Modulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by cell cycle inhibitors

The effects of cell cycle inhibition on the expression of the multidrug resistance transporter P-glycoprotein (P-gp) as well as of the cyclin-dependent kinase (CDK) inhibitors p27(Kip1) and p21(WAF-1) were investigated in DU-145 prostate tumor spheroids. With increasing spheroid size the number of cells in the G(0)/G(1) phase augmented, whereas the number of cells in the G(2)/M phase and the S phase of the cell cycle declined. The number of G(0)/G(1) cells was elevated after incubation with either mimosine, staurosporine or serum-free medium. Mitomycin C and roscovitine increased the number of S phase cells. Roscovitine additionally increased cells in the G(2)/M phase. Incubation in serum-free medium upregulated p21(WAF-1), p27(Kip1) and P-gp. Mimosine treatment resulted in upregulation of p27(Kip1) and P-gp, whereas p21(WAF-1) remained unchanged. Upon roscovitine treatment p27(Kip1) and p21(WAF-1) were downregulated, whereas P-gp was unaltered. Mitomycin C treatment resulted in downregulation of p27(Kip1) and p21(WAF-1); no significant change in P-gp levels was observed. Staurosporine induced upregulation of p21(WAF-1) whereas p27(Kip1) remained unaltered. P-gp was downregulated upon staurosporine treatment, which was owing to an elevation of intracellular reactive oxygen species by this compound. It is concluded that upregulation of P-gp in G(0)/G(1) phase cells requires coexpression of the CDK inhibitor p27(Kip1) I but not the CDK inhibitor p21(WAF-1). (C) 2002 Elsevier Science B.V. All rights reserved.