AUTHOR=Baliza Ingrid R. S. , Silva Suellen L. R. , Santos Luciano de S. , Neto João H. Araujo , Dias Rosane B. , Sales Caroline B. S. , Rocha Clarissa A. Gurgel , Soares Milena B. P. , Batista Alzir A. , Bezerra Daniel P. 

TITLE=Ruthenium Complexes With Piplartine Cause Apoptosis Through MAPK Signaling by a p53-Dependent Pathway in Human Colon Carcinoma Cells and Inhibit Tumor Development in a Xenograft Model

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00582

DOI=10.3389/fonc.2019.00582

ISSN=2234-943X

ABSTRACT=<p>Ruthenium complexes with piplartine, [Ru(piplartine)(dppf)(bipy)](PF<sub>6</sub>)<sub>2</sub> (<bold>1</bold>) and [Ru(piplartine)(dppb)(bipy)](PF<sub>6</sub>)<sub>2</sub> (<bold>2</bold>) (dppf = 1,1-bis(diphenylphosphino) ferrocene; dppb = 1,4-bis(diphenylphosphino)butane and bipy = 2,2′-bipyridine), were recently synthesized and displayed more potent cytotoxicity than piplartine in different cancer cells, regulated RNA transcripts of several apoptosis-related genes, and induced reactive oxygen species (ROS)-mediated apoptosis in human colon carcinoma HCT116 cells. The present work aimed to explore the underlying mechanisms through which these ruthenium complexes induce cell death in HCT116 cells <italic>in vitro</italic>, as well as their <italic>in vivo</italic> action in a xenograft model. Both complexes significantly increased the percentage of apoptotic HCT116 cells, and co-treatment with inhibitors of JNK/SAPK, p38 MAPK, and MEK, which inhibits the activation of ERK1/2, significantly reduced the apoptosis rate induced by these complexes. Moreover, significant increase in phospho-JNK2 (T183/Y185), phospho-p38α (T180/Y182), and phospho-ERK1 (T202/Y204) expressions were observed in cells treated with these complexes, indicating MAPK-mediated apoptosis. In addition, co-treatment with a p53 inhibitor (cyclic pifithrin-α) and the ruthenium complexes significantly reduced the apoptosis rate in HCT116 cells, and increased phospho-p53 (S15) and phospho-histone H2AX (S139) expressions, indicating induction of DNA damage and p53-dependent apoptosis. Both complexes also reduced HCT116 cell growth in a xenograft model. Tumor mass inhibition rates were 35.06, 29.71, and 32.03% for the complex <bold>1</bold> (15 μmol/kg/day), complex <bold>2</bold> (15 μmol/kg/day), and piplartine (60 μmol/kg/day), respectively. These data indicate these ruthenium complexes as new anti-colon cancer drugs candidates.</p>