Department of Surgery, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Department of Molecular Physiology and Biophsics, The University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Sci Rep. 2020 Oct 19;10(1):17649. doi: 10.1038/s41598-020-74806-2.
Pharmacological ascorbate (P-AscH, high-dose, intravenous vitamin C) is cytotoxic to tumor cells in doses achievable in humans. Phase I studies in pancreatic cancer (PDAC) utilizing P-AscH have demonstrated increases in progression free survival, suggesting a reduction in metastatic disease burden. The purpose of this study was to determine the effects of P-AscH on metastatic PDAC. Several in vitro and in vivo mechanisms involved in PDAC metastases were investigated following treatment with P-AscH. Serum from PDAC patients in clinical trials with P-AscH were tested for the presence and quantity of circulating tumor cell-derived nucleases. P-AscH inhibited invasion, basement membrane degradation, decreased matrix metalloproteinase expression, as well as clonogenic survival and viability during exposure to fluid shear stress. In vivo, P-AscH significantly decreased formation of ascites, tumor burden over time, circulating tumor cells, and hepatic metastases. Both in vitro and in vivo findings were reversed with the addition of catalase suggesting that the effect of P-AscH on metastatic disease is mediated by hydrogen peroxide. Finally, P-AscH decreased CTC-derived nucleases in subjects with stage IV PDAC in a phase I clinical trial. We conclude that P-AscH attenuates the metastatic potential of PDAC and may prove to be effective for treating advanced disease.
药理剂量的抗坏血酸（P-AscH，高剂量，静脉注射维生素 C）在人类可达到的剂量下对肿瘤细胞具有细胞毒性。在胰腺癌（PDAC）中进行的 I 期研究利用 P-AscH 证明无进展生存期增加，表明转移性疾病负担减少。本研究的目的是确定 P-AscH 对转移性 PDAC 的影响。在用 P-AscH 治疗后，研究了几种涉及 PDAC 转移的体外和体内机制。检测了接受 P-AscH 临床试验的 PDAC 患者的血清中是否存在和循环肿瘤细胞衍生核酶的数量。P-AscH 抑制侵袭、基底膜降解、降低基质金属蛋白酶表达以及在暴露于流体切应力时的克隆形成存活和活力。在体内，P-AscH 显著减少腹水的形成、随时间推移的肿瘤负担、循环肿瘤细胞和肝转移。体外和体内的发现都被添加的过氧化氢酶逆转，表明 P-AscH 对转移性疾病的影响是由过氧化氢介导的。最后，在 I 期临床试验中，P-AscH 降低了 IV 期 PDAC 患者的 CTC 衍生核酶。我们得出结论，P-AscH 减弱了 PDAC 的转移潜力，并且可能对治疗晚期疾病有效。
