Novel phenylenediamine bridged mixed ligands dimetallic square planner Pt(II) complex inhibits MMPs expression via p53 and caspase-dependent signaling and suppress cancer metastasis and invasion.
Novel phenylenediamine bridged mixed ligands dimetallic square planner Pt(II) complex (L-Pt-Py) was synthesized from simple commercially available precursors in good yield and characterized by1H,13C, 2D NOESY NMR and high resolution mass spectrometry (HR-ESI-MS). The stability of L-Pt-Py was checked by1H NMR in mixed DMSO-d6/D2O solvents. L-Pt-Py showed considerable in vitro cytotoxicity in lung (A549), breast (MCF-7) and liver (HepG2) cancer cell lines and strong in vivo growth inhibition in Escherichia coli (E. coli). These results were compared to the well-known market available platinum anticancer drug cisplatin. L-Pt-Py has strong ability to suppress the growth of multiple cancer cells. Mechanistically, it enhanced p53 protein expression and regulated p53-dependent genes expression such as p21, PUMA, MYC and hTERT. The TUNEL assay showed that L-Pt-Py induced cell death in cancer cells. Inhibition of caspase signaling with caspase inhibitor Z-VAD-FMK suggested that cell death induced by this complex was caspase-dependent. Importantly, L-Pt-Py has the ability to suppress the invasion and migration of human lung and luminal-like breast cancer cells. Similarly L-Pt-Py suppressed the expression of several matrix metalloproteinases (MMPs) such as MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9 to inhibit lung and breast cancer cell metastasis. L-Pt-Py showed stronger inhibitory effects on bacterial growth and also resulted in filamentous morphology of bacterial cells. The gel electrophoresis study of DNA migration revealed the strong interaction of L-Pt-Py with DNA. Taken altogether, L-Pt-Py was highly stable and the in vitro and in vivo biological study results corroborated this complex to be effective anticancer agent.
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Jiangsu, China.
Faiz-Ur
FU
Rahman
Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai 200241, China; Institute of Integrative Biosciences, CECOS University of IT and Emerging Sciences, Peshawar, KPK, Pakistan.
Amjad
A
Ali
Lab of Molecular Immunology, State Key Lab of Genetic Engineering, School of Life Sciences, Fudan University, 220 Handan Road, Shanghai 200433, China.
Inam Ullah
IU
Khan
Institute of Research and Development, Duy Tan University, K7/25 Quang Trung, Danang, Viet Nam.
Hong-Quan
HQ
Duong
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Jiangsu, China.
Rong
R
Guo
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Jiangsu, China. Electronic address: wanghui@fudan.edu.cn.
Hui
H
Wang
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Jiangsu, China.
Zhan-Ting
ZT
Li
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, Jiangsu, China. Electronic address: zhangdw@fudan.edu.cn.
Dan-Wei
DW
Zhang
D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004926:Escherichia coli / Q000187:drug effects; D004927:Escherichia coli Infections / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010655:Phenylenediamines / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D061965:Matrix Metalloproteinase Inhibitors; D009944:Organoplatinum Compounds; D010655:Phenylenediamines; D016159:Tumor Suppressor Protein p53; D020169:Caspases; D020782:Matrix Metalloproteinases
Anticancer Pt(II) complex; Cytotoxicity; DNA interaction; Dimetallic Pt(II) complex; E. coli growth inhibition