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Anticancer Activity of Platinum (II) Complex with 2-Benzoylpyridine by Induction of DNA Damage, S-Phase Arrest, and Apoptosis

[ Vol. 20 , Issue. 4 ]

Author(s):

Yu-Lan Li, Xin-Li Gan, Rong-Ping Zhu, Xuehong Wang, Duan-Fang Liao, Junfei Jin* and Zhaoquan Huang*   Pages 504 - 517 ( 14 )

Abstract:


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.

Keywords:

Pt(II)-Bpy, anticancer activity, apoptosis, DNA damage, S-phase arrest, HepG2.

Affiliation:

Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, Department of Pathology, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, Division of Stem Cell Regulation and Application, State Key Laboratory of Chinese Medicine Powder and Medicine Innovation in Hunan (Incubation), Hunan University of Chinese Medicine, Changsha, Hunan, Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, Department of Pathology, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi

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