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Anticancer activity and mechanism of bis-pyrimidine based dimetallic Ru(II)(η6-p-cymene) complex in human non-small cell lung cancer via p53-dependent pathway.

Abstract：

:Non-small cell lung cancer (NSCLC) is the most common cancer worldwide, which is related with poor prognosis and resistance to chemotherapy. Notably, ruthenium-based complexes have emerged as good alternative to the currently used platinum-based drugs for cancer therapy. In the present study, we synthesized a novel bis-pyrimidine based ligand 1,3-bis(2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)benzene (L) and used it in the synthesis of a dimetallic Ru(II) cymene complex [(Ru(η6-p-cymene)Cl)2(1,3-bis(2-methyl-6-(pyridin-2-yl)pyrimidin-4-yl)benzene)] (L-Ru). We checked the stability of this complex in solution state in D2O/DMSO‑d6 mixture and found it to be highly stable under these conditions. We determined the anticancer activity and mechanism of action of L-Ru in human NSCLC A549 and A427 by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and related biological analyses. These results revealed that L-Ru exerted a strong inhibitory effect on the cells proliferation,G0/G1-arrest, accompanied with upregulation of p53, p21, p15, cleaved Poly (ADP-ribose) polymerase (PARP) protein and downregulation of cell cycle markers. L-Ru inhibited cell migration and invasion. The mitochondria-mediated apoptosis of NSCLC induced by L-Ru was also observed followed by the increase of apoptosis regulator B-cell lymphoma 2 associated X (BAX), and activation of caspase-3/-9. The effects of L-Ru on the cell viability, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cells and Annexin V-positive cells apoptosis induction were remarkably attenuated. This complex induced DNA damage, cell cycle arrest and cell death via caspase-dependent apoptosis involving PARP activation and induction of p53-dependent pathway. These findings suggested that this ruthenium complex might be a potential effective chemotherapeutic agent in NSCLC therapy.

journal_name

J Inorg Biochem

journal_title

Journal of inorganic biochemistry

authors

Bhatti MZ,Ali A,Duong HQ,Chen J,Rahman FU

doi

10.1016/j.jinorgbio.2019.01.019

subject

Has Abstract

pub_date

2019-05-01 00:00:00

pages

52-64

eissn

0162-0134

issn

1873-3344

pii

S0162-0134(18)30585-3

journal_volume

194

pub_type

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Anticancer activity and mechanism of bis-pyrimidine based dimetallic Ru(II)(η6-p-cymene) complex in human non-small cell lung cancer via p53-dependent pathway.