Inhibition of cancer cell growth by ruthenium complexes

Abstract

Background: Previous studies suggest that certain transition metal complexes, such as cisplatin, are efficacious for treating various cancer types, including ovarian, lung, and breast.

Methods: In order to further evaluate ruthenium (Ru) complexes as potential anti-cancer agents, we synthesized and evaluated Ru-arene complexes. Two complexes with the general formula [Ru (η (6)-p-cym) (N-N) Cl](+) were tested for their abilities to inhibit cancer cells.

Results: The complex with o-phenylenediamine as the N-N ligand (o-PDA) significantly inhibited growth of breast (MDA-MB-231, MCF-7, SKBR-3, and SUM149), lymphoma (Raji), melanoma (Bowes), and osteosarcoma (HT1080); however, the complex with o-benzoquinonediimine (o-BQDI) was ineffective except for SUM149. In contrast, o-PDA failed to inhibit growth of human breast epithelial cells, MCF-10A. Treatment of MDA-MBA-231 cells with o-PDA resulted in a significant reduction of productions of PDGF-AA, GM-CSF, and VEGF-A proteins at the transcriptional levels. Finally, we demonstrated that o-PDA synergistically inhibited MDA-MB-231 cell growth with cyclophosphamide but not doxorubicin or paclitaxel.

Conclusion: These results suggest that Ru-arene complexes are promising anti-cancer drugs that inhibit progression and metastasis by blocking multiple processes for breast and other types of cancer.

Fig. 1

Structures of Ru-complexes used in this study. Structure of ruthenium complexes used in this study where N–N is either 1,2-phenylenediammine (o-pda) or 1,2-benzoquinonediimine (o-bqdi)

Fig. 2

Inhibition of growth factor production from MDA_MB-231 cells treated with o-PDA. MDA-MB-231 cells were incubated in the presence of o-PDA or o-BQDI at a concentration of 130 μM for 48 h in serum-free RPMI1640. a Conditioned medium was harvested, centrifuged, and subjected to Human Growth Factor Array. b Cells were harvested and total RNA was purified, transcribed, and then subjected to RT-PCR reactions using specific primer sets for GM-CSF, VEGF-A, and PDGF-AA

Fig. 3

Inhibition of cell growth by o-PDA and cyclophosphamide. MDA-MB-231 cells (1.25 × 10⁴ cells/well) were incubated over various time periods in the presence of cyclophosphamide alone (10 mM) (), o-PDA alone (32 μΜ) (), or the combination of the two reagents () for up to 48 h. Cells were incubated with Puromycin (25 mM) for 48 h (). Cell growth was evaluated by colorimetric assays using WST- as an indicator. Experiments were repeated three times. Results were demonstrated as a mean ± SD of OD₄₅₀. *p < 0.001 (calculated by Student’s two-tailed t test)

Fig. 4

Inhibition of cell growth by the combination of o-PDA with other cytotoxic agents. MDA-MB-231 cells (1.25 × 10⁴ cells/well) were incubated for 2 days in the presence of Doxorubicin (DOX, 5 μM) (a), Paclitaxel (PT 5 μM) (b) or cyclophosphamide (CY 10 mM) (c) with or without o-PDA (32 μΜ). Puromycin (25 mM) was used as a positive control. Cell growth was evaluated by colorimetric assays using WST-1 as an indicator. Experiments were repeated three times. Results were demonstrated as a mean ± SD of OD₄₅₀. *p < 0.001 (calculated by Student’s two-tailed t test)