Differential Cytotoxicity, Cellular Uptake, Apoptosis and Inhibition of BRCA1 Expression of BRCA1-Defective and Sporadic Breast Cancer Cells Induced by an Anticancer Ruthenium(II)-Arene Compound, RAPTA-EA1

Author(s): Adisorn Ratanaphan, Tidarat Nhukeaw, Khwanjira Hongthong, Paul J. Dyson.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry

Volume 17 , Issue 2 , 2017

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Abstract:

Background: The RAPTA-EA1 complex [ruthenium(II)-arene 1,3,5-triaza-7-phosphaadamantane (pta) complex with an arene-tethered ethacrynic acid ligand] has been reported to overcome drug resistance that developed due to the current use of platinum-based treatments. However, the exact mechanism of action of RAPTA-EA1 remains largely unexplored and unknown.

Objective: Here we have further studied the effect of RAPTA-EA1 on BRCA1-defective HCC1937 breast cancer cells and compared its effects on BRCA1-competent MCF-7 breast cancer cells.

Method: HCC1937 and MCF-7 breast cancer cells were treated with the RAPTA-EA1 complex. The cytotoxicity of ruthenium-induced cells was evaluated by a MTT assay. Cellular uptake of ruthenium was determined by ICP-MS. Cell cycle and apoptosis were assessed using a flow cytometer. Expression of BRCA1 mRNA and its encoded protein was quantitated by a real-time RT-PCR and Western blotting.

Results: Differences in cytotoxicity were correlated with the differential accumulations of ruthenium and the induction of apoptosis. The ruthenium complex caused dramatically more damage to the BRCA1 gene in the BRCA1-defective HCC1937 cells than to the BRCA1-competent MCF-7 cells. It decreased the expression of BRCA1 mRNA in the BRCA1-competent cells, while in contrast, its expression increased in the BRCA1-defective cells. However, the expression of the BRCA1 protein was significantly reduced in both types of breast cancer cells.

Conclusion: The results presented here have demonstrated a differential cellular response for the BRCA1-defective and BRCA1-competent breast cancer cells to RAPTA-EA1. These findings have provided more insight into the actions and development of the ruthenium-based compounds for use for the treatment of breast cancer.

Keywords: Breast cancer, RAPTA-EA1, replication, transcription, BRCA1 expression.

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Article Details

VOLUME: 17
ISSUE: 2
Year: 2017
Page: [212 - 220]
Pages: 9
DOI: 10.2174/1871520616666160404110953
Price: $58

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