期刊
BIOMETALS
卷 32, 期 1, 页码 89-100出版社
SPRINGER
DOI: 10.1007/s10534-018-0160-0
关键词
Ruthenium compounds; Triple negative breast cancer; Topoisomerase; PARP inhibitor
资金
- Sao Paulo Research Foundation (FAPESP) [2012/21529-7, 2016/22429-7, 2016/16312-0]
- Coordinating Committee for Advancement of Higher Education Staff in Brazil (CAPES)
- Brazilian National Council of Technological and Scientific Development (CNPq)
Due to their unique and versatile biochemical properties, ruthenium-based compounds have emerged as promising anticancer agents. Previous studies showed that three ruthenium(II) compounds: [Ru(pySH)(bipy)(dppb)]PF6 (1), [Ru(HSpym)(bipy)(dppb)]PF6 (2) and Ru[(SpymMe(2))(bipy)(dppb)]PF6 (3) presented anticancer properties higher than doxorubicin and cisplatin and acted as human topoisomerase IB (Topo I) inhibitors. Here, we focused our studies on in vitro intestinal permeability and anticancer mechanisms of these three complexes. Caco-2 permeation studies showed that 1 did not permeate the monolayer of intestinal cells, suggesting a lack of absorption on oral administration, while 2 and 3 permeated the cells after 60 and 120min, respectively. Complexes 2 and 3 fully inhibited Topo II relaxation activity at 125 mu M. In previously studies, 3 was the most potent inhibitor of Topo I, here, we concluded that it is a dual topoisomerase inhibitor. Moreover, it presented selectivity to cancer cells when evaluated by clonogenic assay. Thus, 3 was selected to gene expression assay front MDA-MB-231 cells from triple-negative breast cancer (TNBC), which represents the highly aggressive subgroup of breast cancers with poor prognosis. The analyses revealed changes of 27 out of 84 sought target genes. PARP1 and PARP2 were 5.29 and 1.83 times down-regulated after treatment with 3, respectively. PARPs have been attractive antitumor drug targets, considering PARP inhibition could suppress DNA damage repair and sensitize tumor cells to DNA damage agents. Recent advances in DNA repair studies have shown that an approach that causes cell lethality using synthetic PARP-inhibiting drugs has produced promising results in TNBC.
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