Efflux transporters, namely
ATP-binding cassette (ABC), are one of the primary reasons for
cancer chemoresistance and the clinical failure of
chemotherapy.
Ganciclovir (GCV) is an
antiviral agent used in herpes simplex virus
thymidine kinase (HSV-TK) gene therapy. In this
therapy, HSV-TK gene is delivered together with GCV into
cancer cells to activate the phosphorylation process of GCV to active GCV-
triphosphate,
a DNA polymerase inhibitor. However, GCV interacts with efflux transporters that are responsible for the resistance of HSV-TK/GCV
therapy. In the present study, it was explored whether GCV and its more lipophilic derivative (1) could inhibit effluxing of another chemotherapeutic,
methotrexate (MTX), out of the human
breast cancer cells. Firstly, it was found that the combination of GCV and MTX was more hemocompatible than the corresponding combination with compound 1. Secondly, both GCV and compound 1 enhanced the cellular accumulation of MTX in MCF-7 cells, the MTX exposure being 13-21 times greater compared to the MTX uptake alone. Subsequently, this also reduced the number of viable cells (41-56%) and increased the number of late apoptotic cells (46-55%). Moreover, both GCV and compound 1 were found to interact with
breast cancer resistant
protein (BCRP) more effectively than multidrug-resistant
proteins (MRPs) in these cells. Since the expression of BCRP was higher in MCF-7 cells than in MDA-MB-231 cells, and the cellular uptake of GCV and compound 1 was smaller but increased in the presence of BCRP-selective inhibitor (
Fumitremorgin C) in MCF-7 cells, we concluded that the improved apoptotic effects of higher MTX exposure were raised mainly from the inhibition of BCRP-mediated efflux of MTX. However, the effects of GCV and its derivatives on MTX metabolism and the quantitative expression of MTX metabolizing
enzymes in various
cancer cells need to be studied more thoroughly in the future.