Abstract
Purine cyclin-dependent kinase inhibitors have been recognized as promising candidates for the treatment of various cancers; nevertheless, data regarding interaction of these substances with drug efflux transporters is still lacking. Recently, we have demonstrated inhibition of breast cancer resistance protein (ABCG2) by olomoucine II and purvalanol A and shown that these compounds are able to synergistically potentiate the antiproliferative effect of mitoxantrone, an ABCG2 substrate. In this follow up study, we investigated whether olomoucine II and purvalanol A are transported by ABCG2 and ABCB1 (P-glycoprotein). Using monolayers of MDCKII cells stably expressing human ABCB1 or ABCG2, we demonstrated that olomoucine II, but not purvalanol A, is a dual substrate of both ABCG2 and ABCB1. We, therefore, assume that pharmacokinetics of olomoucine II will be affected by both ABCB1 and ABCG2 transport proteins, which might potentially result in limited accumulation of the compound in tumor tissues or lead to drug-drug interactions. Pharmacokinetic behavior of purvalanol A, on the other hand, does not seem to be affected by either ABCG2 or ABCB1, theoretically favoring this drug in the potential treatment of efflux transporter-based multidrug resistant tumors. In addition, we observed intensive sulfatation of olomoucine II in MDCKII cell lines with subsequent active efflux of the metabolite out of the cells. Therefore, care should be taken when performing pharmacokinetic studies in MDCKII cells, especially if radiolabeled substrates are used; the generated sulfated conjugate may largely contaminate pharmacokinetic analysis and result in misleading interpretation. With regard to chemical structures of olomoucine II and purvalanol A, our data emphasize that even drugs with remarkable structure similarity may show different pharmacokinetic behavior such as interactions with ABC transporters or biotransformation enzymes.
Highlights
Olomoucine II and purvalanol A are potent cyclin-dependent kinase inhibitors (CDKi) that belong to the group of 2,6,9trisubstituted purine derivatives [1,2]
We investigated whether olomoucine II and purvalanol A are transported by ABCG2 and/or ABCB1
In our current work, using cellular monolayer transport assays with ABCG2 and ABCB1 transduced MDCKII cells, we demonstrate that olomoucine II is a dual substrate of ABCG2 and ABCB1 (Fig. 6)
Summary
Olomoucine II and purvalanol A are potent cyclin-dependent kinase inhibitors (CDKi) that belong to the group of 2,6,9trisubstituted purine derivatives [1,2]. These compounds effectively stop cellular proliferation, block transcription of essential genes and induce apoptosis [3,4,5]. For their favorable pharmacodynamic properties, purine CDKi have become modern alternatives in cancer therapy [6,7]. Possible interactions with other biological structures, such as drug transporters, have not been properly investigated to date
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