Unprecedented Monoterpenoid Polyprenylated Acylphloroglucinols with a Rare 6/6/5/4 Tetracyclic Core, Enhanced MCF-7 Cells’ Sensitivity to Camptothecin by Inhibiting the DNA Damage Response

(±)-Hypersines A–C (1–3), the three pairs of enantiomerically pure monoterpenoid polyprenylated acylphloroglucinols with an unprecedented 6/6/5/4 fused ring system, were isolated from Hypericum elodeoides. Their structures, including absolute configurations, were elucidated by comprehensive spectroscopic data, single-crystal X-ray diffraction, and quantum chemical calculations. The plausible, biosynthetic pathway of 1–3 was proposed. Moreover, the bioactivity evaluation indicated that 1a might be a novel DNA damage response inhibitor, and could enhance MCF-7 cell sensitivity to the anticancer agent, camptothecin.

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Expression of human BRCA1Δ17–19 alternative splicing variant with a truncated BRCT domain in MCF-7 cells results in impaired assembly of DNA repair complexes and aberrant DNA damage response

Cellular Signalling ◽

10.1016/j.cellsig.2013.02.008 ◽

2013 ◽

Vol 25 (5) ◽

pp. 1186-1193 ◽

Cited By ~ 20

Author(s):

Jan Sevcik ◽

Martin Falk ◽

Libor Macurek ◽

Petra Kleiblova ◽

Filip Lhota ◽

...

Keyword(s):

Dna Damage ◽

Dna Repair ◽

Alternative Splicing ◽

Dna Damage Response ◽

Brct Domain ◽

Splicing Variant ◽

Damage Response ◽

Alternative Splicing Variant ◽

Mcf 7

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PP2Cδ inhibits p300-mediated p53 acetylation via ATM/BRCA1 pathway to impede DNA damage response in breast cancer

Science Advances ◽

10.1126/sciadv.aaw8417 ◽

2019 ◽

Vol 5 (10) ◽

pp. eaaw8417 ◽

Cited By ~ 1

Author(s):

Qun Li ◽

Qiongyu Hao ◽

Wei Cao ◽

Jieqing Li ◽

Ke Wu ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Dna Damage Response ◽

Protein Phosphatase ◽

Transcriptional Activity ◽

Histological Grade ◽

Anticancer Effect ◽

Damage Response ◽

Underlying Mechanisms ◽

Mcf 7

Although nuclear type 2C protein phosphatase (PP2Cδ) has been demonstrated to be pro-oncogenic with an important role in tumorigenesis, the underlying mechanisms that link aberrant PP2Cδ levels with cancer development remain elusive. Here, we found that aberrant PP2Cδ activity decreases p53 acetylation and its transcriptional activity and suppresses doxorubicin-induced cell apoptosis. Mechanistically, we show that BRCA1 facilitates p300-mediated p53 acetylation by complexing with these two proteins and that S1423/1524 phosphorylation is indispensable for this regulatory process. PP2Cδ, via dephosphorylation of ATM, suppresses DNA damage–induced BRCA1 phosphorylation, leading to inhibition of p300-mediated p53 acetylation. Furthermore, PP2Cδ levels correlate with histological grade and are inversely associated with BRCA1 phosphorylation and p53 acetylation in breast cancer specimens. C23, our newly developed PP2Cδ inhibitor, promotes the anticancer effect of doxorubicin in MCF-7 xenograft–bearing nude mice. Together, our data indicate that PP2Cδ impairs p53 acetylation and DNA damage response by compromising BRCA1 function.

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RO3280: A Novel PLK1 Inhibitor, Suppressed the Proliferation of MCF-7 Breast Cancer Cells Through the Induction of Cell Cycle Arrest at G2/M Point

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520619666190618162828 ◽

2019 ◽

Vol 19 (15) ◽

pp. 1846-1854 ◽

Cited By ~ 4

Author(s):

Mustafa Ergul ◽

Filiz Bakar-Ates

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Dna Damage ◽

Cell Cycle Arrest ◽

Cancer Cells ◽

Dna Damage Response ◽

Breast Cancer Cells ◽

Cycle Arrest ◽

Damage Response ◽

Mcf 7

Background: As a member of serine/threonine-protein kinase, Polo‐like kinase 1 (PLK1) plays crucial roles during mitosis and also contributes to DNA damage response and repair. PLK1 is aberrantly expressed in many types of tumor cells and increased levels of PLK1 is closely related to tumorigenesis and poor clinical outcomes. Therefore, PLK1 is accepted as one of the potential targets for the discovery of novel anticancer agents. The objective of this study was to assess the cytotoxic effects of a novel PLK1 inhibitor, RO3280, against MCF-7, human breast cancer cells; HepG2, human hepatocellular carcinoma cells; and PC3, human prostate cancer cells, as well as non-cancerous L929 fibroblast cells. Methods: Antiproliferative activity of RO3280 was examined using the XTT assay. Flow cytometry assay was performed to evaluate cell cycle distribution, apoptosis, multicaspase activity, mitochondrial membrane potential, and DNA damage response. We also examined apoptosis with fluorescence imaging studies. Results: According to the results of XTT assay, although RO3280 displayed potent cytotoxicity in all treated cancer cells, the most sensitive cell line was identified as MCF-7 cells that were selected for further studies. The compound induced a cell cycle arrest in MCF-7 cells at G2/M phase and significantly induced apoptosis, multicaspase activity, DNA damage response, and decreased mitochondrial membrane potential of MCF-7 cells. Conclusion: Overall, RO3280 induces anticancer effects promoted mainly by DNA damage, cell cycle arrest, and apoptosis in breast cancer cells. Further studies are needed to assess its usability as an anticancer agent with specific cancer types.

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