Nilotinib, a Discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer

Abstract Background: Overexpression of Discoidin domain receptor 1(DDR1) is known to enhance the malignancy of breast cancer considerably. This study reports the identification of a potent DDR1 inhibitor, Nilotinib for the treatment of breast cancer. Methods: MTT assay was used to evaluate the inhibitory activity of Nilotinib and meantime we used flow cytometry to evaluate the pro-apoptotic activity of Nilotinib against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by shRNA. The effect of DDR1 or treatment with Nilotinib on cell migration was assayed. The expression of p-DDR1, DDR1, p-ERK1/2, ERK1/2 and E-cadherin，Vimentin, Snail1 were detected by western blot and immuno-fluorescent staining . Results: Nilotinib against MCF-7 (IC 50 =0.403 μM) and MDA-MB-231 (IC 50 =0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respective ly. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of Nilotinib to MCF-7 was reduced. Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.

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Nilotinib, a Discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer

10.21203/rs.2.15285/v3 ◽

2020 ◽

Author(s):

Shufang Yu ◽

Shuang Wang ◽

Yanping Xie ◽

Aina Bao ◽

Jing Li ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Cell Death ◽

Apoptotic Cell ◽

Cellular Migration ◽

Fluorescent Staining ◽

Discoidin Domain Receptor ◽

Apoptotic Activity ◽

Discoidin Domain Receptor 1 ◽

Mcf 7

Abstract Background: Overexpression of Discoidin domain receptor 1(DDR1) is known to enhance the malignancy of breast cancer considerably. This study reports the identification of a potent DDR1 inhibitor, Nilotinib for the treatment of breast cancer. Methods: MTT assay was used to evaluate the inhibitory activity of Nilotinib and meantime we used flow cytometry to evaluate the pro-apoptotic activity of Nilotinib against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by shRNA. The effect of DDR1 or treatment with Nilotinib on cell migration was assayed. The expression of p-DDR1, DDR1, p-ERK1/2, ERK1/2 and E-cadherin，Vimentin, Snail1 were detected by western blot and immuno-fluorescent staining . Results: Nilotinib against MCF-7 (IC 50 =0.403 μM) and MDA-MB-231 (IC 50 =0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respective ly. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of Nilotinib to MCF-7 was reduced. Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.

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Nilotinib, a Discoidin domain receptor 1 (DDR1) inhibitor, induces apoptosis and inhibits migration in breast cancer

10.21203/rs.2.15285/v4 ◽

2020 ◽

Author(s):

Shufang Yu ◽

Shuang Wang ◽

Yanping Xie ◽

Aina Bao ◽

Jing Li ◽

...

Keyword(s):

Breast Cancer ◽

Flow Cytometry ◽

Cell Death ◽

Apoptotic Cell ◽

Cellular Migration ◽

Fluorescent Staining ◽

Discoidin Domain Receptor ◽

Apoptotic Activity ◽

Discoidin Domain Receptor 1 ◽

Mcf 7

Abstract Background: Overexpression of Discoidin domain receptor 1(DDR1) is known to enhance the malignancy of breast cancer considerably. This study reports the identification of a potent DDR1 inhibitor, Nilotinib for the treatment of breast cancer. Methods: MTT assay was used to evaluate the inhibitory activity of Nilotinib and meantime we used flow cytometry to evaluate the pro-apoptotic activity of Nilotinib against MCF-7 and MDA-MB-231. Expression of DDR1 was manipulated in MCF-7 cell lines with low level DDR1 expression by transfecting with plasmids containing by shRNA. The effect of DDR1 or treatment with Nilotinib on cell migration was assayed. The expression of p-DDR1, DDR1, p-ERK1/2, ERK1/2 and E-cadherin，Vimentin, Snail1 were detected by western blot and immuno-fluorescent staining.Results: Nilotinib against MCF-7 (IC50=0.403 μM) and MDA-MB-231 (IC50=0.819 μM) and also indicated induced apoptotic cell death after co-cuturing with Nilotinib (500 nM), apoptosis rate is 29.60 % ± 2.19% and 18.75 % ± 2.30% respectively. Moreover, Nilotinib effectually blocked cellular migration of MCF-7. Interestingly, Knock-down DDR1 could significantly block the migration of breast cancer, meantime the sensitivity of MCF-7 to Nilotinib was reduced.Conclusion: Targeting DDR1 therapeutically could potentially affect survival and influence metabolism in breast cancer, and Nilotinib could as a candidate for the treatment of breast cancer.

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Plumbagin from a tropical pitcher plant (Nepenthes alata Blanco) induces apoptotic cell death via a p53-dependent pathway in MCF-7 human breast cancer cells

Food and Chemical Toxicology ◽

10.1016/j.fct.2018.11.040 ◽

2019 ◽

Vol 123 ◽

pp. 492-500 ◽

Cited By ~ 18

Author(s):

Umasankar De ◽

Ji Yeon Son ◽

Yukyoung Jeon ◽

Song-Yi Ha ◽

Yu Jin Park ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Apoptotic Cell ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Pitcher Plant ◽

Dependent Pathway ◽

Mcf 7

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HDAC3–ERα Selectively Regulates TNF-α-Induced Apoptotic Cell Death in MCF-7 Human Breast Cancer Cells via the p53 Signaling Pathway

Cells ◽

10.3390/cells9051280 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1280

Author(s):

Seung-Ho Park ◽

Hyunhee Kim ◽

Sungmin Kwak ◽

Ji-Hoon Jeong ◽

Jangho Lee ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Cancer Cells ◽

Human Breast Cancer ◽

Breast Cancer Cells ◽

Apoptotic Cell ◽

Human Breast Cancer Cells ◽

Human Breast ◽

Tnf Α ◽

Mcf 7

Tumor necrosis factor-α (TNF-α) plays a significant role in inflammation and cancer-related apoptosis. We identified a TNF-α-mediated epigenetic mechanism of apoptotic cell death regulation in estrogen receptor-α (ERα)-positive human breast cancer cells. To assess the apoptotic effect of TNF-α, annexin V/ propidium iodide (PI) double staining, cell viability assays, and Western blotting were performed. To elucidate this mechanism, histone deacetylase (HDAC) activity assay and immunoprecipitation (IP) were conducted; the mechanism was subsequently confirmed through chromatin IP (ChIP) assays. Finally, we assessed HDAC3–ERα-mediated apoptotic cell death after TNF-α treatment in ERα-positive human breast cancer (MCF-7) cells via the transcriptional activation of p53 target genes using luciferase assay and quantitative reverse transcription PCR. The TNF-α-induced selective apoptosis in MCF-7 cells was negatively regulated by the HDAC3–ERα complex in a caspase-7-dependent manner. HDAC3 possessed a p53-binding element, thus suppressing the transcriptional activity of its target genes. In contrast, MCF-7 cell treatment with TNF-α led to dissociation of the HDAC3–ERα complex and substitution of the occupancy on the promoter by the p53–p300 complex, thus accelerating p53 target gene expression. In this process, p53 stabilization was accompanied by its acetylation. This study showed that p53-mediated apoptosis in ERα-positive human breast cancer cells was negatively regulated by HDAC3–ERα in a caspase-7-dependent manner. Therefore, these proteins have potential application in therapeutic strategies.

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Aviculin Isolated from Lespedeza cuneata Induce Apoptosis in Breast Cancer Cells through Mitochondria-Mediated Caspase Activation Pathway

Molecules ◽

10.3390/molecules25071708 ◽

2020 ◽

Vol 25 (7) ◽

pp. 1708 ◽

Cited By ~ 2

Author(s):

Dahae Lee ◽

Yong Hoon Lee ◽

Kwang Ho Lee ◽

Bum Soo Lee ◽

Akida Alishir ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Breast Cancer Cells ◽

Apoptotic Cell ◽

Underlying Mechanism ◽

Intrinsic Apoptosis ◽

Lespedeza Cuneata ◽

Apoptosis Pathway ◽

Intrinsic Apoptosis Pathway ◽

Mcf 7

The global incidence of breast cancer has increased. However, there are many impediments to the development of safe and effective anticancer drugs. The aim of the present study was to evaluate the effect of aviculin isolated from Lespedeza cuneata (Dum. Cours.) G. Don. (Fabaceae) on MCF-7 human breast cancer cells and determine the underlying mechanism. Using the bioassay-guided isolation by water soluble tetrazolium salt (WST-1)-based Ez-Cytox assay, nine compounds (four lignan glycosides (1–4), three flavonoid glycosides (5–7), and two phenolic compounds (8 and 9)) were isolated from the ethyl acetate (EA) fraction of the L. cuneata methanolic extract. Of these, aviculin (2), a lignan glycoside, was the only compound that reduced metabolic activity on MCF-7 cells below 50% (IC50: 75.47 ± 2.23 μM). The underlying mechanism was analyzed using the annexin V Alexa Fluor 488 binding assay and Western blotting. Aviculin (2) was found to induce apoptotic cell death through the intrinsic apoptosis pathway, as indicated by the increased expression of initiator caspase-9, executioner caspase-7, and poly (ADP-ribose) polymerase (PARP). Aviculin (2)-induced apoptotic cell death was accompanied by an increase in the Bax/Bcl-2 ratio. These findings demonstrated that aviculin (2) could induce breast cancer cell apoptosis through the intrinsic apoptosis pathway, and it can therefore be considered an excellent candidate for herbal treatment of breast cancer.

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