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NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function
Author(s) -
Ye Shunan,
Zhang Jianming,
Shen Jacson,
Gao Yan,
Li Ying,
Choy Edwin,
Cote Gregory,
Harmon David,
Mankin Henry,
Gray Nathanael S,
Hornicek Francis J,
Duan Zhenfeng
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13395
Subject(s) - multiple drug resistance , pharmacology , medicine , doxorubicin , p glycoprotein , osteosarcoma , paclitaxel , cancer , cancer research , drug resistance , chemotherapy , biology , microbiology and biotechnology
Background and purpose Increased expression of P‐glycoprotein (PGP1) is one of the major causes of multidrug resistance (MDR) in cancer, including in osteosarcoma, which eventually leads to the failure of cancer chemotherapy. Thus, there is an urgent need to develop effective therapeutic strategies to override the expression and function of PGP1 to counter MDR in cancer patients. Experimental Approach In an effort to search for new chemical entities targeting PGP1‐associated MDR in osteosarcoma, we screened a 500+ compound library of known kinase inhibitors with established kinase selectivity profiles. We aimed to discover potential drug synergistic effects among kinase inhibitors and general chemotherapeutics by combining inhibitors with chemotherapy drugs such as doxorubicin and paclitaxel. The human osteosarcoma MDR cell lines U2OSR2 and KHOSR2 were used for the initial screen and secondary mechanistic studies. Key Results After screening 500+ kinase inhibitors, we identified NVP‐TAE684 as the most effective MDR reversing agent. NVP‐TAE684 significantly reversed chemoresistance when used in combination with doxorubicin, paclitaxel, docetaxel, vincristine, ET‐743 or mitoxantrone. NVP‐TAE684 itself is not a PGP1 substrate competitive inhibitor, but it can increase the intracellular accumulation of PGP1 substrates in PGP1‐overexpressing cell lines. NVP‐TAE684 was found to inhibit the function of PGP1 by stimulating PGP1 ATPase activity, a phenomenon reported for other PGP1 inhibitors. Conclusions and Implications The application of NVP‐TAE684 to restore sensitivity of osteosarcoma MDR cells to the cytotoxic effects of chemotherapeutics will be useful for further study of PGP1‐mediated MDR in human cancer and may ultimately benefit cancer patients.