An Insight into the Anti-Angiogenic and Anti-Metastatic Effects of Oridonin: Current Knowledge and Future Potential

Cancer is one of the leading causes of death worldwide, with a mortality rate of more than 9 million deaths reported in 2018. Conventional anti-cancer therapy can greatly improve survival however treatment resistance is still a major problem especially in metastatic disease. Targeted anti-cancer therapy is increasingly used with conventional therapy to improve patients’ outcomes in advanced and metastatic tumors. However, due to the complexity of cancer biology and metastasis, it is urgent to develop new agents and evaluate the anti-cancer efficacy of available treatments. Many phytochemicals from medicinal plants have been reported to possess anti-cancer properties. One such compound is known as oridonin, a bioactive component of Rabdosia rubescens. Several studies have demonstrated that oridonin inhibits angiogenesis in various types of cancer, including breast, pancreatic, lung, colon and skin cancer. Oridonin’s anti-cancer effects are mediated through the modulation of several signaling pathways which include upregulation of oncogenes and pro-angiogenic growth factors. Furthermore, oridonin also inhibits cell migration, invasion and metastasis via suppressing epithelial-to-mesenchymal transition and blocking downstream signaling targets in the cancer metastasis process. This review summarizes the recent applications of oridonin as an anti-angiogenic and anti-metastatic drug both in vitro and in vivo, and its potential mechanisms of action.

[1]  Z. Werb,et al.  Concepts of extracellular matrix remodelling in tumour progression and metastasis , 2020, Nature Communications.

[2]  Tao Chen,et al.  Oridonin inhibits 4T1 tumor growth by suppressing Treg differentiation via TGF-β receptor. , 2020, International immunopharmacology.

[3]  H. Bu,et al.  AMPK/mTOR/ULK1 Axis-Mediated Pathway Participates in Apoptosis and Autophagy Induction by Oridonin in Colon Cancer DLD-1 Cells , 2020, OncoTargets and therapy.

[4]  Jiye Cai,et al.  Oridonin exhibits anti-angiogenic activity in human umbilical vein endothelial cells by inhibiting VEGF-induced VEGFR-2 signaling pathway. , 2020, Pathology, research and practice.

[5]  Hong-Jian Zhu,et al.  On-Target Anti-TGF-β Therapies Are Not Succeeding in Clinical Cancer Treatments: What Are Remaining Challenges? , 2020, Frontiers in Cell and Developmental Biology.

[6]  Zhuocheng Zhang,et al.  Oridonin inhibits the migration and epithelial‐to‐mesenchymal transition of small cell lung cancer cells by suppressing FAK‐ERK1/2 signalling pathway , 2020, Journal of cellular and molecular medicine.

[7]  M. Fares,et al.  Molecular principles of metastasis: a hallmark of cancer revisited , 2020, Signal Transduction and Targeted Therapy.

[8]  Ying Xu,et al.  ERK/MAPK signalling pathway and tumorigenesis , 2020, Experimental and therapeutic medicine.

[9]  S. Tsang,et al.  Mechanistic Pathways and Molecular Targets of Plant-Derived Anticancer ent-Kaurane Diterpenes , 2020, Biomolecules.

[10]  A. Ehinger,et al.  Expression of HIF-1α is related to a poor prognosis and tamoxifen resistance in contralateral breast cancer , 2019, PloS one.

[11]  Qian Zhou,et al.  Oridonin induces apoptosis in HGC-27 cells by activating the JNK signaling pathway , 2019, Oncology letters.

[12]  M. Xie,et al.  Role of hypoxia in cancer therapy by regulating the tumor microenvironment , 2019, Molecular Cancer.

[13]  Yitao Wang,et al.  Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine , 2019, Chinese Medicine.

[14]  A. Dimberg,et al.  Tumor angiogenesis: causes, consequences, challenges and opportunities , 2019, Cellular and Molecular Life Sciences.

[15]  Yuan Liao,et al.  Oridonin inhibits hypoxia-induced epithelial-mesenchymal transition and cell migration by the hypoxia-inducible factor-1α/matrix metallopeptidase-9 signal pathway in gallbladder cancer. , 2019, Anti-cancer drugs.

[16]  F. Shen,et al.  The inhibitory effect of oridonin on colon cancer was mediated by deactivation of TGF-β1/Smads-PAI-1 signaling pathway in vitro and vivo , 2019, OncoTargets and therapy.

[17]  X. Ci,et al.  Oridonin Sensitizes Cisplatin-Induced Apoptosis via AMPK/Akt/mTOR-Dependent Autophagosome Accumulation in A549 Cells , 2019, Front. Oncol..

[18]  O. Straume,et al.  Are 90% of deaths from cancer caused by metastases? , 2019, Cancer medicine.

[19]  Shuquan Li,et al.  Downregulation of lncRNA AFAP1-AS1 by oridonin inhibits the epithelial-to-mesenchymal transition and proliferation of pancreatic cancer cells. , 2019, Acta biochimica et biophysica Sinica.

[20]  F. Liu,et al.  Oridonin induces Mdm2‐p60 to promote p53‐mediated apoptosis and cell cycle arrest in neuroblastoma , 2019, Cancer medicine.

[21]  Bin Xu,et al.  Oridonin overcomes the gemcitabine resistant PANC-1/Gem cells by regulating GST pi and LRP/1 ERK/JNK signalling , 2019, OncoTargets and therapy.

[22]  Yihan Wu,et al.  Oridonin synergistically enhances the anti-tumor efficacy of doxorubicin against aggressive breast cancer via pro-apoptotic and anti-angiogenic effects. , 2019, Pharmacological research.

[23]  Jian Zhang,et al.  Oridonin inhibits the proliferation, migration and invasion of human osteosarcoma cells via suppression of matrix metalloproteinase expression and STAT3 signalling pathway. , 2019, Journal of B.U.ON. : official journal of the Balkan Union of Oncology.

[24]  N. Hudorović,et al.  TGF-BETA IN THE NATURAL HISTORY OF PROSTATE CANCER , 2019, Acta clinica Croatica.

[25]  Xu Song,et al.  The antibacterial mechanism of oridonin against methicillin-resistant Staphylococcus aureus (MRSA) , 2019, Pharmaceutical biology.

[26]  A. Nasir Angiogenic Signaling Pathways and Anti-angiogenic Therapies in Human Cancer , 2018, Predictive Biomarkers in Oncology.

[27]  Jianwei Zhu,et al.  Oridonin prevents epithelial-mesenchymal transition and TGF-β1-induced epithelial-mesenchymal transition by inhibiting TGF-β1/Smad2/3 in osteosarcoma. , 2018, Chemico-biological interactions.

[28]  Enxu Bi,et al.  Oridonin induces growth inhibition and apoptosis in human gastric carcinoma cells by enhancement of p53 expression and function , 2018, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[29]  Jiang Pi,et al.  Oridonin‐induced mitochondria‐dependent apoptosis in esophageal cancer cells by inhibiting PI3K/AKT/mTOR and Ras/Raf pathways , 2018, Journal of cellular biochemistry.

[30]  Ye Wang,et al.  Oridonin inhibits metastasis of human ovarian cancer cells by suppressing the mTOR pathway , 2018, Archives of medical science : AMS.

[31]  O. Casanovas,et al.  Unraveling the Role of Angiogenesis in Cancer Ecosystems , 2018, Frontiers in Oncology.

[32]  Qingsong Liu,et al.  Oridonin is a covalent NLRP3 inhibitor with strong anti-inflammasome activity , 2018, Nature Communications.

[33]  J. Beckford,et al.  Upregulation of the EMT marker vimentin is associated with poor clinical outcome in acute myeloid leukemia , 2018, Journal of Translational Medicine.

[34]  Qi Wang,et al.  Oridonin inhibits VEGF-A-associated angiogenesis and epithelial-mesenchymal transition of breast cancer in vitro and in vivo , 2018, Oncology letters.

[35]  J. Xiong,et al.  FBW7 loss promotes epithelial-to-mesenchymal transition in non-small cell lung cancer through the stabilization of Snail protein. , 2018, Cancer letters.

[36]  Quan Du,et al.  Analysis of LncRNA expression in cell differentiation , 2018, RNA biology.

[37]  P. Carmeliet,et al.  How Endothelial Cells Adapt Their Metabolism to Form Vessels in Tumors , 2017, Front. Immunol..

[38]  Qi Wang,et al.  Oridonin inhibits migration, invasion, adhesion and TGF-β1-induced epithelial-mesenchymal transition of melanoma cells by inhibiting the activity of PI3K/Akt/GSK-3β signaling pathway. , 2017, Oncology letters.

[39]  K. Khoo,et al.  Fibronectin in cell adhesion and migration via N-glycosylation , 2017, Oncotarget.

[40]  F. Pan,et al.  The regulation of immune tolerance by FOXP3 , 2017, Nature Reviews Immunology.

[41]  F. Portillo,et al.  EMT: Present and future in clinical oncology , 2017, Molecular oncology.

[42]  Caihong Li,et al.  Oridonin inhibits breast cancer growth and metastasis through blocking the Notch signaling , 2017, Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society.

[43]  Guofu Zhu,et al.  Antiangiogenic effects of oridonin , 2017, BMC Complementary and Alternative Medicine.

[44]  Yuexin Xu,et al.  Oridonin induces G2/M cell cycle arrest and apoptosis via the PI3K/Akt signaling pathway in hormone-independent prostate cancer cells. , 2017, Oncology letters.

[45]  D. He,et al.  Targeting 3-phosphoinositide-dependent protein kinase 1 associated with drug-resistant renal cell carcinoma using new oridonin analogs , 2017, Cell Death & Disease.

[46]  Hui Zhou,et al.  Oridonin induces autophagy via inhibition of glucose metabolism in p53-mutated colorectal cancer cells , 2017, Cell Death and Disease.

[47]  R. Weinberg,et al.  Emerging Biological Principles of Metastasis , 2017, Cell.

[48]  Y. Zhang,et al.  Oridonin effectively reverses the drug resistance of cisplatin involving induction of cell apoptosis and inhibition of MMP expression in human acute myeloid leukemia cells , 2017, Saudi journal of biological sciences.

[49]  Jia Zhou,et al.  Discovery and Development of Natural Product Oridonin‐Inspired Anticancer Agents , 2016 .

[50]  Qianqian Liu,et al.  Oridonin inhibits pancreatic cancer cell migration and epithelial-mesenchymal transition by suppressing Wnt/β-catenin signaling pathway , 2016, Cancer Cell International.

[51]  M. Tan,et al.  Study of Clinical Survival and Gene Expression in a Sample of Pancreatic Ductal Adenocarcinoma by Parsimony Phylogenetic Analysis. , 2016, Omics : a journal of integrative biology.

[52]  N. Matsumura,et al.  Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells , 2016, Clinical Cancer Research.

[53]  J. Segall,et al.  Tumor cell intravasation. , 2016, American journal of physiology. Cell physiology.

[54]  Wei Liu,et al.  Oridonin effectively reverses cisplatin drug resistance in human ovarian cancer cells via induction of cell apoptosis and inhibition of matrix metalloproteinase expression. , 2016, Molecular medicine reports.

[55]  P. Steeg,et al.  Targeting metastasis , 2016, Nature Reviews Cancer.

[56]  Yun Xu,et al.  Oridonin Attenuates Synaptic Loss and Cognitive Deficits in an Aβ1–42-Induced Mouse Model of Alzheimer’s Disease , 2016, PloS one.

[57]  R. Xia,et al.  Oridonin Suppresses Proliferation of Human Ovarian Cancer Cells via Blockage of mTOR Signaling. , 2016, Asian Pacific journal of cancer prevention : APJCP.

[58]  N. Bhowmick,et al.  Role of EMT in Metastasis and Therapy Resistance , 2016, Journal of clinical medicine.

[59]  Ke Wang,et al.  High levels of EGFR expression in tumor stroma are associated with aggressive clinical features in epithelial ovarian cancer , 2016, OncoTargets and therapy.

[60]  T. Chuangsuwanich,et al.  High vascular endothelial growth factor gene expression predicts poor outcome in patients with non-luminal A breast cancer. , 2015, Molecular and clinical oncology.

[61]  Meiyan Wu,et al.  HIF-1α Promotes Epithelial-Mesenchymal Transition and Metastasis through Direct Regulation of ZEB1 in Colorectal Cancer , 2015, PloS one.

[62]  J. Xie,et al.  Advanced research on vasculogenic mimicry in cancer , 2015, Journal of cellular and molecular medicine.

[63]  Tao Zhang,et al.  Oridonin Inhibits Tumor Growth and Metastasis through Anti-Angiogenesis by Blocking the Notch Signaling , 2014, PloS one.

[64]  R. Vandenbroucke,et al.  Is there new hope for therapeutic matrix metalloproteinase inhibition? , 2014, Nature Reviews Drug Discovery.

[65]  G. Sun,et al.  Transforming growth factor-beta polymorphisms and serum level in the development of osteosarcoma. , 2014, DNA and cell biology.

[66]  E. Wieczorek,et al.  Matrix metalloproteinases and genetic mouse models in cancer research: a mini-review , 2014, Tumor Biology.

[67]  Stephen Fox,et al.  Role of p53 in the progression of gastric cancer , 2014, Oncotarget.

[68]  Eunyoung Kang,et al.  High EGFR gene copy number predicts poor outcome in triple-negative breast cancer , 2014, Modern Pathology.

[69]  S. Hochwald,et al.  The role of FAK in tumor metabolism and therapy. , 2014, Pharmacology & therapeutics.

[70]  A. Reuss,et al.  Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[71]  Michael W Sill,et al.  Improved survival with bevacizumab in advanced cervical cancer. , 2014, The New England journal of medicine.

[72]  Dong-hai Wu,et al.  Chinese Journal of Cancer , 2022 .

[73]  Yeh-long Chen,et al.  Inhibition of EGF/EGFR activation with naphtho[1,2-b]furan-4,5-dione blocks migration and invasion of MDA-MB-231 cells. , 2013, Toxicology in vitro : an international journal published in association with BIBRA.

[74]  G. Berx,et al.  Regulatory networks defining EMT during cancer initiation and progression , 2013, Nature Reviews Cancer.

[75]  Yitao Wang,et al.  Oridonin induces apoptosis, inhibits migration and invasion on highly-metastatic human breast cancer cells. , 2013, The American journal of Chinese medicine.

[76]  Kou-Juey Wu,et al.  Hypoxia-regulated target genes implicated in tumor metastasis , 2012, Journal of Biomedical Science.

[77]  H. Dvorak,et al.  Heterogeneity of the tumor vasculature: the need for new tumor blood vessel type-specific targets , 2012, Clinical & Experimental Metastasis.

[78]  Wei Gu,et al.  Dual Roles of MDM2 in the Regulation of p53: Ubiquitination Dependent and Ubiquitination Independent Mechanisms of MDM2 Repression of p53 Activity. , 2012, Genes & cancer.

[79]  A. Maity,et al.  Molecular Neuroscience Review Article , 2011 .

[80]  M. Shibuya Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies. , 2011, Genes & cancer.

[81]  B. Krock,et al.  Hypoxia-induced angiogenesis: good and evil. , 2011, Genes & cancer.

[82]  Robert A. Weinberg,et al.  Tumor Metastasis: Molecular Insights and Evolving Paradigms , 2011, Cell.

[83]  B. Rini,et al.  MDSC as a mechanism of tumor escape from sunitinib mediated anti-angiogenic therapy. , 2011, International immunopharmacology.

[84]  Carolyn J. Brown,et al.  The functional role of long non-coding RNA in human carcinomas , 2011, Molecular Cancer.

[85]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[86]  Karen H. Vousden,et al.  p53 and its mutants in tumor cell migration and invasion , 2011, The Journal of cell biology.

[87]  H. Gómez,et al.  Chemotherapy resistance in metastatic breast cancer: the evolving role of ixabepilone , 2010, Breast Cancer Research.

[88]  R. Goldman,et al.  Vimentin induces changes in cell shape, motility, and adhesion during the epithelial to mesenchymal transition , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[89]  Li Yang TGFβ and cancer metastasis: an inflammation link , 2010, Cancer and Metastasis Reviews.

[90]  A. Sonnenberg,et al.  Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing , 2010, EMBO reports.

[91]  Ker-Chau Li,et al.  p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug , 2009, Nature Cell Biology.

[92]  Ker-Chau Li,et al.  p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug , 2009, Nature Cell Biology.

[93]  P. Vaupel,et al.  Tumor hypoxia and malignant progression. , 2009, Methods in enzymology.

[94]  R. Raychowdhury,et al.  Transcriptional switch of dormant tumors to fast-growing angiogenic phenotype. , 2009, Cancer research.

[95]  Jingyi Yang,et al.  Synthesis and biological evaluation of novel 1-O- and 14-O-derivatives of oridonin as potential anticancer drug candidates. , 2008, Bioorganic & medicinal chemistry letters.

[96]  N. Demartines,et al.  mTORC2 regulates PGE2-mediated endothelial cell survival and migration. , 2008, Biochemical and biophysical research communications.

[97]  Kou-Juey Wu,et al.  TWIST activation by hypoxia inducible factor-1 (HIF-1): Implications in metastasis and development , 2008, Cell cycle.

[98]  L. Xie,et al.  The effects of oridonin on cell growth, cell cycle, cell migration and differentiation in melanoma cells. , 2006, Journal of ethnopharmacology.

[99]  J. Kitajewski,et al.  Notch function in the vasculature: insights from zebrafish, mouse and man , 2004, BioEssays : news and reviews in molecular, cellular and developmental biology.

[100]  B. Weinstein,et al.  Angiogenic network formation in the developing vertebrate trunk , 2003, Development.

[101]  C. Fenoglio-Preiser,et al.  TP53 and gastric carcinoma: A review , 2003, Human mutation.

[102]  J. Thiery Epithelial–mesenchymal transitions in tumour progression , 2002, Nature Reviews Cancer.

[103]  P. Kantoff,et al.  Prognostic significance of plasma vascular endothelial growth factor levels in patients with hormone-refractory prostate cancer treated on Cancer and Leukemia Group B 9480. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[104]  M. Hall,et al.  TOR2 is required for organization of the actin cytoskeleton in yeast. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[105]  Cynthia A. Reinhart-King,et al.  Mechanical Forces in Tumor Angiogenesis. , 2018, Advances in experimental medicine and biology.

[106]  Mingsan Mao,et al.  Study on the Application of Chinese Patent Drug and Chinese Formula of Rabdosia Rubescens , 2018 .

[107]  Zhifang Gui,et al.  Oridonin inhibition and miR‑200b‑3p/ZEB1 axis in human pancreatic cancer. , 2017, International journal of oncology.

[108]  S. Dubinett,et al.  Drug Development for Metastasis Prevention. , 2015, Critical reviews in oncogenesis.

[109]  Sui Chen 陈穗,et al.  Efficacy of rabdosia rubescens in the treatment of gingivitis , 2009, Journal of Huazhong University of Science and Technology [Medical Sciences].

[110]  I. Olver,et al.  Tirapazamine: from bench to clinical trials. , 2006, Current clinical pharmacology.

[111]  M. Young,et al.  Protein phosphatase-2A regulates protein tyrosine phosphatase activity in Lewis lung carcinoma tumor variants , 2004, Clinical & Experimental Metastasis.

[112]  G. Petruzzelli,et al.  Endothelial cell response to human head and neck squamous cell carcinomas involves downregulation of protein phosphatases-1/2A, cytoskeletal depolymerization and increased motility. , 1997, Invasion & metastasis.

[113]  U. G. Dailey Cancer,Facts and Figures about. , 2022, Journal of the National Medical Association.