Extended-stage small cell lung cancer (SCLC) responds to platinum/vepeside-based
first-line chemotherapy but relapses rapidly as drug-resistant tumor. Topotecan (TPT) is the single
chemotherapeutic agent approved for second-line treatment of SCLC. However, the
response to TPT is short-lived and novel treatment modalities need to be
developed. Sequential treatment of cytotoxic drugs and inhibitors of
cyclin-dependent kinases (CDKs) showed promising preclinical anticancer
activity and, in the present work, combinations of TPT with CDK inhibitors olomoucine,
roscovitine and CDK4I are shown to exhibit synergistic cytotoxic activity
against SCLC cell lines. Highest activity was found against TPT-resistant
NCI-H417 and DMS153 cell lines and moderate chemosensitizing effects against a
primary SCLC cell line and sensitive GLC19 cells at levels of CDK inhibitors
which exerted low toxicity. A combination of 0.6 μM TPT with 0.6 μM
roscovitine, exhibiting no significant cytotoxicity as single agents, reduced
viability of the TPT-resistant NCI-H417 line
(IC50 > 10 μM) by 50%. In the TPT resistant cell lines olomoucine and
roscovitine, targeting CDK1,2,5,7, were highly effective, whereas in the
more sensitive cell lines CDK4I, inhibiting mainly CDK4/6, showed activity. In NCI-417 cells,
preincubation with roscovitine for one day proved synergistic with TPT. Thus,
in good accordance with previous findings, CDK inhibitors are able to convert
SCLC cancer cells which are cell-cycle arrested by a blockade of topoisomerase
I by TPT to apoptotic cells. Since nowadays several CDK inhibitors are at various phases of clinical
testing their combination with TPT seems to constitute a promising approach to
improve second-line chemotherapy in SCLC.