Objective: To overcome the disadvantages of cisplatin, numerous platinum (Pt) complexes have been prepared. However, the anticancer activity and mechanism of Pt(II) complexed with 2-benzoylpyridine [Pt(II)- Bpy]: [PtCl2(DMSO)L] (DMSO = dimethyl sulfoxide, L = 2-benzoylpyridine) in cancer cells remain unknown.
Methods: Pt(II)-Bpy was synthesized and characterized by spectrum analysis. Its anticancer activity and underlying mechanisms were demonstrated at the cellular, molecular, and in vivo levels.
Results: Pt(II)-Bpy inhibited tumor cell growth, especially HepG2 human liver cancer cells, with a halfmaximal inhibitory concentration of 9.8±0.5μM, but with low toxicity in HL-7702 normal liver cells. Pt(II)- Bpy induced DNA damage, which was demonstrated through a marked increase in the expression of cleavedpoly (ADP ribose) polymerase (PARP) and gamma-H2A histone family member X and a decrease in PARP expression. The interaction of Pt(II)-Bpy with DNA at the molecular level was most likely through an intercalation mechanism, which might be evidence of DNA damage. Pt(II)-Bpy initiated cell cycle arrest at the S phase in HepG2 cells. It also caused severe loss of the mitochondrial membrane potential; a decrease in the expression of caspase-9 and caspase-3; an increase in reactive oxygen species levels; the release of cytochrome c and apoptotic protease activation factor; and the activation of caspase-9 and caspase-3 in HepG2 cells, which in turn resulted in apoptosis. Meanwhile, changes in p53 and related proteins were observed including the upregulation of p53, the phosphorylation of p53, p21, B-cell lymphoma-2-associated X protein, and NOXA; and the downregulation of B-cell lymphoma 2. Moreover, Pt(II)-Bpy displayed marked inhibitory effects on tumor growth in the HepG2 nude mouse model.
Conclusion: Pt(II)-Bpy is a potential candidate for cancer chemotherapy.
[http://dx.doi.org/10.2165/00003495-200059004-00003] [PMID: 10864227]
[http://dx.doi.org/10.1016/j.ejmech.2010.05.044] [PMID: 20576328]
[http://dx.doi.org/10.1016/j.bmc.2009.08.063] [PMID: 19773176]
[http://dx.doi.org/10.1016/j.ejmech.2013.03.047] [PMID: 23644191]
[http://dx.doi.org/10.1016/j.jinorgbio.2014.04.001] [PMID: 24798373]
[http://dx.doi.org/10.1021/jm5012484] [PMID: 25650792]
[http://dx.doi.org/10.1039/c0dt00761g] [PMID: 21165516]
[http://dx.doi.org/10.1002/chem.200903078] [PMID: 20376825]
[http://dx.doi.org/10.1039/B813363H] [PMID: 19089006]
Zeller, M.; Natarajan, K. Evaluation on the role of terminal N-substitution in 6-methoxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones on the biological properties of new water-soluble nickel (ii) complexes. RSC Advances, 2012, 2, 8515-8525.
[http://dx.doi.org/10.1016/j.critrevonc.2004.08.008] [PMID: 15607931]
[http://dx.doi.org/10.1016/j.canlet.2006.09.008] [PMID: 17055640]
[http://dx.doi.org/10.1016/j.cbi.2015.02.004] [PMID: 25684395]