Vosaroxin is a quinolone-derivative anticancer agent with inhibitory activity on type II DNA topoisomerases (TOP2). The aim of the present study was to investigate its cytotoxic effect and potential molecular mechanisms in human cervical cancer HeLa cells. Vosaroxin decreased cell viability and increased lactate dehydrogenase (LDH) release in a dose- and time-dependent manner in HeLa cells, but not in normal cervical epithelial cells. Vosaroxin also induced apoptosis and increased caspase-3 activity in HeLa cells. These effects were accompanied by increased mitochondrial reactive oxygen species (ROS) generation, lipid peroxidation, mitochondrial swelling and reduced ATP production. Western blot analysis showed that vosaroxin significantly reduced hypoxia-inducible factor 1α (HIF-1α) protein levels. However, it had no effect on HIF-1α protein degradation and HIF-1α mRNA levels. The results showed that vosaroxin inhibited the synthesis of HIF-1α protein and interfered with the dimerization of HIF-1α and aryl hydrocarbon receptor nuclear translocator (ARNT). In addition, vosaroxin stimulated mitochondrial enzyme activities and superoxide dismutase 2 (SOD2) deacetylation via activating (Sir2 like protein 3) Sirt3. More importantly, vosaroxin-induced inhibition on HIF-1α and its cytotoxic effects, as measured by cell viability, LDH release and apoptosis, were partially prevented by Sirt3 knockdown or the AMP-activated protein kinase (AMPK) inhibitor compound C. Overall, vosaroxin is demonstrated to be a chemotherapeutic agent targeting the Sirt3/HIF-1 pathway and could be beneficial for inducing cytotoxicity in human cervical cancer cells.

Vosaroxin是一种喹诺酮衍生物抗癌药，对II型DNA拓扑异构酶（TOP2）具有抑制活性。本研究的目的是研究其在人宫颈癌HeLa细胞中的细胞毒作用和潜在的分子机制。Vosaroxin在HeLa细胞中降低了细胞活力，并增加了乳酸脱氢酶（LDH）的释放，呈剂量和时间依赖性，但在正常宫颈上皮细胞中却没有。Vosaroxin还诱导HeLa细胞凋亡并增加caspase-3活性。这些作用伴随着线粒体活性氧（ROS）生成增加，脂质过氧化，线粒体肿胀和ATP生成减少。蛋白质印迹分析表明，vosaroxin显着降低了缺氧诱导因子1α（HIF-1α）蛋白的水平。然而，它对HIF-1α蛋白降解和HIF-1αmRNA水平没有影响。结果表明，vosaroxin抑制HIF-1α蛋白的合成，并干扰HIF-1α和芳烃受体核转运子（ARNT）的二聚化。此外，vosaroxin通过激活（Sir2像蛋白3）Sirt3刺激线粒体酶活性和超氧化物歧化酶2（SOD2）脱乙酰作用。更重要的是，通过Sirt3敲低或AMP激活的蛋白激酶（AMPK）抑制剂化合物C可以部分阻止vosaroxin诱导的对HIF-1α的抑制及其细胞毒性作用（通过细胞活力，LDH释放和凋亡来衡量）。被证明是靶向Sirt3 / HIF-1途径的化学治疗剂，可能对诱导人宫颈癌细胞的细胞毒性有益。