Laboratory of Hepatobiliary and Pancreatic Surgery, the Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi, China.
Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Guilin Medical University, Guilin 541001, Guangxi, China.
Anticancer Agents Med Chem. 2020;20(4):504-517. doi: 10.2174/1871520619666191112114340.
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.
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.
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.
Pt(II)-Bpy is a potential candidate for cancer chemotherapy.
为了克服顺铂的缺点，已经制备了许多铂（Pt）配合物。然而，Pt(II)与 2-苯甲酰吡啶配合物[Pt(II)-Bpy]：[PtCl2(DMSO)L]（DMSO=二甲基亚砜，L=2-苯甲酰吡啶）在癌细胞中的抗癌活性和机制尚不清楚。
通过光谱分析合成并表征 Pt(II)-Bpy。在细胞、分子和体内水平上研究了其抗癌活性和潜在机制。
Pt(II)-Bpy 抑制肿瘤细胞生长，特别是 HepG2 人肝癌细胞，半数最大抑制浓度为 9.8±0.5μM，而对 HL-7702 正常肝细胞的毒性较低。Pt(II)-Bpy 诱导 DNA 损伤，这表现为 cleavedpoly（ADP 核糖）聚合酶（PARP）和γ-H2A 组蛋白家族成员 X 的表达明显增加，以及 PARP 表达的减少。Pt(II)-Bpy 与 DNA 的分子水平相互作用最可能通过嵌入机制，这可能是 DNA 损伤的证据。Pt(II)-Bpy 在 HepG2 细胞中使细胞周期停滞在 S 期。它还导致线粒体膜电位严重丧失；caspase-9 和 caspase-3 的表达减少；活性氧水平升高；细胞色素 c 和凋亡蛋白酶激活因子的释放；以及 caspase-9 和 caspase-3 在 HepG2 细胞中的激活，从而导致细胞凋亡。同时，观察到 p53 和相关蛋白的变化，包括 p53 的上调、p53、p21、B 细胞淋巴瘤-2 相关 X 蛋白和 NOXA 的磷酸化以及 B 细胞淋巴瘤 2 的下调。此外，Pt(II)-Bpy 在 HepG2 裸鼠模型中对肿瘤生长表现出明显的抑制作用。
Pt(II)-Bpy 是一种有潜力的癌症化疗候选药物。
