NVP‐TAE684 reverses multidrug resistance (MDR) in human osteosarcoma by inhibiting P‐glycoprotein (PGP1) function

Abstract

BACKGROUND AND PURPOSEIncreased 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 APPROACHIn 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 RESULTSAfter 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.

Effects of major parameters of nanoparticles on their physical and chemical properties and recent application of nanodrug delivery system in targeted chemotherapy

“…[15][16][17][18][19][20] There has been much research on the mechanism of MDR in the recent years, 21,22 and scientists are trying to explore the mechanisms to overcome MDR such that chemotherapy drugs could exhibit a higher efficacy.…”

Iso-pencillixanthone A from a marine-derived fungus reverses multidrug resistance in cervical cancer cells through down-regulating P-gp and re-activating apoptosis

“…It has been widely reported that many agents play an important role in reversing MDR by inhibiting the function and expression of P-gp. 39 As shown in Fig. 9a, iso-PXA signicantly increases the intracellular accumulation of Rh123, which conrms that iso-PXA inhibits the efflux function of P-gp.…”

P-Glycoprotein Overexpression Is Associated With Cisplatin Resistance in Human Osteosarcoma

“…However, cisplatin resistance is frequently reported, meaning that the enhancement of cisplatin sensitivity is imperative (26). Several studies have reported that inhibition of P-gp reverses drug resistance in OS (27)(28)(29)(30). In the current study, P-gp was found to be overexpressed in cisplatin resistant OS specimens compared to cisplatin sensitive ones.…”