Abstract
Human ATP-binding cassette (ABC) subfamily G member 2 (ABCG2) mediates the transport of a wide variety of conventional cytotoxic anticancer drugs and molecular targeted agents. Consequently, the overexpression of ABCG2 in cancer cells is linked to the development of the multidrug resistance (MDR) phenotype. TP-3654 is an experimental second-generation inhibitor of PIM kinase that is currently under investigation in clinical trials to treat advanced solid tumors and myelofibrosis. In this study, we discovered that by attenuating the drug transport function of ABCG2, TP-3654 resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic ABCG2 substrate drugs topotecan, SN-38 and mitoxantrone. Moreover, our results indicate that ABCG2 does not mediate resistance to TP-3654 and may not play a major role in the induction of resistance to TP-3654 in cancer patients. Taken together, our findings reveal that TP-3654 is a selective, potent modulator of ABCG2 drug efflux function that may offer an additional combination therapy option for the treatment of multidrug-resistant cancers.
Highlights
The ATP-binding cassette (ABC) proteins ABCB1 (MDR1; P-glycoprotein) and ABCG2(BCRP; MXR; ABCP) are transmembrane proteins that utilize energy derived from ATP hydrolysis to translocate a wide range of structurally unrelated chemotherapeutic drugs across membranes [1,2,3]
Considering that ABCB1 and ABCG2 overexpression is highly associated with the development of multidrug resistance (MDR) [3,4] and poor prognosis in patients with solid tumors [10] and hematologic malignancies [11,12,13,14,15], discovering therapeutic agents and strategies to overcome the activity of ABCB1 and ABCG2 is of urgent need
To determine whether cells overexpressing ABCB1 or ABCG2 are less susceptible to TP-3654 treatment, we determined the cytotoxicity of TP-3654 in human KB-3-1 epidermal cancer cell line, human OVCAR-8 ovarian cancer cell line and their respective
Summary
(BCRP; MXR; ABCP) are transmembrane proteins that utilize energy derived from ATP hydrolysis to translocate a wide range of structurally unrelated chemotherapeutic drugs across membranes [1,2,3]. Considering that ABCB1 and ABCG2 overexpression is highly associated with the development of multidrug resistance (MDR) [3,4] and poor prognosis in patients with solid tumors [10] and hematologic malignancies [11,12,13,14,15], discovering therapeutic agents and strategies to overcome the activity of ABCB1 and ABCG2 is of urgent need. TP-3654 selectively interferes with drug transport mediated by ABCG2 and resensitizes ABCG2-overexpressing cancer cells to cytotoxic anticancer drugs. These findings reveal an additional pharmacological activity of TP-3654 that reverses ABCG2-mediated MDR and may be an effective therapeutic strategy for patients with multidrug-resistant cancers
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