Abstract
The emergence of several newly identified members of the ABC transporter family has necessitated the development of antagonists that are able to inhibit more than one transporter. We assessed the ability of the chemosensitizer GF120918 to function as a multispecific antagonist using cytotoxicity assays, rhodamine and calcein efflux assays, and confocal microscopy in cell lines expressing different multidrug resistance transporters. At a concentration of 1 microM in cytotoxicity assays, GF120918 was able to sensitize both S1-B1-20, a subline expressing P-glycoprotein (Pgp), and S1-M1-80, a subline expressing a newly identified mitoxantrone transporter, MXR. GF120918 was ineffective in sensitizing MRP-overexpressing MCF-7 VP-16 cells to etoposide as determined by cytotoxicity studies. In flow cytometry experiments, rhodamine 123 efflux in S1-B1-20 cells was decreased at GF120918 concentrations as low as 25-50 nM, with 250 nM giving complete inhibition of rhodamine efflux. Complete inhibition of rhodamine efflux in mitoxantrone-resistant S1-M1-80 cells required 10 microM. Examination of intracellular mitoxantrone accumulation by confocal microscopy confirmed higher levels of mitoxantrone in S1-B1-20 and S1-M1-80 cells when incubated in the presence of GF120918 than when incubated with mitoxantrone alone. Thus, GF120918 appears to fit the paradigm of a multispecific blocker and is able to block rhodamine and mitoxantrone efflux by the newly identified mitoxantrone transporter. Further studies of this compound should be pursued to determine its feasibility for use in the clinic.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cancer Letters |
| Vol/bind | 146 |
| Udgave nummer | 2 |
| Sider (fra-til) | 117-26 |
| Antal sider | 10 |
| ISSN | 0304-3835 |
| Status | Udgivet - 15 nov. 1999 |