

浏览全部资源
扫码关注微信
1.湖南中医药大学,长沙 410208
2.湖南中医药大学 第一附属医院,长沙 410007
3.湖南省中医药防治眼耳鼻咽喉疾病与视功能保护工程技术研究中心,长沙 410208
4.中医药防治眼耳鼻咽喉疾病湖南省重点实验室,长沙 410208
Received:23 July 2021,
Published Online:20 August 2021,
Published:20 October 2021
移动端阅览
钟文良,熊雨,王贤文等.山柰酚抗肿瘤效应与机制研究进展[J].中国实验方剂学杂志,2021,27(20):219-226.
ZHONG Wen-liang,XIONG Yu,WANG Xian-wen,et al.Anti-tumor Effect and Mechanism of Kaempferol: A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(20):219-226.
钟文良,熊雨,王贤文等.山柰酚抗肿瘤效应与机制研究进展[J].中国实验方剂学杂志,2021,27(20):219-226. DOI: 10.13422/j.cnki.syfjx.20212025.
ZHONG Wen-liang,XIONG Yu,WANG Xian-wen,et al.Anti-tumor Effect and Mechanism of Kaempferol: A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2021,27(20):219-226. DOI: 10.13422/j.cnki.syfjx.20212025.
癌症威胁人类健康,新治疗手段应用于癌症治疗能显著延长患者生存时间,但并未改善放化疗患者的不良反应,提高患者的预后仍需癌症研究学者的不断努力。近年来,中药有效成分的抗肿瘤作用受到广泛关注。山柰酚为黄酮类化合物,主要存在于药用植物山柰中,可用于治疗肥胖、心血管疾病、糖尿病等疾病,且具有良好的抗癌活性,能抑制肝癌、结肠癌、肺癌及卵巢癌等多种恶性肿瘤的发生发展。山柰酚主要抗癌形式为诱导细胞凋亡,通过促使细胞内活性氧(ROS)的生成,诱导细胞发生线粒体途径凋亡。山柰酚还可以通过干扰癌细胞周期,使多数癌细胞周期阻滞在G
2
/M期,并通过诱导细胞自噬发生程序性死亡,抑制细胞迁移侵袭以及血管生成,协同提高化疗药物疗效、减少不良反应等方面发挥抗肿瘤效应。山柰酚作用于一系列细胞内和细胞外靶点,参与肿瘤细胞信号通路调节,涉及磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt),表皮生长因子受体(EGFR),丝裂原活化蛋白激酶(MAPK),Wnt等信号通路,但以调控PI3K/Akt信号通路为主。此外,山柰酚在肿瘤表观遗传学中也发挥重要的调控作用。笔者对山柰酚抗肿瘤活性及其机制研究进行综述,为山柰酚防治肿瘤的深入研究以及抗肿瘤药物的研发提供参考。
Cancer is a threat to human health. New treatments for cancer can significantly prolong the survival time of patients, but fail to improve the adverse reactions induced by chemoradiotherapy. Improving patient outcomes still requires the effort of cancer researchers. In recent years, the anti-tumor effects of active components from Chinese herbs have received wide attention. Kaempferol, a flavonoid mainly found in the medicinal plant
Kaempferia galanga
, can be used to treat obesity, cardiovascular diseases, diabetes and other diseases. It has also exhibited good efficacy in inhibiting the occurrence and development of liver cancer, colon cancer, lung cancer, ovarian cancer, and other malignant tumors. Kaempferol mainly exerts the anti-cancer effect by inducing apoptosis. Specifically, it promotes the production of intracellular reactive oxygen species (ROS) and triggers cell apoptosis through the mitochondrial pathway. Besides, it is capable of interfering with the cancer cell cycle, causing most cancer cells to arrest in the G
2
/M phase, and inducing cell autophagy, a programmed cell death, thus inhibiting cell migration and invasion and angiogenesis, synergistically improving chemotherapeutic drug efficacy, and reducing adverse effects. Kaempferol acts on a series of intracellular and extracellular targets to participate in the regulation of tumor cell signaling pathways, involving phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), epidermal growth factor receptor (EGFR), mitogen activated protein kinase (MAPK), and Wnt signaling pathways, with the PI3K/Akt signaling pathway being most significant. In addition, kaempferol also plays an important regulatory role in tumor epigenetics. This paper reviewed the anti-tumor effect and mechanism of kaempferol, aiming to provide reference for in-depth study on its prevention and treatment of tumor and the development of new anti-tumor drugs.
SUNG H , FERLAY J , SIEGEL R L , et al . Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries [J]. CA Cancer J Clin , 2021 , 71 ( 3 ): 209 - 249 .
ZHANG Y , CHEN L , HU G Q , et al . Gemcitabine and cisplatin induction chemotherapy in nasopharyngeal carcinoma [J]. N Engl J Med , 2019 , 381 ( 12 ): 1124 - 1135 .
CHEN R , MANOCHAKIAN R , JAMES L , et al . Emerging therapeutic agents for advanced non-small cell lung cancer [J]. J Hematol Oncol , 2020 , doi: 10.1186/s13045-020-00881-7 http://dx.doi.org/10.1186/s13045-020-00881-7 .
XIANG Y , GUO Z , ZHU P , et al . Traditional Chinese medicine as a cancer treatment: modern perspectives of ancient but advanced science [J]. Cancer Med , 2019 , 8 ( 5 ): 1958 - 1975 .
李小江 , 邬明歆 , 孔凡铭 , 等 . 中药有效成分抗肿瘤活性及作用机制研究进展 [J]. 中草药 , 2020 , 51 ( 9 ): 2587 - 2592 .
XIAO Y , XIN L , LI L , et al . Quercetin and kaempferol increase the intestinal absorption of isorhamnetin coexisting in Elaeagnus rhamnoides (L.) A. Nelson (Elaeagnaceae) extracts via regulating multidrug resistance-associated protein 2 [J]. Phytomedicine , 2019 , doi: 10.1016/j.phymed.2018.09.028 http://dx.doi.org/10.1016/j.phymed.2018.09.028 .
郑丹丹 , 阮静雅 , 张颖 , 等 . 蛇床子中黄酮类化学成分的分离与结构鉴定 [J]. 中国药物化学杂志 , 2020 , 30 ( 9 ): 542 - 548 .
ALAM W , KHAN H , SHAH M A , et al . Kaempferol as a dietary anti-inflammatory agent: current therapeutic standing [J]. Molecules , 2020 , doi: 10.3390/molecules25184073 http://dx.doi.org/10.3390/molecules25184073 .
FENG X L , ZHAN X X , ZUO L S , et al . Associations between serum concentration of flavonoids and breast cancer risk among Chinese women [J]. Eur J Nutr , 2021 , 60 ( 3 ): 1347 - 1362 .
王丽君 , 戴志升 . 山柰酚对胃癌细胞PARP1以及p53基因表达的影响研究 [J]. 基因组学与应用生物学 , 2020 , 39 ( 3 ): 1270 - 1274 .
QIN Y , CUI W , YANG X , et al . Kaempferol inhibits the growth and metastasis of cholangiocarcinoma in vitro and in vivo [J]. Acta Biochim Biophys Sin (Shanghai) , 2016 , 48 ( 3 ): 238 - 245 .
张敬 , 史晓宇 , 孟玮 , 等 . 山柰酚通过下调ERRα抑制非小细胞肺癌A549细胞的侵袭和迁移 [J]. 中国肿瘤生物治疗杂志 , 2018 , 25 ( 12 ): 1230 - 1236 .
陈育华 , 周克元 , 袁汉尧 . 山柰酚抑制人鼻咽癌CNE-2细胞增殖及诱导其凋亡的实验研究 [J]. 中国现代医学杂志 , 2011 , 21 ( 34 ): 4265 - 4268,4274 .
李鹰飞 , 曾世彬 , 邱华平 , 等 . 山柰酚对乳腺癌细胞增殖及诱导凋亡的作用研究及机制 [J]. 中国临床药理学杂志 , 2020 , 36 ( 22 ): 3679 - 3682 .
LEI X , GUO J , WANG Y , et al . Inhibition of endometrial carcinoma by kaempferol is interceded through apoptosis induction, G 2 /M phase cell cycle arrest, suppression of cell invasion and upregulation of mTOR/PI3K signalling pathway [J]. J BUON , 2019 , 24 ( 4 ): 1555 - 1561 .
HAN X , LIU C F , GAO N , et al . Kaempferol suppresses proliferation but increases apoptosis and autophagy by up-regulating microRNA-340 in human lung cancer cells [J]. Biomed Pharmacother , 2018 , doi: 10.1016/j.biopha.2018.09.087 http://dx.doi.org/10.1016/j.biopha.2018.09.087 .
仇炜 , 雷宇华 , 苏明 , 等 . 下调PCNA和VCAM-1表达参与山柰酚抑制人前列腺癌细胞增殖 [J]. 中国药理学通报 , 2011 , 27 ( 4 ): 553 - 557 .
JEONG J C , KIM M S , KIM T H , et al . Kaempferol induces cell death through ERK and Akt-dependent down-regulation of XIAP and survivin in human glioma cells [J]. Neurochem Res , 2009 , 34 ( 5 ): 991 - 1001 .
ACKLAND M L , VAN DE WAARSENBURG S , JONES R . Synergistic antiproliferative action of the flavonols quercetin and kaempferol in cultured human cancer cell lines [J]. In Vivo , 2005 , 19 ( 1 ): 69 - 76 .
YAO S , WANG X , LI C , et al . Kaempferol inhibits cell proliferation and glycolysis in esophagus squamous cell carcinoma via targeting EGFR signaling pathway [J]. Tumour Biol , 2016 , 37 ( 8 ): 10247 - 10256 .
EVAN G I , VOUSDEN K H . Proliferation, cell cycle and apoptosis in cancer [J]. Nature , 2001 , 411 ( 6835 ): 342 - 348 .
SONG H , BAO J , WEI Y , et al . Kaempferol inhibits gastric cancer tumor growth: an in vitro and in vivo study [J]. Oncol Rep , 2015 , 33 ( 2 ): 868 - 874 .
GAO Y , YIN J , RANKIN G O , et al . Kaempferol Induces G 2 /M cell cycle arrest via checkpoint kinase 2 and promotes apoptosis via death receptors in human ovarian carcinoma A2780/CP70 cells [J]. Molecules , 2018 , doi: 10.3390/molecules23051095 http://dx.doi.org/10.3390/molecules23051095 .
ZHU L , XUE L . Kaempferol Suppresses proliferation and induces cell cycle arrest, apoptosis, and DNA damage in breast cancer cells [J]. Oncol Res , 2019 , 27 ( 6 ): 629 - 634 .
陈卓 , 刘胜楠 , 吴克俭 , 等 . 不同剂量山柰酚对胰腺癌细胞株PANC-1增殖、凋亡的影响及机制探讨 [J]. 山东医药 , 2018 , 58 ( 3 ): 27 - 30 .
TREML J , ŠMEJKAL K . Flavonoids as potent scavengers of hydroxyl radicals [J]. Compr Rev Food Sci Food Saf , 2016 , 15 ( 4 ): 720 - 738 .
KUMAR A D , BEVARA G B , KAJA L K , et al . Protective effect of 3- O -methyl quercetin and kaempferol from Semecarpus anacardium against H 2 O 2 induced cytotoxicity in lung and liver cells [J]. BMC Complement Altern Med , 2016 , doi: 10.1186/s12906-016-1354-z http://dx.doi.org/10.1186/s12906-016-1354-z .
LIAO W , CHEN L , MA X , et al . Protective effects of kaempferol against reactive oxygen species-induced hemolysis and its antiproliferative activity on human cancer cells [J]. Eur J Med Chem , 2016 , doi: 10.1016/j.ejmech.2016.02.045 http://dx.doi.org/10.1016/j.ejmech.2016.02.045 .
SEYDI E , SALIMI A , RASEKH H R , et al . Selective cytotoxicity of luteolin and kaempferol on cancerous hepatocytes obtained from rat model of hepatocellular carcinoma: involvement of ROS-mediated mitochondrial targeting [J]. Nutr Cancer , 2018 , 70 ( 4 ): 594 - 604 .
WANG F , WANG L , QU C , et al . Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling [J]. BMC Cancer , 2021 , 21 ( 1 ): 396 .
MAJUMDER D , DAS A , SAHA C . Catalase inhibition an anti cancer property of flavonoids: a kinetic and structural evaluation [J]. Int J Biol Macromol , 2017 , 104 ( Pt A ): 929 - 935 .
ARIF H , REHMANI N , FARHAN M , et al . Mobilization of copper ions by flavonoids in human peripheral lymphocytes leads to oxidative DNA breakage: a structure activity study [J]. Int J Mol Sci , 2015 , 16 ( 11 ): 26754 - 26769 .
SIMUNKOVA M , BARBIERIKOVA Z , JOMOVA K , et al . Antioxidant vs. prooxidant properties of the flavonoid, kaempferol, in the presence of Cu(Ⅱ) iIons: a ROS-scavenging activity, fenton reaction and DNA damage study [J]. Int J Mol Sci , 2021 , doi: 10.3390/ijms22041619 http://dx.doi.org/10.3390/ijms22041619 .
WU L Y , LU H F , CHOU Y C , et al . Kaempferol induces DNA damage and inhibits DNA repair associated protein expressions in human promyelocytic leukemia HL-60 cells [J]. Am J Chin Med , 2015 , 43 ( 2 ): 365 - 382 .
FOUZDER C , MUKHUTY A , KUNDU R . Kaempferol inhibits Nrf2 signalling pathway via downregulation of Nrf2 mRNA and induces apoptosis in NSCLC cells [J]. Arch Biochem Biophys , 2021 , doi: 10.1016/j.abb.2020.108700 http://dx.doi.org/10.1016/j.abb.2020.108700 .
KASHAFI E , MORADZADEH M , MOHAMADKHANI A , et al . Kaempferol increases apoptosis in human cervical cancer HeLa cells via PI3K/Akt and telomerase pathways [J]. Biomed Pharmacother , 2017 , doi: 10.1016/j.biopha.2017.02.061 http://dx.doi.org/10.1016/j.biopha.2017.02.061 .
HUANG W W , CHIU Y J , FAN M J , et al . Kaempferol induced apoptosis via endoplasmic reticulum stress and mitochondria-dependent pathway in human osteosarcoma U-2 OS cells [J]. Mol Nutr Food Res , 2010 , 54 ( 11 ): 1585 - 1595 .
HEO J R , LEE G A , KIM G S , et al . Phytochemical-induced reactive oxygen species and endoplasmic reticulum stress-mediated apoptosis and differentiation in malignant melanoma cells [J]. Phytomedicine , 2018 , doi: 10.1016/j.phymed.2017.12.006 http://dx.doi.org/10.1016/j.phymed.2017.12.006 .
ZHAO Y , TIAN B , WANG Y , et al . Kaempferol sensitizes human ovarian cancer cells-OVCAR-3 and SKOV-3 to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis via JNK/ERK-CHOP pathway and up-regulation of death receptors 4 and 5 [J]. Med Sci Monit , 2017 , doi: 10.12659/msm.903552 http://dx.doi.org/10.12659/msm.903552 .
ASHRAFIZADEH M , TAVAKOL S , AHMADI Z , et al . Therapeutic effects of kaempferol affecting autophagy and endoplasmic reticulum stress [J]. Phytother Res , 2020 , 34 ( 5 ): 911 - 923 .
KIM T W , LEE S Y , KIM M , et al . Kaempferol induces autophagic cell death via IRE1-JNK-CHOP pathway and inhibition of G9a in gastric cancer cells [J]. Cell Death Dis , 2018 , 9 ( 9 ): 875 .
CHEN S , MA J , YANG L , et al . Anti-glioblastoma activity of kaempferol via programmed cell death induction: involvement of autophagy and pyroptosis [J]. Front Bioeng Biotechnol , 2020 , doi: 10.3389/fbioe.2020.614419 http://dx.doi.org/10.3389/fbioe.2020.614419 .
HUANG W W , TSAI S C , PENG S F , et al . Kaempferol induces autophagy through AMPK and Akt signaling molecules and causes G 2 /M arrest via downregulation of CDK1/cyclin B in SK-HEP-1 human hepatic cancer cells [J]. Int J Oncol , 2013 , 42 ( 6 ): 2069 - 2077 .
LIANG S Q , MARTI T M , DORN P , et al . Blocking the epithelial-to-mesenchymal transition pathway abrogates resistance to anti-folate chemotherapy in lung cancer [J]. Cell Death Dis , 2015 , doi: 10.1038/cddis.2015.195 http://dx.doi.org/10.1038/cddis.2015.195 .
张炜 , 全昆 , 宋祖琪 , 等 . 山柰酚抑制EMT阻断神经胶质瘤细胞侵袭和转移 [J]. 时珍国医国药 , 2020 , 31 ( 5 ): 1097 - 1101 .
EBLE J A , NILAND S . The extracellular matrix in tumor progression and metastasis [J]. Clin Exp Metastasis , 2019 , 36 ( 3 ): 171 - 198 .
CHEN H J , LIN C M , LEE C Y , et al . Kaempferol suppresses cell metastasis via inhibition of the ERK-p38-JNK and AP-1 signaling pathways in U-2 OS human osteosarcoma cells [J]. Oncol Rep , 2013 , 30 ( 2 ): 925 - 932 .
HUNG T W , CHEN P N , WU H C , et al . Kaempferol inhibits the invasion and migration of renal cancer cells through the downregulation of Akt and FAK pathways [J]. Int J Med Sci , 2017 , 14 ( 10 ): 984 - 993 .
LEE J , KIM J H . Kaempferol inhibits pancreatic cancer cell growth and migration through the blockade of egfr-related pathway in vitro [J]. PLoS One , 2016 , doi: 10.1371/journal.pone.0155264 http://dx.doi.org/10.1371/journal.pone.0155264 .
YANG G , XING J , AIKEMU B , et al . Kaempferol exhibits a synergistic effect with doxorubicin to inhibit proliferation, migration, and invasion of liver cancer [J]. Oncol Rep , 2021 , doi: 10.3892/or.2021.7983 http://dx.doi.org/10.3892/or.2021.7983 .
吴骞 , 丁榆德 , 程刚 . 山柰酚通过PI3K/Akt信号通路对口腔癌细胞增殖、侵袭及迁移的影响 [J]. 中药材 , 2020 ( 12 ): 3045 - 3049 .
黄茂莘 , 陈玲 , 韩鹏定 , 等 . 山柰酚通过Wnt/ β -catenin信号通路抑制HBx-HepG2细胞增殖、侵袭及迁移 [J]. 中国病理生理杂志 , 2017 , 33 ( 8 ): 1417 - 1422 .
LI S , YAN T , DENG R , et al . Low dose of kaempferol suppresses the migration and invasion of triple-negative breast cancer cells by downregulating the activities of RhoA and Rac1 [J]. Onco Targets Ther , 2017 , doi: 10.2147/OTT.S140886 http://dx.doi.org/10.2147/OTT.S140886 .
CHIN H K , HORNG C T , LIU Y S , et al . Kaempferol inhibits angiogenic ability by targeting VEGF receptor-2 and downregulating the PI3K/Akt, MEK and ERK pathways in VEGF-stimulated human umbilical vein endothelial cells [J]. Oncol Rep , 2018 , 39 ( 5 ): 2351 - 2357 .
LEE C F , YANG J S , TSAI F J , et al . Kaempferol induces ATM/p53-mediated death receptor and mitochondrial apoptosis in human umbilical vein endothelial cells [J]. Int J Oncol , 2016 , 48 ( 5 ): 2007 - 2014 .
WANG J Q , YANG Y , CAI C Y , et al . Multidrug resistance proteins (MRPs): structure, function and the overcoming of cancer multidrug resistance [J]. Drug Resist Updat , 2021 , doi: 10.1016/j.drup.2021.100743 http://dx.doi.org/10.1016/j.drup.2021.100743 .
MORADZADEH M , TABARRAEI A , SADEGHNIA H R , et al . Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes [J]. J Cell Biochem , 2018 , 119 ( 2 ): 2288 - 2297 .
LUO H , DADDYSMAN M K , RANKIN G O , et al . Kaempferol enhances cisplatin's effect on ovarian cancer cells through promoting apoptosis caused by down regulation of cMyc [J]. Cancer Cell Int , 2010 , doi: 10.1186/1475-2867-10-16 http://dx.doi.org/10.1186/1475-2867-10-16 .
LI Q , WEI L , LIN S , et al . Synergistic effect of kaempferol and 5‑fluorouracil on the growth of colorectal cancer cells by regulating the PI3K/Akt signaling pathway [J]. Mol Med Rep , 2019 , 20 ( 1 ): 728 - 734 .
KUO W T , TSAI Y C , WU H C , et al . Radiosensitization of non-small cell lung cancer by kaempferol [J]. Oncol Rep , 2015 , 34 ( 5 ): 2351 - 2356 .
LU L , WANG Y , OU R , et al . DACT2 epigenetic stimulator exerts dual efficacy for colorectal cancer prevention and treatment [J]. Pharmacol Res , 2018 , doi: 10.1016/j.phrs.2017.11.032 http://dx.doi.org/10.1016/j.phrs.2017.11.032 .
QIU W , LIN J , ZHU Y , et al . Kaempferol modulates DNA methylation and downregulates DNMT3B in bladder cancer [J]. Cell Physiol Biochem , 2017 , 41 ( 4 ): 1325 - 1335 .
BERGER A , VENTURELLI S , KALLNISCHKIES M , et al . Kaempferol, a new nutrition-derived pan-inhibitor of human histone deacetylases [J]. J Nutr Biochem , 2013 , 24 ( 6 ): 977 - 985 .
杨生辉 , 黄琰菁 , 莫安薇 , 等 . 山柰酚通过调控miR21抑制非小细胞肺癌A549细胞增殖的研究 [J]. 中国现代应用药学 , 2020 , 37 ( 13 ): 1557 - 1562 .
YANG L , LI H , YANG M , et al . Exploration in the mechanism of kaempferol for the treatment of gastric cancer based on network pharmacology [J]. Biomed Res Int , 2020 , doi: 10.1155/2020/5891016 http://dx.doi.org/10.1155/2020/5891016 .
张永文 , 唐溱 , 赵晓霞 . 对山柰酚与山柰素中文名称的辨正及其在有关药品标准中的正确使用 [J]. 中国药品标准 , 2019 , 20 ( 3 ): 201 - 204 .
COLOMBO M , FIGUEIRó F , DE FRAGA DIAS A , et al . Kaempferol-loaded mucoadhesive nanoemulsion for intranasal administration reduces glioma growth in vitro [J]. Int J Pharm , 2018 , 543 ( 1/2 ): 214 - 223 .
GOVINDARAJU S , ROSHINI A , LEE M H , et al . Kaempferol conjugated gold nanoclusters enabled efficient for anticancer therapeutics to A549 lung cancer cells [J]. Int J Nanomedicine , 2019 , doi: 10.2147/IJN.S209773 http://dx.doi.org/10.2147/IJN.S209773 .
0
Views
20
下载量
3
CSCD
Publicity Resources
Related Articles
Related Author
Related Institution
京公网安备11010802024621