Ramanathan Balakrishnan, Jan Kun-Yan, Chen Chien-Hung, Hour Tzyh-Chyuan, Yu Hong-Jen, Pu Yeong-Shiau
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Cancer Res. 2005 Sep 15;65(18):8455-60. doi: 10.1158/0008-5472.CAN-05-1162.
Paclitaxel, one of the most commonly prescribed chemotherapeutic agents, is active against a wide spectrum of human cancer. The mechanism of its cytotoxicity, however, remains controversial. Our results indicate that paclitaxel treatment increases levels of superoxide, hydrogen peroxide, nitric oxide (NO), oxidative DNA adducts, G2-M arrest, and cells with fragmented nuclei. Antioxidants pyruvate and selenium, the NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester, and the NO scavenger manganese (III) 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide all decreased paclitaxel-mediated DNA damage and sub-G1 cells. In contrast, the glutamylcysteine synthase inhibitor buthionine sulfoximine (BSO) and the superoxide dismutase (SOD) inhibitor 2-methoxyestradiol (2-ME) increased the sub-G1 fraction in paclitaxel-treated cells. These results suggest that reactive oxygen and nitrogen species are involved in paclitaxel cytotoxicity. This notion is further supported with the observation that concentrations of paclitaxel required to inhibit cell growth by 50% correlate with total antioxidant capacity. Moreover, agents such as arsenic trioxide (As2O3), BSO, 2-ME, PD98059, U0126 [mitogen-activated protein/extracellular signal-regulated kinase inhibitors], and LY294002 (phosphatidylinositol 3-kinase/Akt inhibitor), all of which decrease clonogenic survival, also decrease the total antioxidant capacity of paclitaxel-treated cells, regardless whether they are paclitaxel sensitive or paclitaxel resistant. These results suggest that paclitaxel chemosensitivity may be predicted by taking total antioxidant capacity measurements from clinical tumor samples. This, in turn, may then improve treatment outcomes by selecting out potentially responsive patients.
紫杉醇是最常用的化疗药物之一，对多种人类癌症具有活性。然而，其细胞毒性机制仍存在争议。我们的结果表明，紫杉醇处理会增加超氧化物、过氧化氢、一氧化氮（NO）、氧化性DNA加合物、G2-M期阻滞以及核碎片化细胞的水平。抗氧化剂丙酮酸和硒、NO合酶抑制剂N（ω）-硝基-L-精氨酸甲酯以及NO清除剂锰（III）2-（4-羧基苯基）-4,4,5,5-四甲基-咪唑啉-1-氧基-3-氧化物均能降低紫杉醇介导的DNA损伤和亚G1期细胞。相反，谷氨酰半胱氨酸合成酶抑制剂丁硫氨酸亚砜胺（BSO）和超氧化物歧化酶（SOD）抑制剂2-甲氧基雌二醇（2-ME）会增加紫杉醇处理细胞中的亚G1期比例。这些结果表明，活性氧和氮物种参与了紫杉醇的细胞毒性。这一观点进一步得到以下观察结果的支持：抑制细胞生长50%所需的紫杉醇浓度与总抗氧化能力相关。此外，诸如三氧化二砷（As2O3）、BSO、2-ME、PD98059、U0126[丝裂原活化蛋白/细胞外信号调节激酶抑制剂]和LY294002（磷脂酰肌醇3-激酶/Akt抑制剂）等药物，所有这些都会降低克隆形成存活率，也会降低紫杉醇处理细胞的总抗氧化能力，无论它们对紫杉醇敏感还是耐药。这些结果表明，通过测量临床肿瘤样本的总抗氧化能力，可以预测紫杉醇的化疗敏感性。反过来，这可能通过筛选出潜在有反应的患者来改善治疗结果。
