Cyclin-dependent kinase inhibitors (CDKi) have high potential applicability in anticancer
therapy, but various aspects of their pharmacokinetics, especially their interactions with
drug efflux transporters, have not yet been evaluated in detail. Thus, we investigated interactions of five CDKi (
purvalanol A,
olomoucine II,
roscovitine,
flavopiridol and
SNS-032) with the ABCB1 transporter. Four of the compounds inhibited efflux of two ABCB1 substrates,
Hoechst 33342 and
daunorubicin, in MDCKII-ABCB1 cells:
Olomoucine II most strongly, followed by
roscovitine,
purvalanol A, and
flavopiridol.
SNS-032 inhibited ABCB1-mediated efflux of
Hoechst 33342 but not
daunorubicin. In addition,
purvalanol A,
SNS-032 and
flavopiridol lowered the stimulated
ATPase activity in ABCB1 membrane preparations, while
olomoucine II and
roscovitine not only inhibited the stimulated
ATPase but also significantly activated the basal ABCB1
ATPase, suggesting that these two CDKi are ABCB1 substrates. We further revealed that the strongest ABCB1 inhibitors (
purvalanol A,
olomoucine II and
roscovitine) synergistically potentiate the antiproliferative effect of
daunorubicin, a commonly used anticancer
drug and ABCB1 substrate, in MDCKII-ABCB1 cells as well as in human
carcinoma HCT-8 and HepG2 cells. We suggest that this pronounced synergism is at least partly caused by (i) CDKi-mediated inhibition of ABCB1 transporter leading to increased intracellular retention of
daunorubicin and (ii) native cytotoxic activity of the CDKi. Our results indicate that co-administration of the tested CDKi with anticancer drugs that are ABCB1 substrates may allow significant
dose reduction in the treatment of ABCB1-expressing
tumors.