Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells.

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Tytuł:: Curcumin Rescues Doxorubicin Responsiveness via Regulating Aurora a Signaling Network in Breast Cancer Cells.
Autorzy:: Biswas S; Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India.
Mahapatra E; Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India.
Ghosh A; Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India.
Das S; Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India.
Roy M; Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India.
Mukherjee S; Department of Environmental Carcinogenesis & Toxicology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, India.
Źródło:: Asian Pacific journal of cancer prevention : APJCP [Asian Pac J Cancer Prev] 2021 Mar 01; Vol. 22 (3), pp. 957-970. Date of Electronic Publication: 2021 Mar 01.
Typ publikacji:: Journal Article
Język:: English
Imprint Name(s):: Original Publication: Bangkok : Asian Pacific Organization for Cancer Prevention,
MeSH Terms:: Adenocarcinoma/*genetics
Antineoplastic Agents/*pharmacology
Aurora Kinase A/*drug effects
Breast Neoplasms/*genetics
Curcumin/*pharmacology
Doxorubicin/*pharmacology
Drug Resistance, Neoplasm/*drug effects
Adenocarcinoma/drug therapy ; Aurora Kinase A/genetics ; Aurora Kinase A/metabolism ; Breast Neoplasms/drug therapy ; Drug Resistance, Neoplasm/genetics ; Humans ; MCF-7 Cells ; NF-KappaB Inhibitor alpha/metabolism ; NF-kappa B/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Signal Transduction
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Contributed Indexing:: Keywords: Aurora A; Doxorubicin insensitivity; breast cancer; curcumin
Substance Nomenclature:: 0 (Antineoplastic Agents)
0 (NF-kappa B)
139874-52-5 (NF-KappaB Inhibitor alpha)
80168379AG (Doxorubicin)
EC 2.7.11.1 (Aurora Kinase A)
EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
IT942ZTH98 (Curcumin)
Entry Date(s):: Date Created: 20210328 Date Completed: 20211116 Latest Revision: 20211116
Update Code:: 20240105
PubMed Central ID:: PMC8286672
DOI:: 10.31557/APJCP.2021.22.3.957
PMID:: 33773562
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Background: Insensitivity towards anthracycline drugs like doxorubicin poses a significant challenge in the treatment of breast cancer. Among several factors, Aurora A (a mitotic serine threonine kinase) plays crucial roles in acquiring non-responsiveness towards doxorubicin. However, the mechanisms underlying need to be elucidated. The present study was therefore designed to evaluate the underlying mechanisms of Aurora A mediated doxorubicin insensitivity in MCF-7Dox/R, an isolated resistant-subline of MCF-7 (breast adenocarcinoma cell line). Effect of curcumin, a natural phytochemical in restoring doxorubicin sensitivity by targeting Aurora A was assessed furthermore.
Methods: A doxorubicin resistant subline (MCF-7Dox/R) was isolated from the parental MCF-7 cells by treating the cell with gradual step-wise increasing concentration of the drug. Expressions of Aurora A and its target proteins (Akt, IκBα and NFκB) were assessed in both parental and MCF-7Dox/R cells. Both the cell lines were pretreated with curcumin prior to doxorubicin treatment. Cellular proliferation rate was measured using BrdU (5-bromo-2'-deoxyuridine) assay kit. Intracellular doxorubicin accumulation was estimated spectrofluorimetrically. Cellular uptake of curcumin (spectrophotometric and spectrofluorimetric method) and its nuclear localization was confirmed by confocal microscopic study. Protein expressions were determined by western blot analysis. Localization of Aurora A was ascertained by immunofluorescence assay. To explore the possible outcome of impact of curcumin on Aurora A, cell-cycle distribution and apoptosis were performed subsequently.
Results: Higher expressions of Aurora A in MCF-7Dox/R cells led to phosphorylation of Akt as well as IκBα. Phosphorylated IκBα preceded release of NFκB. Phospho-Akt, NFκB consequentially decreased doxorubicin accumulation by enhancing the expressions of ABCG2 and Pgp1 respectively. Curcumin by regulating Aurora A and its target molecules sensitized resistant subline towards doxorubicin mediated G2/M-arrest and apoptosis.
Conclusion: Molecular targeting of Aurora A by curcumin restores chemosensitivity by increasing the efficacy of doxorubicin in breast cancer.
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