Download PDF
Drug Res (Stuttg) 2015; 65(11): 597-601
DOI: 10.1055/s-0034-1395597
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Antitumor Effect of Docetaxel in Osteosarcoma by the Inhibition of Wnt Signal Channel

D.-Z. Wang   *
1   Department of Orthopedics, The People’s Hospital of Zhangqiu, Jinan, Shandong, China
,
J.-F. Gao   *
1   Department of Orthopedics, The People’s Hospital of Zhangqiu, Jinan, Shandong, China
,
S.-F. Jing
1   Department of Orthopedics, The People’s Hospital of Zhangqiu, Jinan, Shandong, China
,
H. Wei
1   Department of Orthopedics, The People’s Hospital of Zhangqiu, Jinan, Shandong, China
,
X.-Y. Huang
1   Department of Orthopedics, The People’s Hospital of Zhangqiu, Jinan, Shandong, China
,
C.-D. Li
1   Department of Orthopedics, The People’s Hospital of Zhangqiu, Jinan, Shandong, China
› Author Affiliations
Further Information

Publication History

received 03 September 2014

accepted 30 October 2014

Publication Date:
16 December 2014 (online)

Also available at
    Permissions and Reprints

Abstract

Osteosarcoma (OS) is the most common type of malignant bone tumor in adults and children. Despite the great strides in biology and medicine, the survival rate of patients with metastatic disease remains very poor. This rate has been staggering with recurrence and metastasis. In the present study, we proposed Wnt/β-catenin pathway as a key biological target for the effective treatment in OS. Wnt signaling has been reported to play important roles in osteoblastogenesis. We hypothesized that docetaxel (DTX) will effectively arrest the osteosarcoma progression by suppressing the Wnt/β-catenin pathway in OS cells. Our results show that DTX significantly inhibited the cell proliferation of U2OS and SaOS-2 cancer cells in a time-dependent and dose-dependent manner. DTX inhibited the intrinsic transcriptional activity of β-catenin/Tcf in U2OS cancer cells and SaOS-2 cancer cells. GSK-3βinhibitor (SB216763) treatment remarkably increased the β-catenin/Tcf transcriptional activities. The transcriptional activities have been increased by around ~200% due to the decrease in the degradation of β-catenin mediated through GSK-3β. Summarizing, present study clearly showed that DTX inhibited Wnt/β-catenin signalling pathways and significantly reduced the matrix metallopeptodase 9 (MMP-9) protein expressions and its activity. Taken together, our findings provide novel insight on the effect of anticancer small molecules to improve the outcomes in osteosarcoma.

Key words

osteosarcoma - docetaxel - Wnt/β-catenin pathway - cell proliferation - MMP-9

* These authors contributed equally to this work.


 

  • References

  • 1 Longhi A, Errani C, De Paolis M et al. Primary bone osteosarcoma in the pediatric age: state of the art. Cancer Treat Rev 2006; 32: 423-436
    CrossrefPubMedSearch in Google Scholar
  • 2 Dass CR, Ek ET, Contreras KG et al. A novel orthotopic murine model provides insights into cellular and molecular characteristics contributing to human osteosarcoma. Clin Exp Metastasis 2006; 23: 367-380
    PubMedSearch in Google Scholar
  • 3 Ferrari S, Smeland S, Mercuri M et al. Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. J Clin Oncol 2005; 23: 8845-8852
    CrossrefPubMedSearch in Google Scholar
  • 4 Geller DS, Gorlick R. Osteosarcoma: a review of diagnosis, management, and treatment strategies. Clin Adv Hematol Oncol 2010; 8: 705-718
    PubMedSearch in Google Scholar
  • 5 Ferguson WS, Goorin AM. Current treatment of osteosarcoma. Canc Invest 2001; 19: 292-315
    PubMedSearch in Google Scholar
  • 6 Patel SJ, Lynch JWJ, Johnson T et al. Dose-intense ifosfamide/doxorubicin/cisplatin based chemotherapy for osteosarcoma in adults. Am J Clin Oncol 2002; 25: 489-495
    CrossrefPubMedSearch in Google Scholar
  • 7 Maran A, Dadsetan M, Buenz CM et al. Hydrogel-PLGA delivery system prolongs 2-methoxyestradiol-mediated anti-tumor effects in osteosarcoma cells. J Biomed Mat Res 2013; 9: 101A
    PubMedSearch in Google Scholar
  • 8 Nusse R. Wnt signaling in disease and in development. Cell Res 2005; 15: 28-32
    CrossrefPubMedSearch in Google Scholar
  • 9 Bodine PV, Komm BS. Wnt signaling and osteoblastogenesis. Rev Endocr Metab Disord 2006; 7: 33-39
    PubMedSearch in Google Scholar
  • 10 Bodine PV. Wnt signaling control of bone cell apoptosis. Cell Res 2008; 18: 248-253
    CrossrefPubMedSearch in Google Scholar
  • 11 Gaur T, Lengner CJ, Hovhannisyan H et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 2005; 280: 33132-33140
    CrossrefPubMedSearch in Google Scholar
  • 12 Polakis P. Wnt signaling and cancer. Genes Dev 2000; 14: 1837-1851
    PubMedSearch in Google Scholar
  • 13 Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 1999; 398: 422-426
    CrossrefPubMedSearch in Google Scholar
  • 14 Afrouz Y, Farnaz E, Sima R et al. Preparation and In Vitro Evaluation of a Pegylated Nano-Liposomal Formulation Containing Docetaxel. Sci Pharm 2009; 77: 453-464
    CrossrefPubMedSearch in Google Scholar
  • 15 Horwitz SB. Mechanism of action of Taxol. Trends Pharmacol Sci 1992; 13: 134-136
    CrossrefPubMedSearch in Google Scholar
  • 16 Hoang BH, Kubo T, Healey JH et al. Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int J Cancer 2004; 109: 106-111
    CrossrefPubMedSearch in Google Scholar
  • 17 Jaiswal AS, Marlow BP, Gupta N et al. Beta-cateninmediated transactivation and cell-cell adhesion pathways are important in curcumin (diferuylmethane)-induced growth arrest and apoptosis in colon cancer cells. Oncogene 2002; 21: 8414-8427
    CrossrefPubMedSearch in Google Scholar
  • 18 Lepourcelet M, Chen YN, France DS et al. Small-molecule Invest New Drugs (2010) 28:766–782 781 antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 2004; 5: 91-102
    CrossrefPubMedSearch in Google Scholar
  • 19 Bjornland K, Flatmark K, Pettersen S et al. Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res 2005; 127: 151-156
    CrossrefPubMedSearch in Google Scholar
  • 20 Uchibori M, Nishida Y, Nagasaka T et al. Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. Int J Oncol 2006; 28: 33-42
    PubMedSearch in Google Scholar
  • 21 Foukas AF, Deshmukh NS, Grimer RJ et al. Stage-IIB osteosarcomas around the knee. A study of MMP-9 in surviving tumour cells. J Bone Joint Surg Br 2002; 84: 706-711
    CrossrefPubMedSearch in Google Scholar
  • 22 Marchenko GN, Marchenko ND, Leng J et al. Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin. Biochem J 2002; 363: 253-262
    CrossrefPubMedSearch in Google Scholar