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Molecular determinants of UCN‐01‐induced growth inhibition in human lung cancer cells

UCN‐01 (7‐hydroxystaurosporine) inhibits the growth of various malignant cell lines in vitro and in vivo. In this study, a human small cell lung carcinoma subline resistant to UCN‐01, SBC‐3/UCN, was established and characterized. SBC‐3/UCN cells showed 8‐fold greater resistance to the UCN‐01‐induced growth‐inhibitory effect than the parent cells, SBC‐3. No UCN‐01‐induced G1 accumulation in SBC‐3 cells was observed in SBC‐3/UCN cells and decreased expression of phosphorylated RB protein was found in SBC‐3 cells. Neither basal expression nor induction of p21Cip1 by UCN‐01 treatment was detected in the SBC‐3/UCN cell line. An inhibitory effect of UCN‐01 on CDK2 activity, which is mediated by p21Cip1/CDK2 complex formation upon UCN‐01 treatment, was observed in SBC‐3 but not in SBC‐3/UCN cells. SBC‐3/UCN showed higher CDK6 activity than SBC‐3 cells. UCN‐01 did not inhibit the CDK4 and CDK6 activities in both cells. We screened the cell cycle regulatory molecules associated with G1/S progression and found a remarked decrease in interferon regulatory factor 1 (IRF‐1), which is known to cooperate with p53 in p21Cip1 induction. Our results suggest that p21Cip1 regulation via the IRF‐1‐associated pathway may represent a major determinant of UCN‐01‐induced growth inhibition in human lung cancer cells. Int. J. Cancer 85:275–280, 2000. ©2000 Wiley‐Liss, Inc.