scholarly journals A Novel Sequential Treatment of 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 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sequential Treatment ◽  
Phase Cell ◽  
Concomitant Treatment ◽  
Dependent Manner ◽  
Effect Of Pd

Abstract Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy lack of sensitivity to chemo-, endocrine and targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been proven to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. So we investigated that whether CDK4/6 inhibitor palbociclib (PD) could enhance effects of cisplatin (CDDP) on TNBC.Methods: The effects of different drug regimens of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells was assessed in vitro and vivo. Immunoblotting illustrated cyclin D1/RB/E2F axis signaling pathway.Results: PD induced G1 phase cell cycle arrest in MDA-MB-231 cell line. However, neither concomitant treatment with PD and CDDP nor immediately sequential treatment with CDDP before or after PD had an influence on cell apoptosis of MDA-MB-231 cells. We further investigated the effect of PD or CDDP withdrawal on the sequential treatment and found that PD used for 48h and then withdrawn for 48h followed by CDDP could significantly increase apoptosis, inhibit cell proliferation, cloning formation and mitotic progression of MDA-MB-231 cells, while in other regimens PD and CDDP represented additive or antagonistic response. PD preferential use synchronized tumor cell cycle which could increase DNA damage by CDDP as measured by γH2AX. These findings above were negative in sh-MDA-MB-231 cells, which indicated that PD enhances the sensitivity of TNBC cells to CDDP in a RB dependent manner. In vivo, this combination treatment inhibited tumor growth and Ki-67 expression compared with single drug treatments in MDA-MB-231 xenograft models. Western blotting analysis presented that PD enhanced sensitivity to CDDP through CDK4/6-cyclin D-RB-E2F pathway. Conclusions: This study indicates that the anti-tumor effect of PD-CDDP functions through CDK4/6-cyclin D1-RB-E2F pathway and the synchronization of cell cycle. PD-CDDP Our study provides a novel and potentially effective treatment for TNBC patients.

scholarly journals A novel sequential treatment of 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 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Sequential Treatment ◽  
Phase Cell ◽  
Dependent Manner ◽  
Effect Of Pd

Abstract Background: Triple-negative breast cancer (TNBC) is a highly aggressive malignancy lack of sensitivity to chemo-, endocrine and targeted therapy. CDK4/6 inhibitors, combined with endocrine therapy, have been proven to be effective in postmenopausal women with HR-positive, HER2-negative advanced or metastatic breast cancer. So we investigated that whether CDK4/6 inhibitor palbociclib (PD) could enhance effects of cisplatin (CDDP) on TNBC.Methods: The effects of different drug regimens of PD and CDDP on MDA-MB-231 and RB-knockdown MDA-MB-231 (sh-MDA-MB-231) cells were assessed in vitro and vivo. MDA-MB-468 and RB-overexpression MDA-MB-468 cells were used to assess the effect of PD-CDDP regimen in vitro. Immunoblotting illustrated cyclin D1/RB/E2F axis signaling pathway.Results: PD induced G1 phase cell cycle arrest in MDA-MB-231 cell line. However, synchronous treatment with PD and CDDP for 24h, PD used for 24h and then followed by CDDP or CDDP used for 24h and then followed by PD all had no influence on cell apoptosis of MDA-MB-231 cells. We further investigated the effect of PD or CDDP withdrawal on sequential treatment and found that PD used for 48h and then withdrawn for 48h followed by CDDP (PD-CDDP) could significantly increase apoptosis, inhibit cell viability and colony formation of MDA-MB-231 cells, while in other regimens PD and CDDP represented additive or antagonistic response. Preferential use of PD could increase DNA damage by CDDP as measured through γH2AX. These findings above were negative in sh-MDA-MB-231 cells and cell function experiments of MDA-MB-468 and RB-overexpression MDA-MB-468 cells could draw similar conclusions, which indicated that PD enhanced the sensitivity of TNBC cells to CDDP in a RB dependent manner. In vivo, this combination treatment inhibited tumor growth and Ki-67 expression compared with single drug treatments in MDA-MB-231 xenograft models. Western blotting analysis presented that PD enhanced sensitivity to CDDP through CDK4/6-cyclin D-RB-E2F pathway. Conclusions: Pre-treatment with PD synchronized tumor cell cycle through CDK4/6-cyclin D1-RB-E2F pathway, which could increase anti-tumor effect of CDDP. PD-CDDP might be an effective treatment for RB-proficient TNBC patients.

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 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 CHFR regulates chemoresistance in triple-negative breast cancer through destabilizing ZEB1

2021 ◽  
Vol 12 (9) ◽  
Author(s):  
Hong Luo ◽  
Zhicheng Zhou ◽  
Shan Huang ◽  
Mengru Ma ◽  
Manyu Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Triple Negative Breast Cancer ◽  
Fatty Acid Synthase ◽  
Triple Negative ◽  
Trichostatin A ◽  
Affinity Purification ◽  
Negative Regulator ◽  
Dependent Manner ◽  
Breast Cancers

AbstractFailures to treat triple-negative breast cancer (TNBC) are mainly due to chemoresistance or radioresistance. We and others previously discovered that zinc finger E-box-binding homeobox 1 (ZEB1) is a massive driver causing these resistance. However, how to dynamically modulate the intrinsic expression of ZEB1 during cell cycle progression is elusive. Here integrated affinity purification combined with mass spectrometry and TCGA analysis identify a cell cycle-related E3 ubiquitin ligase, checkpoint with forkhead and ring finger domains (CHFR), as a key negative regulator of ZEB1 in TNBC. Functional studies reveal that CHFR associates with and decreases ZEB1 expression in a ubiquitinating-dependent manner and that CHFR represses fatty acid synthase (FASN) expression through ZEB1, leading to significant cell death of TNBC under chemotherapy. Intriguingly, a small-molecule inhibitor of HDAC under clinical trial, Trichostatin A (TSA), increases the expression of CHFR independent of histone acetylation, thereby destabilizes ZEB1 and sensitizes the resistant TNBC cells to conventional chemotherapy. In patients with basal-like breast cancers, CHFR levels significantly correlates with survival. These findings suggest the therapeutic potential for targeting CHFR-ZEB1 signaling in resistant malignant breast cancers.

scholarly journals The treatment role of Cyperus rotundus L. to triple-negative breast cancer cells

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Fukai Wang ◽  
Xiang Song ◽  
Shuangshuang Ma ◽  
Chenyu Liu ◽  
Xiaohui SUN ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Ethanol Extract ◽  
Cyperus Rotundus ◽  
Cell Counting ◽  
Chemical Components ◽  
Dependent Manner ◽  
Phytochemical Compounds

Abstract Cyperus rotundus L. is widely used in Traditional Chinese Medicine and studies have reported its anticancer effect, but its chemical composition and therapy mechanism remains unknown. This research aims to analyze the chemical components of the ethanol extract of Cyperus rotundus L. (EECR), detect its treatment effects on human Triple-negative breast cancer (TNBC) cells, and elucidate possible therapy mechanisms. The chemical components of EECR were detected by the Waters UPLC combined with Bruker Q-TOF mass spectrometer (UPLC-Q-TOF-MS). The phytochemical compounds were identified by comparing the mass fragmentations of each metabolite with databases such as METLIN, HMDB, and NCBI. A total of 21 compounds were identified in EECR. MDA-MB-231 and MDA-MB-468 cells were treated with various concentrations of EECR. Cell proliferation was examined using Cell Counting Kit-8 (CCK-8) and colony formation assays. Cell apoptosis and cell cycle were detected by flow cytometry. Apoptosis- and autophagy-related protein expression was detected by Western blot. EECR inhibits the proliferation of TNBC cells (MDA-MB-231 and MDA-MB-468) in a dose-dependent manner, which may be related to the arrest of cell cycle in G0/G1 phase. It induces apoptosis by promoting the expression of BAX and inhibiting the expression of BCL-2. In addition, autophagy inhibitor 3-Methyladenine (3-MA) inhibited TNBC cells pro-survival autophagy and increased the sensitivity of EECR. The present results demonstrated that EECR has potential effects on inhibits the proliferation and induction apoptosis in TNBC.

scholarly journals Chitosan promotes ROS-mediated apoptosis and S phase cell cycle arrest in triple-negative breast cancer cells: evidence for intercalative interaction with genomic DNA

RSC Advances ◽  
2017 ◽  
Vol 7 (68) ◽  
pp. 43141-43150 ◽  
Author(s):  
Fahimeh Salehi ◽  
Hossein Behboudi ◽  
Gholamreza Kavoosi ◽  
Sussan K. Ardestani
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Triple Negative Breast Cancer ◽  
Genomic Dna ◽  
Breast Cancer Cells ◽  
Triple Negative ◽  
S Phase ◽  
Phase Cell ◽  
Cycle Arrest ◽  
Antitumor Properties

Chitosan (CS) is a semi-synthetic bio-based polysaccharide with promising biological and antitumor properties.

scholarly journals Targeting PI3K and AMPKα Signaling Alone or in Combination to Enhance Radiosensitivity of Triple Negative Breast Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1253 ◽  
Author(s):  
Jeremy Johnson ◽  
Zeta Chow ◽  
Dana Napier ◽  
Eun Lee ◽  
Heidi L. Weiss ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cyclin D1 ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Radiation Treatment ◽  
Breast Cancer Subtype ◽  
Apoptosis Induction ◽  
Akt Inhibitor ◽  
Induced Apoptosis

Triple negative breast cancer (TNBC) is the most aggressive breast cancer subtype and is characterized by poor survival. Radiotherapy plays an important role in treating TNBC. The purpose of this study was to determine whether inhibiting the AMP-activated protein kinase (AMPK) and phosphatidylinositol 3-kinase (PI3K) pathways alone or in combination potentiates radiotherapy in TNBC. AMPKα1 and AMPKα2 knockdown diminished cyclin D1 expression and induced G1 cell cycle arrest but did not induce apoptosis alone or in combination with radiotherapy. Next, we analyzed the role of PI3K p85α, p85β, p110α, p110β, Akt1, and Akt2 proteins on TNBC cell cycle progression and apoptosis induction. Akt1 and p110α knockdown diminished cyclin D1 expression and induced apoptosis. Silencing Akt1 promoted synergistic apoptosis induction during radiotherapy and further reduced survival after radiation. Treatment with the Akt inhibitor, MK-2206 48 h after radiotherapy decreased Akt1 levels and potentiated radiation-induced apoptosis. Together, our results demonstrate that AMPKα, p110α, and Akt1 promote TNBC proliferation and that Akt1 is a key regulator of radiosensitivity in TNBC. Importantly, combining radiotherapy with the pharmacological inhibition of Akt1 expression is a potentially promising approach for the treatment of TNBC.

scholarly journals Erianin Induces Triple-Negative Breast Cancer Cells Apoptosis by Activating PI3K/Akt Pathway

2021 ◽  
Author(s):  
Yonggang Xu ◽  
Rong Fang ◽  
Jie Shao ◽  
Zihao Cai
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Morphological Changes ◽  
Cyclin B1 ◽  
Akt Pathway ◽  
Dependent Manner ◽  
Cycle Arrest

Background: Triple-negative breast cancer (TNBC) is a refractory subtype of breast cancer, 25-30% of which have dysregulation in the PI3K/AKT pathway. This study investigated the anti-cancer effect of erianin on triple-negative breast cancer cell line and its underlying mechanism. Methods: After treatment with erianin, MTT assay was employed to determine the MDA-MB-231 and EFM-192A cell proliferation, the nucleus morphological changes were observed by DAPI staining. The cell cycle and apoptotic proportion were detected by flow cytometry. Western blot was performed to determine the cell cycle and apoptosis-related protein expression and PI3K pathways. Finally, the anti-proliferation activity of erianin was further confirmed by adding or not adding PI3K agonists SC79. Results: Erianin inhibited the proliferation of MDA-MB-231 and EFM-192A cells in a dose-dependent manner, the IC50 were 70.96 nM and 78.58 nM, respectively. Erianin could cause cell cycle arrest at the G2/M phase, and the expressions of p21, p27 were upregulated, while the expressions of CDK1 and Cyclin B1 were downregulated. Erianin also induced apoptosis via the mitochondrial pathway, with the upregulation of the expression of Cyto C, PARP, Bax, activity form of Caspase-3, and Caspase-9. Furthermore, p-PI3K and p-Akt expression were downregulated by erianin. After co-incubation with SC79, the cell inhibition rate of erianin was decreased, which further confirmed that the attenuated PI3K/Akt pathway was relevant to the pro-apoptotic effect of erianin. Conclusions: Erianin can inhibit the proliferation of TNBC cells and induce cell cycle arrest and apoptosis, which may ascribe to the abolish the activation of the PI3K/Akt pathway.

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