PD or CDDP withdrawal on the effects of sequential treatment and found that PD treatment for 48 h followed by withdrawal for 48 h and subsequent CDDP treatment (PD-CDDP) significantly increased apoptosis and inhibited the cell viability and colony formation of MDA-MB-231 cells, while with other regimens, PD and CDDP had an additive or antagonistic response. The preferential use of PD increased DNA damage induced by CDDP, as measured through γH2AX immunofluorescence. These findings were not observed in sh-MDA-MB-231 cells, and experiments to assess cell function in MDA-MB-468 and RB-overexpressing MDA-MB-468 cells yielded similar results, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in an RB-dependent manner. In vivo, compared with single drug treatment, combination treatment inhibited tumour growth and Ki-67 expression in MDA-MB-231 xenograft models. Western blot analysis revealed that PD enhanced sensitivity to CDDP through the CDK4/6-cyclin D1-RB-E2F pathway. Conclusions: Pre-treatment with PD synchronized the tumour cell cycle through the CDK4/6-cyclin D1-RB-E2F pathway, which increased the antitumour effect of CDDP. Thus, PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

scholarly journals GCH1 induces immunosuppression through metabolic reprogramming and IDO1 upregulation in triple-negative breast cancer

2021 ◽  
Vol 9 (7) ◽  
pp. e002383
Author(s):  
Jin-Li Wei ◽  
Si-Yu Wu ◽  
Yun-Song Yang ◽  
Yi Xiao ◽  
Xi Jin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Molecular Taxonomy ◽  
Underlying Mechanism ◽  
Metabolic Reprogramming ◽  
Sequencing Data ◽  
Aryl Hydrocarbon

PurposeRegulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental designUsing the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.ResultsWe revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.ConclusionsTumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

scholarly journals Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sofia M. Saraiva ◽  
Carlha Gutiérrez-Lovera ◽  
Jeannette Martínez-Val ◽  
Sainza Lores ◽  
Belén L. Bouzo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Xenograft Model ◽  
Skin Barrier ◽  
Zebrafish Embryos ◽  
Biorelevant Media

AbstractTriple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

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