Icaritin

Icaritin is a prenylflavonoid derivative obtained from the Epimedium genus. It has a wide range of biological and pharmacological functions, including antioxidant, anticancer and immune-enhancing^[9].

Icaritin is able to inhibit PD-L1 expression in both immune cells and cancer cells, leading to its combinational in-vivo efficacy with anti-PD1 antibody in inhibition of malignant tumor growth, because Icaritin functions through immune modulation, particularly immune cells with myeloid lineage, so that THP-1 cell line was employed along with SMMC-7221 cell line^[1]. The phenotype alternation induced by Abeta(25-35) could be reversed by icaritin.The neuroprotective effects of icaritin were estrogen receptor dependent due to the blocking action induced by estrogen receptor antagonist ICI 182,780 and well matched binding affinity with estrogen receptor by a receptor-ligand docking experiment^[3].Icaritin, an intestinal metabolite of Epimedium-derived flavonoids (EF) enhanced osteoblastic differentiation of mesenchymal stem cells (MSCs) only under osteogenic induction conditions. Icaritin was unable to promote proliferation, migration and tube like structure formation by human umbilical vein endothelial cells (HUVECs) in vitro^[5]. Icaritin inhibited AFP expression at mRNA and protein level. Icaritin abrogated murine double minute (Mdm) 2-mediated p53 ubiquitination degradation to improve the stability of p53. Icaritin-mediated decrease of AFP through Mdm2/p53 pathways inhibited HCC cellular proliferation and promoted HCC cellular apoptosis^[7].

Reduced frequency of CD11b+ Gr1+ myeloid-derived suppression cells (MDSCs) infiltration and downregulation of PD-L1 expression on MDSCs after icaritin treatment. This was not limited to MDSCs, as icaritin also decreased the expression of PD-L1 on neutrophils. The combination of anti-PD-1/CTLA-4 and icaritin significantly enhances antitumor ability and increases the efficacy of either treatment alone^[2].ICT treatment not only inhibited the pro-inflammatory cytokine TNF-α production and increased the anti-inflammatory cytokine IL-10 level in myocardium but also reduced the increase in the generation of superoxide content and malondialdehyde (MDA) formation and simultaneously increased the anti-oxidant capability in I/R hearts. Furthermore, ICT treatment increased Akt phosphorylation and inhibited PTEN expression in I/R hearts^[4]. Icaritin suppressed tumor progression and significantly prolonged the survival of mice-bearing orthotopic and subcutaneous HCC tumors. Rather than exerting direct cytotoxic activity against tumor cells, icaritin significantly reduced the accumulation and activation of tumoral and splenic MDSCs, and increased the number and activity of cytotoxic T cells^[6]. Icaritin inhibited tumor growth and induced OC cells apoptosis in patient-derived xenografts, as indicated by the tumor growth delay and increase of TUNEL-positive cells in tumor tissues. The icaritin-induced OC cell apoptosis may be associated with the activation of p53 and the suppression of Akt/mTOR pathway^[8].

References:
[1]: Mo D, Zhu H, et,al. Icaritin inhibits PD-L1 expression by Targeting Protein IκB Kinase α. Eur J Immunol. 2021 Apr;51(4):978-988. doi: 10.1002/eji.202048905. Epub 2021 Feb 9. PMID: 33354776; PMCID: PMC8248075.
[2]: Hao H, Zhang Q, et,al.Icaritin promotes tumor T-cell infiltration and induces antitumor immunity in mice. Eur J Immunol. 2019 Dec;49(12):2235-2244. doi: 10.1002/eji.201948225. Epub 2019 Sep 18. PMID: 31465113.
[3]: Wang Z, Zhang X, et,al. Neuroprotective effects of icaritin against beta amyloid-induced neurotoxicity in primary cultured rat neuronal cells via estrogen-dependent pathway. Neuroscience. 2007 Mar 30;145(3):911-22. doi: 10.1016/j.neuroscience.2006.12.059. Epub 2007 Feb 26. PMID: 17321691.
[4]: Zhang W, Xing B, et,al. Icaritin Attenuates Myocardial Ischemia and Reperfusion Injury Via Anti-Inflammatory and Anti-Oxidative Stress Effects in Rats. Am J Chin Med. 2015;43(6):1083-97. doi: 10.1142/S0192415X15500627. Epub 2015 Sep 14. PMID: 26364662.
[5]: Yao D, Xie XH, et,al. Icaritin, an exogenous phytomolecule, enhances osteogenesis but not angiogenesis--an in vitro efficacy study. PLoS One. 2012;7(8):e41264. doi: 10.1371/journal.pone.0041264. Epub 2012 Aug 30. PMID: 22952579; PMCID: PMC3431393.
[6]: Tao H, Liu M, et,al. Icaritin Induces Anti-tumor Immune Responses in Hepatocellular Carcinoma by Inhibiting Splenic Myeloid-Derived Suppressor Cell Generation. Front Immunol. 2021 Feb 26;12:609295. doi: 10.3389/fimmu.2021.609295. PMID: 33717093; PMCID: PMC7952329.
[7]: Li H, Liu Y, et,al. Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma. BMC Cancer. 2021 Mar 25;21(1):318. doi: 10.1186/s12885-021-08043-9. PMID: 33765973; PMCID: PMC7992931.
[8]: Gao L, Chen M, et,al. Icaritin induces ovarian cancer cell apoptosis through activation of p53 and inhibition of Akt/mTOR pathway. Life Sci. 2018 Jun 1;202:188-194. doi: 10.1016/j.lfs.2018.03.059. Epub 2018 Apr 3. PMID: 29625193.
[9]: Qian ZQ, Wang YW, et,al. Icariin prevents hypertension-induced cardiomyocyte apoptosis through the mitochondrial apoptotic pathway. Biomed Pharmacother. 2017 Apr;88:823-831. doi: 10.1016/j.biopha.2017.01.147. Epub 2017 Feb 5. PMID: 28171848.