Li Zhoulei, He Peng, Luo Ganhua, Shi Xinchong, Yuan Gang, Zhang Bing, Seidl Christof, Gewies Andreas, Wang Yue, Zou Yuan, Long Yali, Yue Dianchao, Zhang Xiangsong
Department of Nuclear Medicine, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Department of Geriatrics, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
Front Pharmacol. 2020 Sep 23;11:570939. doi: 10.3389/fphar.2020.570939. eCollection 2020.
The anticancer potential of pharmacologic ascorbic acid (AA) has been detected in a number of cancer cells. However, study suggested a strongly reduced cytotoxic activity of AA. It was known that pH could be a critical influencing factor for multiple anticancer treatments. In this study, we explored the influence of pH on the cytotoxicity of ascorbic acid. We employed castration-resistant prostate cancer (CRPC) cell lines PC3 and DU145 to observe the therapeutic effect of AA on PCa cells that were cultured with different pH . We also analyzed the influence of pH and extracellular oxidation on cytotoxicity of AA in cancer cells using reactive oxygen species (ROS) assay, cellular uptake of AA, and NADPH assay. Male BALB/c nude mice bearing prostate carcinoma xenografts (PC3 or DU145) were used to assess treatment response to AA with or without bicarbonate . The cellular uptake of AA in PCa xenografts was detected using positron emission tomography (PET). Small animal PET/CT scans were performed on mice after the administration of 6-deoxy-6-[F] fluoro-L-ascorbic acid (F-DFA).
Our studies demonstrate that acidic pH attenuates the cytotoxic activity of pharmacologic ascorbic acid by inhibiting AA uptake in PCa cells. Additionally, we found that the cancer cell-selective toxicity of AA depends on ROS. , combination of AA and bicarbonate could provide a significant better therapeutic outcome in comparison with controls or AA single treated mice. F-DFA PET imaging illustrated that the treatment with NaHCO could significantly increase the AA uptake in tumor.
The alkalinity of tumor microenvironment plays an important role in anticancer efficiency of AA in CRPC. F-DFA PET/CT imaging could predict the therapeutic response of PCa animal model through illustration of tumoral uptake of AA. F-DFA might be a potential PET tracer in clinical diagnosis and treatment for CRPC.
在多种癌细胞中已检测到药理剂量的抗坏血酸（AA）的抗癌潜力。然而，研究表明AA的细胞毒性活性大幅降低。已知pH可能是多种抗癌治疗的关键影响因素。在本研究中，我们探讨了pH对抗坏血酸细胞毒性的影响。我们使用去势抵抗性前列腺癌（CRPC）细胞系PC3和DU145来观察AA对在不同pH条件下培养的前列腺癌细胞的治疗效果。我们还使用活性氧（ROS）测定、AA的细胞摄取和NADPH测定分析了pH和细胞外氧化对癌细胞中AA细胞毒性的影响。使用携带前列腺癌异种移植瘤（PC3或DU145）的雄性BALB/c裸鼠来评估AA联合或不联合碳酸氢盐的治疗反应。使用正电子发射断层扫描（PET）检测前列腺癌异种移植瘤中AA的细胞摄取。在给予6-脱氧-6-[F]氟-L-抗坏血酸（F-DFA）后对小鼠进行小动物PET/CT扫描。
我们的研究表明，酸性pH通过抑制前列腺癌细胞对AA的摄取来减弱药理剂量抗坏血酸的细胞毒性活性。此外，我们发现AA的癌细胞选择性毒性取决于ROS。与对照组或单独使用AA治疗的小鼠相比，AA与碳酸氢盐联合使用可提供明显更好的治疗效果。F-DFA PET成像表明，用NaHCO治疗可显著增加肿瘤中AA的摄取。
肿瘤微环境的碱度在CRPC中AA的抗癌效率中起重要作用。F-DFA PET/CT成像可通过显示肿瘤对AA的摄取来预测前列腺癌动物模型的治疗反应。F-DFA可能是CRPC临床诊断和治疗中的一种潜在PET示踪剂。
