A-770041 reverses paclitaxel and doxorubicin resistance in osteosarcoma cells
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- 作者：Zhenfeng Duan (11)
Jianming Zhang (12)
Shunan Ye (11)
Jacson Shen (11)
Edwin Choy (11)
Gregory Cote (11)
David Harmon (11)
Henry Mankin (11)
Yingqi Hua (13)
Yu Zhang (14)
Nathanael S Gray (15)
Francis J Hornicek (11)
11. Center for Sarcoma and Connective Tissue Oncology ; Massachusetts General Hospital ; 100 Blossom St. ; Jackson 1115 ; Boston ; 02114 ; MA ; USA
12. Cutaneous Biology Research Center ; Massachusetts General Hospital ; Boston ; 02114 ; MA ; USA
13. Shanghai First People鈥檚 Hospital ; Shanghai Jiaotong University ; Shanghai ; 200080 ; China
14. Department of Orthopedic Surgery ; Liu Hua Qiao Hospital ; Guangzhou ; 510010 ; China
15. Dana Farber Cancer Institute ; Harvard Medical School ; Boston ; MA ; 02115 ; USA - 关键词：Osteosarcoma ; MDR ; Src kinase ; Doxorubicin
- 刊名：BMC Cancer
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：14
- 期：1
- 全文大小：1,377 KB
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45. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/681/prepub - 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
- 出版者：BioMed Central
- ISSN：1471-2407
文摘
Background Reversing multidrug resistance (MDR) has been an important goal for clinical and investigational oncologists. In the last few decades, significant effort has been made to search for inhibitors to reverse MDR by targeting ATP-binding cassette (ABC) transporters (Pgp, MRP) directly, but these efforts have achieved little clinical success. Protein kinases play important roles in many aspects of tumor cell growth and survival. Combinations of kinase inhibitors and chemotherapeutics have been observed to overcome cancer drug resistance in certain circumstances. Methods We screened a kinase specific inhibitor compound library in human osteosarcoma MDR cell lines to identify inhibitors that were capable of reversing chemoresistance to doxorubicin and paclitaxel. Results We identified 18 small molecules that significantly increase chemotherapy drug-induced cell death in human osteosarcoma MDR cell lines U-2OSMR and KHOSR2. We identified A-770041 as one of the most effective MDR reversing agents when combined with doxorubicin or paclitaxel. A-770041 is a potent Src family kinase (Lck and Src) inhibitor. Western blot analysis revealed A-770041 inhibits both Src and Lck activation and expression. Inhibition of Src expression in U-2OSMR and KHOSR2 cell lines using lentiviral shRNA also resulted in increased doxorubicin and paclitaxel drug sensitivity. A-770041 increases the intracellular drug accumulation as demonstrated by calcein AM assay. Conclusions These results indicate that small molecule inhibitor A-770041 may function to reverse ABCB1/Pgp-mediated chemotherapy drug resistance. Combination of Src family kinase inhibitor with regular chemotherapy drug could be clinically effective in MDR osteosarcoma.