淫羊藿素的药理作用及分子机制研究进展

doi:10.3969/j.issn.1674-490X.2023.06.001

摘要/Abstract

摘要： 淫羊藿素(icaritin)是中国传统中草药淫羊藿(Epimedium)的单体有效成分,具有免疫调节、心血管保护、骨保护、抗氧化等广泛的药理学活性,同时,淫羊藿素通过阻滞细胞周期、促进凋亡、抑制转移、免疫调节等多种途径对不同肿瘤均有抑制作用。综述有关淫羊藿素的化学成分及国内外在抗肿瘤和非抗肿瘤药理作用的最新研究进展,为淫羊藿素进一步开发和临床精准应用提供理论依据。

关键词: 淫羊藿素, 淫羊藿, 抗肿瘤, 免疫调节, 细胞凋亡

Abstract: Icaritin, as a single active ingredient of the Chinese herbal medicine Epimedium, shows a wide range of pharmacological activities, such as anti-inflammatory, immunomodulatory, cardiovascular protection, bone protection and antioxidant, etc. Meanwhile, Icaritin has an inhibitory effect on different tumors through blocking the cell cycle, promoting apoptosis, metastasis inhibition and immunomodulation. This paper reviews the chemical composition of icaritin and the latest research progress at home and abroad in anti-tumor activity, non-anti-tumor pharmacological effects. This review focus on the chemical composition of icaritin and the latest research progress in anti/non-anti-tumor pharmacological effects to provide a theoretical basis for the further development of Epimedium and its precise clinical application.

Key words: icaritin, Epimedium, antitumor, immunomodulation, apoptosis

中图分类号:

R285

吴迪,米甜,王贺东,王骏飞,李文娟. 淫羊藿素的药理作用及分子机制研究进展[J]. 医学研究与教育, 2023, 40(6): 1-11.

WU Di, MI Tian, WANG Hedong, WANG Junfei, LI Wenjuan. Advances on the pharmacological effects and molecular mechanisms of Icaritin[J]. Journal of Hebei Medical College for Continuing Education, 2023, 40(6): 1-11.

参考文献

[1] 严福林,王波,朱光福,等.淫羊藿属(Epimedium)植物系统分类研究进展[J].贵州科学, 2019, 37(5):37-47. DOI: 10.3969/j.issn.1003-6563.2019.05.008.
[2] HUONG N T, SON N T. Icaritin: a phytomolecule with enormous pharmacological values[J]. Phytochemistry, 2023, 213: 113772. DOI: 10.1016/j.phytochem.2023.113772.
[3] WANG M, GAO H Y, LI W H, et al. Icariin and its metabolites regulate lipid metabolism: from effects to molecular mechanisms[J]. Biomedecine Pharmacother, 2020, 131: 110675. DOI: 10.1016/j.biopha.2020.110675.
[4] LI Y Y, HUANG N Q, FENG F, et al. Icaritin improves memory and learning ability by decreasing BACE-1 expression and the Bax/bcl-2 ratio in senescence-accelerated mouse prone 8(SAMP8)mice[J]. Evid Based Complement Alternat Med, 2020, 2020: 8963845. DOI: 10.1155/2020/8963845.
[5] ZHANG W, XING B C, YANG L L, et al. Icaritin attenuates myocardial ischemia and reperfusion injury via anti-inflammatory and anti-oxidative stress effects in rats[J]. Am J Chin Med, 2015, 43(6): 1083-1097. DOI: 10.1142/S0192415X15500627.
[6] TAN E M, LI L, INDRAN I R, et al. TRAF6 mediates suppression of osteoclastogenesis and prevention of ovariectomy-induced bone loss by a novel prenylflavonoid[J]. J Bone Miner Res, 2017, 32(4): 846-860. DOI: 10.1002/jbmr.3031.
[7] ZHENG Q, LIU W W, LI B, et al. Anticancer effect of icaritin on human lung cancer cells through inducing S phase cell cycle arrest and apoptosis[J].J Huazhong Univ Sci Technolog Med Sci., 2014, 34(4): 497-503. DOI: 10.1007/s11596-014-1305-1.
[8] WU C T, YANG T H, CHEN M C, et al. Therapeutic effect of icaritin on cerebral ischemia-reperfusion-induced senescence and apoptosis in an acute ischemic stroke mouse model[J]. Molecules, 2022, 27(18): 5783. DOI: 10.3390/molecules27185783.
[9] JIANG M C, CHEN X H, ZHAO X, et al. Involvement of IGF-1 receptor signaling pathway in the neuroprotective effects of Icaritin against MPP(+)-induced toxicity in MES23.5 cells[J]. Eur J Pharmacol, 2016, 786: 53-59. DOI: 10.1016/j.ejphar.2016.05.031.
[10] LIU L M, ZHAO Z X, LU L W, et al. Icariin and icaritin ameliorated hippocampus neuroinflammation via mediating HMGB1 expression in social defeat model in mice[J]. Int Immunopharmacol, 2019, 75: 105799. DOI: 10.1016/j.intimp.2019.105799.
[11] 曾华婷,郭健,陈彦.淫羊藿素药理作用及其新型给药系统的研究进展[J].中草药, 2020, 51(20): 5372-5380. DOI: 10.7501/j.issn.0253-2670.2020.20.031.
[12] ZHANG Z K, LI J, YAN D X, et al. Icaritin inhibits collagen degradation-related factors and facilitates collagen accumulation in atherosclerotic lesions: a potential action for plaque stabilization[J]. Int J Mol Sci, 2016, 17(2): 169. DOI: 10.3390/ijms17020169.
[13] MANH N, HA,. Wedelolactone: a molecule of interests[J]. Fitoterapia, 2023, 164: 105355. DOI: 10.1016/j.fitote.2022.105355.
[14] SUN K H, MEI W H, MO S, et al. Lead exposure inhibits osteoblastic differentiation and inactivates the canonical Wnt signal and recovery by icaritin in MC3T3-E1 subclone 14 cells[J]. Chem Biol Interact, 2019, 303: 7-13. DOI: 10.1016/j.cbi.2019.01.039.
[15] LIM R, LI L, CHEW N, et al. The prenylflavonoid Icaritin enhances osteoblast proliferation and function by signal transducer and activator of transcription factor 3(STAT-3)regulation of C-X-C chemokine receptor type 4(CXCR4)expression[J]. Bone, 2017, 105: 122-133. DOI: 10.1016/j.bone.2017.08.028.
[16] DIAZ-MORALLI S, TARRADO-CASTELLARNAU M, MIRANDA A, et al. Targeting cell cycle regulation in cancer therapy[J]. Pharmacol Ther, 2013, 138(2): 255-271. DOI: 10.1016/j.pharmthera.2013.01.011.
[17] COATS S, FLANAGAN W M, NOURSE J, et al. Requirement of p27Kip1 for restriction point control of the fibroblast cell cycle[J]. Science, 1996, 272(5263): 877-880. DOI: 10.1126/science.272.5263.877.
[18] ZHANG C, WANG X, ZHANG C B. Icaritin inhibits CDK2 expression and activity to interfere with tumor progression[J]. iScience, 2022, 25(9): 104991. DOI: 10.1016/j.isci.2022.104991.
[19] GU Y, CHEN T X, LÓPEZ E, et al. The therapeutic target of estrogen receptor-alpha36 in estrogen-dependent tumors[J]. J Transl Med, 2014, 12: 16. DOI: 10.1186/1479-5876-12-16.
[20] WANG X, ZHENG N, DONG J, et al. Estrogen receptor-α36 is involved in icaritin induced growth inhibition of triple-negative breast cancer cells[J]. J Steroid Biochem Mol Biol, 2017, 171: 318-327. DOI: 10.1016/j.jsbmb.2017.05.009.
[21] LI C F, PENG W C, SONG X, et al. Anticancer effect of icaritin inhibits cell growth of colon cancer through reactive oxygen species, Bcl-2 and cyclin D1/E signaling[J]. Oncol Lett, 2016, 12(5): 3537-3542. DOI: 10.3892/ol.2016.5089.
[22] SHARILI A S, ALLEN S, SMITH K, et al. Snail2 promotes osteosarcoma cell motility through remodelling of the actin cytoskeleton and regulates tumor development[J]. Cancer Lett, 2013, 333(2): 170-179. DOI: 10.1016/j.canlet.2013.01.027.
[23] HUANG X, ZHU D Y, LOU Y J. A novel anticancer agent, icaritin, induced cell growth inhibition, G1 arrest and mitochondrial transmembrane potential drop in human prostate carcinoma PC-3 cells[J]. Eur J Pharmacol, 2007, 564(1/2/3): 26-36. DOI: 10.1016/j.ejphar.2007.02.039.
[24] GUO Y M, ZHANG X T, MENG J, et al. An anticancer agent icaritin induces sustained activation of the extracellular signal-regulated kinase(ERK)pathway and inhibits growth of breast cancer cells[J]. Eur J Pharmacol, 2011, 658(2/3): 114-122. DOI: 10.1016/j.ejphar.2011.02.005.
[25] FARES J, FARES M Y, KHACHFE H H, et al. Molecular principles of metastasis: a hallmark of cancer revisited[J]. Signal Transduct Target Ther, 2020, 5(1): 28. DOI: 10.1038/s41392-020-0134-x.
[26] YE XIN, WEINBERG R A. Epithelial-mesenchymal plasticity: a central regulator of cancer progression[J]. Trends Cell Biol, 2015, 25(11): 675-686. DOI: 10.1016/j.tcb.2015.07.012.
[27] KESSENBROCK K, PLAKS V, WERB Z. Matrix metalloproteinases: regulators of the tumor microenvironment[J]. Cell, 2010, 141(1): 52-67. DOI: 10.1016/j.cell.2010.03.015.
[28] XU B, JIANG C W, HAN H X, et al. Icaritin inhibits the invasion and epithelial-to-mesenchymal transition of glioblastoma cells by targeting EMMPRIN via PTEN/AKt/HIF-1α signalling[J]. Clin Exp Pharmacol Physiol, 2015, 42(12): 1296-1307. DOI: 10.1111/1440-1681.12488.
[29] WANG X F, WANG J. Icaritin suppresses the proliferation of human osteosarcoma cells in vitro by increasing apoptosis and decreasing MMP expression[J]. Acta Pharmacol Sin, 2014, 35(4): 531-539. DOI: 10.1038/aps.2013.178.
[30] ZHAO X Q, LIN Y, JIANG B J, et al. Icaritin inhibits lung cancer-induced osteoclastogenesis by suppressing the expression of IL-6 and TNF-a and through AMPK/mTOR signaling pathway[J]. Anticancer Drugs, 2020, 31(10): 1004-1011. DOI: 10.1097/CAD.0000000000000976.
[31] MAJIDPOOR J, MORTEZAEE K. Steps in metastasis: an updated review[J]. Med Oncol, 2021, 38(1): 3. DOI: 10.1007/s12032-020-01447-w.
[32] TU S M, MAO D X, SHI M X, et al. Icaritin ameliorates extracellular microparticles-induced inflammatory pre-metastatic niche via modulating the cGAS-STING signaling[J]. Phytother Res, 2022, 36(5): 2127-2142. DOI: 10.1002/ptr.7433.
[33] WONG R S Y. Apoptosis in cancer: from pathogenesis to treatment[J]. J Exp Clin Cancer Res, 2011, 30(1): 87. DOI: 10.1186/1756-9966-30-87.
[34] ASHKENAZI A. Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions[J]. J Clin Invest, 2015, 125(2): 487-489. DOI: 10.1172/JCI80420.
[35] WU T, WANG S M, WU J F, et al. Icaritin induces lytic cytotoxicity in extranodal NK/T-cell lymphoma[J]. J Exp Clin Cancer Res, 2015, 34(1): 17. DOI: 10.1186/s13046-015-0133-x.
[36] XIANG L L, LI Y, GU X Y, et al. Nucleolin recognizing silica nanoparticles inhibit cell proliferation by activating the Bax/Bcl-2/caspase-3 signalling pathway to induce apoptosis in liver cancer[J]. Front Pharmacol, 2023, 14: 1117052. DOI: 10.3389/fphar.2023.1117052.
[37] LI H, LIU Y J, JIANG W, et al. Icaritin promotes apoptosis and inhibits proliferation by down-regulating AFP gene expression in hepatocellular carcinoma[J]. BMC Cancer, 2021, 21(1): 318. DOI: 10.1186/s12885-021-08043-9.
[38] JIN L M, MIAO J H, LIU Y J, et al. Icaritin induces mitochondrial apoptosis by up-regulating miR-124 in human oral squamous cell carcinoma cells[J]. Biomedecine Pharmacother, 2017, 85: 287-295. DOI: 10.1016/j.biopha.2016.11.023.
[39] SUN L, PENG Q S, QU L L, et al. Anticancer agent icaritin induces apoptosis through caspase-dependent pathways in human hepatocellular carcinoma cells[J]. Mol Med Rep, 2015, 11(4): 3094-3100. DOI: 10.3892/mmr.2014.3007.
[40] CHAE H S, HONG S T. Overview of cancer metabolism and signaling transduction[J]. Int J Mol Sci, 2022, 24(1): 12. DOI: 10.3390/ijms24010012.
[41] PIETROBON V. Cancer metabolism[J]. J Transl Med, 2021, 19(1): 87. DOI: 10.1186/s12967-021-02753-1.
[42] AKI S, NAKAHARA R, MAEDA K, et al. Cancer metabolism within tumor microenvironments[J]. Biochim Biophys Acta Gen Subj, 2023, 1867(5): 130330. DOI: 10.1016/j.bbagen.2023.130330.
[43] 邓冬杰,李励,谈相云,等.淫羊藿素通过Akt/mTOR调控糖酵解抑制肝内胆管癌细胞增殖的作用机制研究[J].中草药, 2022, 53(10):3061-3069. DOI: 10.7501/j.issn.0253-2670.2022.10.016.
[44] GRIVENNIKOV S I, GRETEN F R, KARIN M. Immunity, inflammation, and cancer[J]. Cell, 2010, 140(6): 883-899. DOI: 10.1016/j.cell.2010.01.025.
[45] KSIZ·AKOWSKA-ŁAKOMA K, Z·YŁA M, WILCZYSKI J R. Mitochondrial dysfunction in cancer[J]. Przeglad Menopauzalny, 2014, 13(2): 136-144. DOI: 10.5114/pm.2014.42717.
[46] LI H, LIANG Q, WANG L. Icaritin inhibits glioblastoma cell viability and glycolysis by blocking the IL-6/Stat3 pathway[J]. J Cell Biochem, 2019, 120(5): 7257-7264. DOI: 10.1002/jcb.28000.
[47] ZHENG X, GOU Y D, JIANG Z Y, et al. Icaritin-induced FAM99A affects GLUT1-mediated glycolysis via regulating the JAK2/STAT3 pathway in hepatocellular carcinoma[J]. Front Oncol, 2021, 11: 740557. DOI: 10.3389/fonc.2021.740557.
[48] BAXEVANIS C N, PEREZ S A, PAPAMICHAIL M. Cancer immunotherapy[J]. Crit Rev Clin Lab Sci, 2009, 46(4): 167-189. DOI: 10.1080/10408360902937809.
[49] TAO H M, LIU M Y, WANG Y, et al. Icaritin induces anti-tumor immune responses in hepatocellular carcinoma by inhibiting splenic myeloid-derived suppressor cell generation[J]. Front Immunol, 2021, 12: 609295. DOI: 10.3389/fimmu.2021.609295.
[50] ZHOU J M, WU J F, CHEN X H, et al. Icariin and its derivative, ICT, exert anti-inflammatory, anti-tumor effects, and modulate myeloid derived suppressive cells(MDSCs)functions[J]. Int Immunopharmacol, 2011, 11(7): 890-898. DOI: 10.1016/j.intimp.2011.01.007.
[51] MO D L, ZHU H, WANG J, et al. Icaritin inhibits PD-L1 expression by targeting protein IκB kinase Α[J]. Eur J Immunol, 2021, 51(4): 978-988. DOI: 10.1002/eji.202048905.
[52] HAO H B, ZHANG Q, ZHU H, et al. Icaritin promotes tumor T-cell infiltration and induces antitumor immunity in mice[J]. Eur J Immunol, 2019, 49(12): 2235-2244. DOI: 10.1002/eji.201948225.
[53] SHIRLEY S, MICHEAU O. Targeting c-FLIP in cancer[J]. Cancer Lett, 2013, 332(2): 141-150. DOI: 10.1016/j.canlet.2010.10.009.
[54] HAN H X, XU B, HOU P Z, et al. Icaritin sensitizes human glioblastoma cells to TRAIL-induced apoptosis[J]. Cell Biochem Biophys, 2015, 72(2): 533-542. DOI: 10.1007/s12013-014-0499-y.
[55] ZHAO H, GUO Y M, LI S, et al. A novel anti-cancer agent Icaritin suppresses hepatocellular carcinoma initiation and malignant growth through the IL-6/Jak2/Stat3 pathway[J]. Oncotarget, 2015, 6(31): 31927-31943. DOI: 10.18632/oncotarget.5578.
[56] CEBALLOS M P, RIGALLI J P, CERÉ L I, et al. ABC transporters: regulation and association with multidrug resistance in hepatocellular carcinoma and colorectal carcinoma[J]. Curr Med Chem, 2019, 26(7): 1224-1250. DOI: 10.2174/0929867325666180105103637.
[57] SUN L, CHEN W G, QU L L, et al. Icaritin reverses multidrug resistance of HepG2/ADR human hepatoma cells via downregulation of MDR1 and P-glycoprotein expression[J]. Mol Med Rep, 2013, 8(6): 1883-1887. DOI: 10.3892/mmr.2013.1742.
[58] PAN X W, LI L, HUANG Y, et al. Icaritin acts synergistically with epirubicin to suppress bladder cancer growth through inhibition of autophagy[J]. Oncol Rep, 2016, 35(1): 334-342. DOI: 10.3892/or.2015.4335.
[59] YU Z, GUO J F, HU M Y, et al. Icaritin exacerbates mitophagy and synergizes with doxorubicin to induce immunogenic cell death in hepatocellular carcinoma[J]. ACS Nano, 2020, 14(4): 4816-4828. DOI: 10.1021/acsnano.0c00708.
[60] ZHU S C, XING C, ZHANG G S, et al. Icaritin induces cellular senescence by accumulating the ROS production and regulation of the Jak2/Stat3/p21 pathway in imatinib-resistant, chronic myeloid leukemia cells[J]. Am J Transl Res, 2021, 13(8): 8860-8872.