Yang Yang, Zhang Guangyuan, Li Chuangang, Wang Sihan, Zhu Manning, Wang Jinan, Yue Hangtian, Ma Xiaodong, Zhen Yuhong, Shu Xiaohong
College of Integrative Medicine, Dalian Medical University, Dalian 116044, People's Republic of China.
College of Pharmacy, Dalian Medical University, Dalian 116044, People's Republic of China.
Cancer Manag Res. 2019 May 21;11:4631-4642. doi: 10.2147/CMAR.S206748. eCollection 2019.
Resveratrol (RV), a promising anti-cancer candidate, is limited in application for its poor bioavailability. However, the better bioavailability has been found in some RV derivatives. So in this paper, we explore the structure-activity relationship and the metabolic profiles of RV and its analogs (polydatin [PD], oxyresveratrol [ORV], acetylresveratrol [ARV]) in human bladder cancer T24 cells, and then evaluate their active forms and key chemical functional groups which may determine the fate of tumor cells. Drug sensitivity is evaluated by MTT assay, HE staining and flow cytometry analysis after T24 cells treated with RV, PD, ORV and ARV, respectively. Then the drug metabolites, in alive and dead T24 cells, also in T24 cell supernatant and lysates, are qualitatively and quantitatively analyzed by high-performance liquid chromatography, liquid chromatography coupled with tandem mass spectrum and high-resolution mass spectrometry technologies, respectively. RV, ORV and ARV inhibit bladder cancer cells growth in a dose- and time-dependent manner, and exert the anti-tumor potency to T24 cells in order of ORV>ARV>RV>PD. Meanwhile, similar metabolic profiles of the above compounds are found not only in cell supernatant and lysate, but also in dead and alive T24 cells after drug treatment, and the main metabolites of RV, ORV and PD are their prototypes, but ARV is mainly metabolized to RV. The inhibitory potencies to T24 cells in the order of ORV>ARV>RV>PD are related to the structure and metabolism of RV and its analogs. Meanwhile, the number and position of free phenolic hydroxyl groups play a prominent role in antitumor activities. Therefore, protecting phenolic hydroxyl groups, and inhibiting drug metabolism to keep phenolic hydroxyl groups free would be the promising strategies to ensure the bioactivity of RV and its analogs, and thus to improve RV's bioactivity and promote RV clinical translation.
白藜芦醇（RV）是一种很有前景的抗癌候选药物，但由于其生物利用度差，应用受到限制。然而，在一些白藜芦醇衍生物中发现了更好的生物利用度。因此，在本文中，我们探讨了白藜芦醇及其类似物（虎杖苷[PD]、氧化白藜芦醇[ORV]、乙酰白藜芦醇[ARV]）在人膀胱癌T24细胞中的构效关系和代谢谱，然后评估它们的活性形式以及可能决定肿瘤细胞命运的关键化学官能团。在用RV、PD、ORV和ARV分别处理T24细胞后，通过MTT法、HE染色和流式细胞术分析评估药物敏感性。然后，分别采用高效液相色谱、液相色谱-串联质谱和高分辨率质谱技术，对活的和死的T24细胞、T24细胞上清液和裂解物中的药物代谢产物进行定性和定量分析。RV、ORV和ARV以剂量和时间依赖性方式抑制膀胱癌细胞生长，对T24细胞的抗肿瘤效力顺序为ORV>ARV>RV>PD。同时，不仅在细胞上清液和裂解物中，而且在药物处理后的死的和活的T24细胞中，发现上述化合物具有相似的代谢谱，RV、ORV和PD的主要代谢产物是它们的原型，而ARV主要代谢为RV。ORV>ARV>RV>PD对T24细胞的抑制效力与白藜芦醇及其类似物的结构和代谢有关。同时，游离酚羟基的数量和位置在抗肿瘤活性中起显著作用。因此，保护酚羟基并抑制药物代谢以保持酚羟基游离，将是确保白藜芦醇及其类似物生物活性、从而提高白藜芦醇生物活性并促进其临床转化的有前景的策略。
