Chen Gloria Y, O'Leary Brianne R, Du Juan, Carroll Rory S, Steers Garett J, Buettner Garry R, Cullen Joseph J
Departments of Surgery, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Free Radical and Radiation Biology Division, Department of Radiation Oncology, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
Antioxidants (Basel). 2024 Mar 18;13(3):361. doi: 10.3390/antiox13030361.
The toxicity of ionizing radiation limits its effectiveness in the treatment of pancreatic ductal adenocarcinoma. Pharmacologic ascorbate (P-AscH) has been shown to radiosensitize pancreatic cancer cells while simultaneously radioprotecting normal cells. We hypothesize that P-AscH protects the small intestine while radiosensitizing pancreatic cancer cells partially through an oxidative stress mechanism. Duodenal samples from pancreaticoduodenectomy specimens of patients who underwent radio-chemotherapy ± P-AscH and mouse tumor and jejunal samples treated with radiation ± P-AscH were evaluated. Pancreatic cancer and non-tumorigenic cells were treated with radiation ± P-AscH to assess lipid peroxidation. To determine the mechanism, pancreatic cancer cells were treated with selenomethionine or RSL3, an inhibitor of glutathione peroxidase 4 (GPx4). Radiation-induced decreases in villi length and increases in 4-HNE immunofluorescence were reversed with P-AscH in human duodenum. In vivo, radiation-induced decreases in villi length and increased collagen deposition were reversed in P-AscH-treated jejunal samples. P-AscH and radiation increased BODIPY oxidation in pancreatic cancer cells but not in non-tumorigenic cells. Selenomethionine increased GPx4 protein and activity in pancreatic cancer and reversed P-AscH-induced toxicity and lipid peroxidation. RSL3 treatment inhibited GPx4 activity and increased lipid peroxidation. Differences in oxidative stress may play a role in radioprotecting normal cells while radiosensitizing pancreatic cancer cells when treated with P-AscH.
电离辐射的毒性限制了其在治疗胰腺导管腺癌方面的有效性。药理剂量的抗坏血酸盐（P-AscH）已被证明可使胰腺癌细胞对辐射敏感，同时对正常细胞起到辐射防护作用。我们假设P-AscH在使胰腺癌细胞对辐射敏感的同时，部分通过氧化应激机制保护小肠。对接受放化疗±P-AscH的患者的胰十二指肠切除术标本中的十二指肠样本，以及接受辐射±P-AscH处理的小鼠肿瘤和空肠样本进行了评估。用辐射±P-AscH处理胰腺癌细胞和非致瘤细胞，以评估脂质过氧化。为确定其机制，用硒代蛋氨酸或谷胱甘肽过氧化物酶4（GPx4）抑制剂RSL3处理胰腺癌细胞。在人体十二指肠中，P-AscH可逆转辐射引起的绒毛长度减少和4-羟基壬烯醛免疫荧光增加。在体内，P-AscH处理的空肠样本中，辐射引起的绒毛长度减少和胶原沉积增加得到逆转。P-AscH和辐射可增加胰腺癌细胞中的硼二吡咯氧化，但对非致瘤细胞无此作用。硒代蛋氨酸可增加胰腺癌细胞中GPx4的蛋白表达和活性，并逆转P-AscH诱导的毒性和脂质过氧化。RSL3处理可抑制GPx4活性并增加脂质过氧化。氧化应激的差异可能在使用P-AscH治疗时对正常细胞起到辐射防护作用，同时使胰腺癌细胞对辐射敏感方面发挥作用。
