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Metabolic profile and structure–activity relationship of resveratrol and its analogs in human bladder cancer cells

Authors Yang Y, Zhang G, Li C, Wang S, Zhu M, Wang J, Yue H, Ma X, Zhen Y, Shu X

Received 26 February 2019

Accepted for publication 9 April 2019

Published 21 May 2019 Volume 2019:11 Pages 4631—4642


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo

Yang Yang,1,2 Guangyuan Zhang,2 Chuangang Li,3 Sihan Wang,2 Manning Zhu,2 Jinan Wang,2 Hangtian Yue,2 Xiaodong Ma,2 Yuhong Zhen,2 Xiaohong Shu1,2

1College of Integrative Medicine, Dalian Medical University, Dalian 116044, People’s Republic of China; 2College of Pharmacy, Dalian Medical University, Dalian 116044, People’s Republic of China; 3Department of Urology, The Second Affiliated Hospital of Dalian Medical University, Dalian 116023, People’s Republic of China

Purpose: 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.
Methods: 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.
Results: 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.
Conclusion: 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.

Keywords: bladder cancer, resveratrol, oxyresveratrol, acetylresveratrol, polydatin, structure–activity relationship

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