Research Papers: Pathology:
Co-targeting of DNA, RNA, and protein molecules provides optimal outcomes for treating osteosarcoma and pulmonary metastasis in spontaneous and experimental metastasis mouse models
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Chao Jian1,2, Mei-Juan Tu2, Pui Yan Ho2, Zhijian Duan2, Qianyu Zhang2, Jing-Xin Qiu3, Ralph W. DeVere White4, Theodore Wun5, Primo N. Lara5,6, Kit S. Lam2, Ai-Xi Yu1 and Ai-Ming Yu2
1 Department of Orthopedics, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
2 Department of Biochemistry & Molecular Medicine, UC Davis School of Medicine, Sacramento, CA, USA
3 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA
4 Department of Urology, UC Davis School of Medicine, Sacramento, CA, USA
5 Division of Hematology Oncology, UC Davis School of Medicine, Sacramento, CA, USA
6 Department of Internal Medicine, Comprehensive Cancer Center, UC Davis School of Medicine, Sacramento, CA, USA
Ai-Xi Yu, email:
Ai-Ming Yu, email:
Keywords: therapy, metastasis, doxorubicin, miR-34a, sorafenib, Pathology Section
Received: February 06, 2017 Accepted: March 03, 2017 Published: March 18, 2017
Metastasis is a major cause of mortality for cancer patients and remains as the greatest challenge in cancer therapy. Driven by multiple factors, metastasis may not be controlled by the inhibition of single target. This study was aimed at assessing the hypothesis that drugs could be rationally combined to co-target critical DNA, RNA and protein molecules to achieve “saturation attack” against metastasis. Independent actions of the model drugs DNA-intercalating doxorubicin, RNA-interfering miR-34a and protein-inhibiting sorafenib on DNA replication, RNA translation and protein kinase signaling in highly metastatic, human osteosarcoma 143B cells were demonstrated by the increase of γH2A.X foci formation, reduction of c-MET expression and inhibition of Erk1/2 phosphorylation, respectively, and optimal effects were found for triple-drug combination. Consequently, triple-drug treatment showed a strong synergism in suppressing 143B cell proliferation and the greatest effects in reducing cell invasion. Compared to single- and dual-drug treatment, triple-drug therapy suppressed pulmonary metastases and orthotopic osteosarcoma progression to significantly greater degrees in orthotopic osteosarcoma xenograft/spontaneous metastases mouse models, while none showed significant toxicity. In addition, triple-drug therapy improved the overall survival to the greatest extent in experimental metastases mouse models. These findings demonstrate co-targeting of DNA, RNA and protein molecules as a novel therapeutic strategy for the treatment of metastasis.
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