Inhibition of cyclin D1 expression in human pancreatic cancer cells is associated with increased chemosensitivity and decreased expression of multiple chemoresistance genes

Cyclin D1 belongs to a family of protein kinases that have been implicated in cell cycle regulation. Inhibition of cyclin D1 expression has been recen tly shown (M, Kornmann, et al., J. Clin. Invest., 101: 344-352, 1998) to su ppress pancreatic cancer cell growth and increase cytotoxic actions of cisp latinum. The aim of the present study was to determine whether inhibition o f cyclin D1 expression also modulates the effects of other antineoplastic d rugs and whether it is associated with alterations in the level of expressi on of drug resistance genes. The suppression of cyclin D1 expression after the stable transfection of a cyclin D1 antisense construct in PANC-1 and CO LO-357 human pancreatic cancer cells resulted in a significant increase in sensitivity to the fluoropyrimidines 5-fluorouracil and 5-fluoro-2'-deoxyur idine and to mitoxantrone. All of the antisense-expressing clones exhibited a decrease in thymidylate synthase and an increase in thymidine phosphoryl ase mRNA expression as determined by reverse transcription-PCR analysis and decreased levels of MDR-1 and MRP mRNA as determined by Northern blotting. These findings demonstrate that the inhibition of cyclin D1, in addition t o suppressing the growth of pancreatic cancer cells, enhances their respons iveness to multiple chemotherapeutic agents and suggest that this effect ma y be due to the altered expression of several chemoresistance genes.