Jiang YY, Dong HH, Zhou WT, Luo JZ, Wei X, Huang YQ. Preparation of kakkatin derivatives and their anti-tumor activity. World J Clin Oncol 2024; 15(8): 1078-1091 [PMID: 39193163 DOI: 10.5306/wjco.v15.i8.1078]
Corresponding Author of This Article
Xian Wei, PhD, Professor, Research Center for the Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for Nationalities, No. 98 Countryside Road, Baise 533000, Guangxi Zhuang Autonomous Region, China. 27848258@qq.com
Research Domain of This Article
Research & Experimental Medicine
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Yu-Ying Jiang, Hui-Hua Dong, Wen-Ting Zhou, Yan-Qiang Huang, Guangxi Technology Innovation Cooperation Base of Prevention and Control Pathogenic Microbes with Drug Resistance, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
Yu-Ying Jiang, Hui-Hua Dong, Wen-Ting Zhou, Jia-Zi Luo, Xian Wei, Key Laboratory of the Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
Jia-Zi Luo, Collaborative Innovation Center for Guangxi Ethnic Medicine, The School of Chemistry and Pharmaceutical Sciences, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
Xian Wei, Research Center for the Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for Nationalities, Baise 533000, Guangxi Zhuang Autonomous Region, China
Co-first authors: Yu-Ying Jiang and Hui-Hua Dong.
Co-corresponding authors: Xian Wei and Yan-Qiang Huang.
Author contributions: Jiang YY and Dong HH were responsible for the experimental research, performed to consult literature, involved in the data collection and analysis, drafted the manuscript, and contributed equally to this work; Zhou WT and Luo JZ contributed new reagents and analytic tools; Wei X and Huang YQ designed, checked and modified finalize the manuscript, and contributed equally to this work; all authors were involved in the critical review of the results and have read and approved the final manuscript.
Institutional review board statement: This study was reviewed and approved by the Youjiang Medical University for Nationalities Institution review board.
Conflict-of-interest statement: The authors declare they have no competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data sharing statement: All data included in this study are available upon request by contact with the corresponding author at 27848258@qq.com.
ARRIVE guidelines statement: The authors have read the ARRIVE Guidelines, and the manuscript was prepared and revised according to the ARRIVE Guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xian Wei, PhD, Professor, Research Center for the Prevention and Treatment of Drug Resistant Microbial Infecting, Youjiang Medical University for Nationalities, No. 98 Countryside Road, Baise 533000, Guangxi Zhuang Autonomous Region, China. 27848258@qq.com
Received: March 21, 2024 Revised: July 20, 2024 Accepted: July 29, 2024 Published online: August 24, 2024 Processing time: 147 Days and 18.6 Hours
Abstract
BACKGROUND
Modern pharmacological studies have confirmed that plant-derived compounds from Puerariae flos (PF) has significant biological activities against liver damage, tumors and inflammation. Kakkatin is an isoflavone polyphenolic compound isolated from PF flower. However, the effect of kakkatin and its derivatives on anti-tumor has not been well explored.
AIM
To design and synthesize a kakkatin derivative [6-(hept-6-yn-1-yloxy)-3-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one (HK)] to explore its anti-tumor biological activity.
METHODS
Hept-6-yn-1-yl ethanesulfonate was introduced to replace hydrogen at the hydroxyl position of kakkatin phenol, and the derivative of kakkatin was prepared; the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide was used to detect cell viability, a clone formation assay was adopted to detect cell proliferation, apoptosis, necrosis, and cell cycles were analyzed by Annexin V/propidium iodide staining and flow cytometry. Cell migration and invasion ability were evaluated by cell scratch assay and transwell assay. The potential mechanism of HK on hepatocellular carcinoma (HCC) SMMC-7721 cells was explored through network pharmacology and molecular docking, and finally real-time PCR assays was used to verify the potential targets and evaluate the biological activity of HK.
RESULTS
Compared with kakkatin, the modified HK did not significantly increase the inhibitory activity of gastric cancer MGC803 cells, but the inhibitory activity of HCC SMMC-7721 cells was increased by about 30 times, with an IC50 value of 2.5 μM, and the tumor inhibition effect was better than cisplatin, which could significantly inhibit the cloning, invasion and metastasis of HCC SMMC-7721 cells, and induce apoptosis and G2/M cycle arrest. Its mechanism of action is mainly related to the upregulation of PDE3B and NFKB1 target proteins in the cAMP pathway.
CONCLUSION
HK have a significant inhibitory effect on HCC SMMC-7721 cells, and the targets of their action may be PDE3B and NFKB1 proteins in the cAMP pathway, making it a good lead drug for the treatment of HCC.
Core Tip: We synthesized a new kakkatin derivative [6-(hept-6-yn-1-yloxy)-3-(4-hydroxyphenyl)-7-methoxy-4H-chromen-4-one (HK)] and explored its anti-tumor activity against liver cancer, gastric cancer and its potential mechanism of action. It was found that the synthesized HK increased the anti-hepatoma activity by nearly 30 times compared with kakkatin, but the inhibitory effect on gastric cancer MGC803 cells was not much different from that of kakkatin, indicating that the anti-tumor activity of HK may be more specific. PDE3B and NFKB1 proteins in the cAMP pathway are the targets of the HK on HCC SMMC-7721 cells.
