Antitumor Mechanism and Therapeutic Potential of Cordycepin Derivatives

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2024 Jan 23

PMID 38257396

Authors

Linlin Cui

Li Zhao

Guanghuan Shen

Dahai Yu

Tian Yuan

Yingyu Zhang

Bo Yang

Affiliations

Soon will be listed here.

Abstract

Cordycepin has good antitumor activity, but its clinical application is limited due to the easy deamination of N6 in structure. In this study, a large lipolysis group was introduced at the cordycepin N6 to improve the problem, cordycepin derivatives (-) were synthesized, and biological evaluation of compounds was studied. In this study, the vitro antitumor activity of the compounds against MCF7 cells, HepG2 cells and SGC-7901 cells was evaluated by MTT assay. In the results, compound showed the most obvious inhibitory effect on MCF7 cells with an IC value of 27.57 ± 0.52 μM, which was much lower than cordycepin. Compound showed high selectivity between MCF7 and normal MCF-10A cells. Further biological evaluation showed that compound promoted apoptosis and blocked the cell cycle in the G0/G1 phase. Then, Western Blot was used to detect related apoptotic proteins. It was found that Compound could down-regulate the expression of Bcl-2 protein and up-regulate the expression of p53, Bax, Caspase-3 and Caspase-9 proteins. The mitochondrial membrane potential decreased continuously and the positive expression rate decreased. It was speculated that compound induced the apoptosis of MCF7 cells through the mitochondrial pathway.

References

Yue K, Ye M, Zhou Z, Sun W, Lin X . The genus Cordyceps: a chemical and pharmacological review. J Pharm Pharmacol. 2013; 65(4):474-93. DOI: 10.1111/j.2042-7158.2012.01601.x. View

Han F, Dou M, Wang Y, Xu C, Li Y, Ding X . Cordycepin protects renal ischemia/reperfusion injury through regulating inflammation, apoptosis, and oxidative stress. Acta Biochim Biophys Sin (Shanghai). 2020; 52(2):125-132. DOI: 10.1093/abbs/gmz145. View

Lee C, Huang K, Shaw J, Chen J, Kuo W, Shen G . Trends in the Immunomodulatory Effects of : Total Extracts, Polysaccharides and Cordycepin. Front Pharmacol. 2020; 11:575704. PMC: 7735063. DOI: 10.3389/fphar.2020.575704. View

Dong J, Li Y, Xiao H, Luo D, Zhang S, Zhu C . Cordycepin sensitizes breast cancer cells toward irradiation through elevating ROS production involving Nrf2. Toxicol Appl Pharmacol. 2018; 364:12-21. DOI: 10.1016/j.taap.2018.12.006. View

Liao X, Gao Y, Zhao H, Zhou M, Chen D, Tao L . Cordycepin Reverses Cisplatin Resistance in Non-small Cell Lung Cancer by Activating AMPK and Inhibiting AKT Signaling Pathway. Front Cell Dev Biol. 2021; 8:609285. PMC: 7843937. DOI: 10.3389/fcell.2020.609285. View

Bi Y, Li H, Yi D, Sun Y, Bai Y, Zhong S . Cordycepin Augments the Chemosensitivity of Human Glioma Cells to Temozolomide by Activating AMPK and Inhibiting the AKT Signaling Pathway. Mol Pharm. 2018; 15(11):4912-4925. DOI: 10.1021/acs.molpharmaceut.8b00551. View

Zhang X, Huang W, Tang P, Sun Y, Zhang X, Qiu L . Anti-inflammatory and neuroprotective effects of natural cordycepin in rotenone-induced PD models through inhibiting Drp1-mediated mitochondrial fission. Neurotoxicology. 2021; 84:1-13. DOI: 10.1016/j.neuro.2021.02.002. View

Chang M, Hong S, Yang S, Wu C, Wang C, Huang B . Anti-Cancer Effect of Cordycepin on FGF9-Induced Testicular Tumorigenesis. Int J Mol Sci. 2020; 21(21). PMC: 7672634. DOI: 10.3390/ijms21218336. View

Yin J, Xin X, Weng Y, Gui Z . Transcriptome-wide analysis reveals the progress of Cordyceps militaris subculture degeneration. PLoS One. 2017; 12(10):e0186279. PMC: 5657973. DOI: 10.1371/journal.pone.0186279. View

10.

Wen Z, Du X, Meng N, Li Y, Mi R, Li X . Tussah silkmoth pupae improve anti-tumor properties of (L.) Link by increasing the levels of major metabolite cordycepin. RSC Adv. 2022; 9(10):5480-5491. PMC: 9060897. DOI: 10.1039/c8ra09491h. View

11.

Nasser M, Masood M, Wei W, Li X, Zhou Y, Liu B . Cordycepin induces apoptosis in SGC‑7901 cells through mitochondrial extrinsic phosphorylation of PI3K/Akt by generating ROS. Int J Oncol. 2017; 50(3):911-919. DOI: 10.3892/ijo.2017.3862. View

12.

Yoon S, Park S, Park Y . The Anticancer Properties of Cordycepin and Their Underlying Mechanisms. Int J Mol Sci. 2018; 19(10). PMC: 6212910. DOI: 10.3390/ijms19103027. View

13.

Thomadaki H, Tsiapalis C, Scorilas A . Polyadenylate polymerase modulations in human epithelioid cervix and breast cancer cell lines, treated with etoposide or cordycepin, follow cell cycle rather than apoptosis induction. Biol Chem. 2005; 386(5):471-80. DOI: 10.1515/BC.2005.056. View

14.

CUNNINGHAM K, Manson W, SPRING F, Hutchinson S . Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (Linn.) Link. Nature. 1950; 166(4231):949. DOI: 10.1038/166949a0. View

15.

Fei X, Zhang X, Zhang G, Bao W, Zhang Y, Zhang M . Cordycepin inhibits airway remodeling in a rat model of chronic asthma. Biomed Pharmacother. 2017; 88:335-341. DOI: 10.1016/j.biopha.2017.01.025. View

16.

Park J, Lee J, Lee K, Ha S, Hong E . Cordyceps militaris extract protects human dermal fibroblasts against oxidative stress-induced apoptosis and premature senescence. Nutrients. 2014; 6(9):3711-26. PMC: 4179184. DOI: 10.3390/nu6093711. View

17.

Radhi M, Ashraf S, Lawrence S, Tranholm A, Wellham P, Hafeez A . A Systematic Review of the Biological Effects of Cordycepin. Molecules. 2021; 26(19). PMC: 8510467. DOI: 10.3390/molecules26195886. View

18.

Zhou Y, Guo Z, Meng Q, Lu J, Wang N, Liu H . Cordycepin Affects Multiple Apoptotic Pathways to Mediate Hepatocellular Carcinoma Cell Death. Anticancer Agents Med Chem. 2016; 17(1):143-149. View

19.

Liu W, Zhang L, Sun S, Tang L, He S, Chen A . Cordycepin inhibits inflammatory responses through suppression of ERK activation in zebrafish. Dev Comp Immunol. 2021; 124:104178. DOI: 10.1016/j.dci.2021.104178. View

20.

Lee H, Burger P, Vogel M, Friese K, Bruning A . The nucleoside antagonist cordycepin causes DNA double strand breaks in breast cancer cells. Invest New Drugs. 2012; 30(5):1917-25. DOI: 10.1007/s10637-012-9859-x. View