Dihydroartiminisin inhibits the growth and metastasis of epithelial ovarian cancer.

Dihydroartiminisin (DHA), the active component of a Chinese herb (Artemisia annua), has been utilised as an anti-malarial drug since ancient China. DHA has also been shown to inhibit proliferation of cancer in vitro. However, the capacity of DHA to inhibit the development of ovarian cancer is still unclear. The adhesion, invasion, and migration of human ovarian cancer cell line (HO8910PM) was determined following DHA treatment in vitro, using Matrigel coated plate, transwell membrane chamber, and wound healing models, respectively. A mouse ovarian cancer model was established by orthotopic inoculation of HO8910PM cell line in nude mice. The growth and metastasis in vivo was determined 8 weeks post-implantation in response to DHA treatment. The expression of phosphorylated focal adhesion kinase (pFAK) and matrix metalloproteinases (MMP-2 and MMP-9) was evaluated using Western blotting. The expression of Von Willebrand factor (vWF) and infiltration of macrophages were determined, using immunohistochemistry. DHA inhibits ovarian cancer cell proliferation, adhesion, migration and invasion in vitro in a dose-dependent manner, consistent with decreased expression of pFAK and MMP-2, but not MMP-9. DHA inhibited metastasis significantly in vivo, associated with reduced vWF expression and macrophage infiltration. In conclusion, DHA inhibits the development of ovarian cancer, in part via down-regulating pFAK, MMP-2, vWF and macrophage infiltration.

[1]  R. Kong,et al.  Dihydroartemisinin inactivates NF-kappaB and potentiates the anti-tumor effect of gemcitabine on pancreatic cancer both in vitro and in vivo. , 2010, Cancer letters.

[2]  Hyung Gyun Kim,et al.  Suppression of PMA-induced tumor cell invasion by dihydroartemisinin via inhibition of PKCalpha/Raf/MAPKs and NF-kappaB/AP-1-dependent mechanisms. , 2010, Biochemical pharmacology.

[3]  Ao Li,et al.  Dihydroartemisinin improves the efficiency of chemotherapeutics in lung carcinomas in vivo and inhibits murine Lewis lung carcinoma cell line growth in vitro , 2010, Cancer Chemotherapy and Pharmacology.

[4]  Liying Gu,et al.  TWEAK promotes ovarian cancer cell metastasis via NF-kappaB pathway activation and VEGF expression. , 2009, Cancer letters.

[5]  Paolo P. Provenzano,et al.  The role of focal adhesion kinase in tumor initiation and progression , 2009, Cell adhesion & migration.

[6]  R. Nicoletti,et al.  Artemisinin reduces human melanoma cell migration by down-regulating αVβ3 integrin and reducing metalloproteinase 2 production , 2009, Investigational New Drugs.

[7]  A. Jemal,et al.  Cancer Statistics, 2009 , 2009, CA: a cancer journal for clinicians.

[8]  N. Hunt,et al.  The role of granulocyte macrophage-colony-stimulating factor in acute intestinal inflammation , 2008, Cell Research.

[9]  K. Shen,et al.  [Effects of dihydroartiminisin on the adhesion, migration, and invasion of epithelial ovarian cancer cells]. , 2008, Zhonghua yi xue za zhi.

[10]  Hui Wang,et al.  Experimental Therapy of Hepatoma with Artemisinin and Its Derivatives: In vitro and In vivo Activity, Chemosensitization, and Mechanisms of Action , 2008, Clinical Cancer Research.

[11]  Tao Chen,et al.  Dihydroartemisinin induces apoptosis and sensitizes human ovarian cancer cells to carboplatin therapy , 2008, Journal of cellular and molecular medicine.

[12]  S. Fan,et al.  Dihydroartemisinin is an inhibitor of ovarian cancer cell growth , 2007, Acta Pharmacologica Sinica.

[13]  Wei-Ping Zhang,et al.  Dihydroartemisinin exerts cytotoxic effects and inhibits hypoxia inducible factor‐1α activation in C6 glioma cells , 2007, The Journal of pharmacy and pharmacology.

[14]  Woong Nam,et al.  Effects of artemisinin and its derivatives on growth inhibition and apoptosis of oral cancer cells , 2007, Head & neck.

[15]  T. Efferth,et al.  Microarray expression profiles of angiogenesis-related genes predict tumor cell response to artemisinins , 2006, The Pharmacogenomics Journal.

[16]  J. Pollard,et al.  Distinct role of macrophages in different tumor microenvironments. , 2006, Cancer research.

[17]  Narendra Singh,et al.  Oral artemisinin prevents and delays the development of 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in the rat. , 2006, Cancer letters.

[18]  Richard Schlegel,et al.  Dihydroartemisinin is cytotoxic to papillomavirus-expressing epithelial cells in vitro and in vivo. , 2005, Cancer research.

[19]  W. Di,et al.  Suppression of human ovarian carcinoma metastasis by the metastasis‐suppressor gene, BRMS1 , 2005, International Journal of Gynecologic Cancer.

[20]  Sabrina Cattaruzza,et al.  Proteoglycan control of cell movement during wound healing and cancer spreading. , 2005, Matrix biology : journal of the International Society for Matrix Biology.

[21]  Neil O. Carragher,et al.  The role of focal-adhesion kinase in cancer — a new therapeutic opportunity , 2005, Nature Reviews Cancer.

[22]  P. O’Neill.  Medicinal chemistry: A worthy adversary for malaria , 2004, Nature.

[23]  D. Schlaepfer,et al.  Control of motile and invasive cell phenotypes by focal adhesion kinase. , 2004, Biochimica et biophysica acta.

[24]  H. Chan,et al.  Differential effects of Matrigel and its components on functional activity of CFTR and ENaC in mouse endometrial epithelial cells , 2003, Cell biology international.

[25]  S. Meshnick,et al.  Artemisinin: mechanisms of action, resistance and toxicity. , 2002, International journal for parasitology.

[26]  N. Singh,et al.  Selective toxicity of dihydroartemisinin and holotransferrin toward human breast cancer cells. , 2001, Life sciences.

[27]  J. Verweij,et al.  Matrix metalloproteinase inhibitors: current developments and future perspectives. , 2001, The Oncologist.

[28]  E. Lengyel,et al.  Expression of latent matrix metalloproteinase 9 (MMP-9) predicts survival in advanced ovarian cancer. , 2001, Gynecologic oncology.

[29]  T. Efferth,et al.  The anti-malarial artesunate is also active against cancer. , 2001, International journal of oncology.

[30]  S. Weed,et al.  Focal Adhesion Kinase: a regulator of focal adhesion dynamics and cell movement , 2000, Oncogene.

[31]  Z. Gu,et al.  Establishment of a highly metastatic human ovarian cancer cell line (HO-8910PM) and its characterization. , 1999, Journal of experimental & clinical cancer research : CR.

[32]  F Pozza,et al.  Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. , 1992, Journal of the National Cancer Institute.

[33]  A. Mantovani,et al.  Expression of adhesion molecules and chemotactic cytokines in cultured human mesothelial cells , 1992, The Journal of experimental medicine.

[34]  J. Folkman,et al.  Tumor angiogenesis and metastasis--correlation in invasive breast carcinoma. , 1991, The New England journal of medicine.

[35]  M. M. Bradford.  A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. , 1976, Analytical biochemistry.

[36]  J. Folkman,et al.  Tumor angiogenesis: a quantitative method for histologic grading. , 1972, Journal of the National Cancer Institute.

[37]  Jingjing Zhang,et al.  Arsenic trioxide (As(2)O(3)) inhibits peritoneal invasion of ovarian carcinoma cells in vitro and in vivo. , 2006, Gynecologic Oncology.

[38]  F. Marincola,et al.  Peritoneal and subperitoneal stroma may facilitate regional spread of ovarian cancer. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  P. Strebel,et al.  Epidemiology of ovarian cancer: a status report , 2005 .

[40]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.