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.

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.

• Authors: Adisorn Ratanaphan, Tidarat Nhukeaw, Khwanjira Hongthong, Paul J Dyson
• Journal: Anti-cancer agents in medicinal chemistry (Anticancer Agents Med Chem) Vol. 17 Issue 2 Pg. 212-220 ( 2017) ISSN: 1875-5992 [Electronic] Netherlands
• PMID: 27039925 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• BRCA1 Protein
• BRCA1 protein, human
• Organometallic Compounds
• RNA, Messenger
• Ruthenium

Topics

• Antineoplastic Agents (chemistry, pharmacokinetics, pharmacology)
• Apoptosis (drug effects)
• BRCA1 Protein (genetics)
• Breast Neoplasms (drug therapy, genetics, pathology)
• Cell Line, Tumor
• Down-Regulation (drug effects)
• Female
• Genes, BRCA1 (drug effects)
• Humans
• MCF-7 Cells
• Organometallic Compounds (chemistry, pharmacokinetics, pharmacology)
• RNA, Messenger (genetics)
• Ruthenium (chemistry, pharmacokinetics, pharmacology)