Nguewa Paul A, Fuertes Miguel A, Cepeda Victoria, Alonso Carlos, Quevedo Celia, Soto Manuel, Pérez José M
Departamento de Parasitología, Facultad de Farmacia, Universidad de La Laguna, Tenerife, Spain.
Med Chem. 2006 Jan;2(1):47-53. doi: 10.2174/157340606775197697.
Cisplatin is one of the most widely used antitumor drugs. However, as all the anticancer drugs currently used in clinic, cisplatin shows the phenomenon of drug resistance (intrinsic or acquired) against a wide variety of tumors. Poly (ADP-ribose) polymerase-1 is an enzyme involved in DNA repair and apoptotic cell death, which may be inhibited to increase cisplatin chemosensitivity of tumor cells so that cisplatin resistance may be circumvented. In the present study we report that PARP-1 inhibitor 3-aminobenzamide (3-AB) increases the cytotoxic activity of the platinum compounds cisplatin, trans-[PtCl(2)(4-picoline)(piperazine)] and transplatin against CH1cisR cisplatin-resistant ovarian tumor cells. In fact, a concentration of 3-AB of 1 mM not only increases the cytotoxic activity of these platinum complexes but also switches the mode of cell death from necrosis to apoptosis. Altogether, these data suggest that pharmacological modulation of PARP-1 by inhibitors may be a suitable strategy to fight against tumor resistance to platinum drugs.
顺铂是应用最为广泛的抗肿瘤药物之一。然而，如同目前临床使用的所有抗癌药物一样，顺铂对多种肿瘤表现出耐药现象（内在性或获得性）。聚（ADP - 核糖）聚合酶 -1是一种参与DNA修复和凋亡性细胞死亡的酶，抑制该酶可能会增加肿瘤细胞对顺铂的化学敏感性，从而规避顺铂耐药。在本研究中，我们报告聚（ADP - 核糖）聚合酶 -1抑制剂3 - 氨基苯甲酰胺（3 - AB）可增强铂类化合物顺铂、反式 - [PtCl₂(4 - 甲基吡啶)(哌嗪)]和顺铂对CH1cisR顺铂耐药卵巢肿瘤细胞的细胞毒活性。事实上，1 mM的3 - AB不仅增强了这些铂配合物的细胞毒活性，还将细胞死亡模式从坏死转变为凋亡。总之，这些数据表明，通过抑制剂对聚（ADP - 核糖）聚合酶 -1进行药理学调节可能是对抗肿瘤对铂类药物耐药的一种合适策略。
