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. 2014 Feb 17;19(2):2077-88.
doi: 10.3390/molecules19022077.

Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines

Gerhard Hamilton  1 , Lukas Klameth  2 , Barbara Rath  3 , Theresia Thalhammer  4
Affiliations

Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines

Gerhard Hamilton et al. Molecules. .

Abstract

Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our recent finding of synergistic enhancement of the cytotoxic activity of camptothecin (CPT) by cyclin-dependent kinase 4 inhibitors is extended here to a panel of camptothecin analogs comprising 10-hydroxy-CPT (HOCPT), topotecan (TPT; 9-[(dimethylamino)-methyl]-10-hydroxy-CPT), 9-amino-CPT (9AC), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin) and 10-hydroxy-9-nitrocamptothecin (CPT109) in combination with PD0332991, CDK4I, roscovitine and olomoucine. SCLC cell lines employed are chemoresistant NCI-H417 and DMS153 and the chemosensitive SCLC26A line established at our institution. The CPT analogs exhibiting highest cytotoxicity towards the three SCLC lines tested were SN38 and 9AC, followed by rubitecan, HOCPT, TPT and CPT109. NCI-H417 and DMS153 revealed an approximately 25-fold and 7-fold higher resistance compared to the chemosensitive SCLC26A cell line. Whereas the CDK4/6 inhibitor PD0332991 proved less effective to chemosensitize SCLC cells to CPT analogs, the CDK inhibitors CDK4I, roscovitine and olomoucine gave comparable chemosensitization effects in combination with 9AC, SN38, rubitecan and to a lesser extent with TPT and CPT109, not directly related with topoisomerase mRNA expression. In conclusion, small chemical modifications of the parent CPT structure result in differing cytotoxicities and chemomodulatory effects in combination with CDKIs of the resulting analogs.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of camptothecins used in the present study.
Figure 2
Figure 2
CPT, 10-hydroxy-CPT (HOCPT), topotecan (TPT), 9-aminocamptothecin (9AC), rubitecan, SN38 and CPT109 were tested for their cytotoxicity against NCI-H417, DMS153 and SCLC26A SCLC cell lines using MTT assays. IC50 values are presented as mean ± SEM (n = 3).
Figure 3
Figure 3
Cells were treated with the indicated concentrations of the CPT analogs (µM) in tissue culture for three days and the fixed and stained with propidium iodide for flow cytometric analysis (mean values ± SD).
Figure 4
Figure 4
Apoptotic DMS153 cells were detected as SubG1 cells in cell cycle analyses of CPT analog-treated cultures (mean values ± SD; all values significantly different, except for SN38 and 9AC).
Figure 5
Figure 5
The different CDK inhibitors employed in this study were assayed for cell cycle effects in NCI-H417 and DMS153 cells. Increases in G1/0 were significant for all CDK inhibitors, except for PD0332991, and for the reduction in G2M for all inhibitors for the NCI-H417 cells. In DMS153 cells, G1/0 was significantly increased in response to CDK4I, reduced in response to PD0332991 and olomoucine, whereas G2M was increased for PD0332991 and olomoucine, but reduced for roscovitine.
Figure 6
Figure 6
IC50 values for all CPT analogs in absence or presence of the respective inhibitors were calculated from dose-response curves. Since the CDK inhibitors exhibited no cytotoxic activity themselves at concentrations which showed synergistic effects with CPT cytotoxicity, the shift in IC50 values was measured and related to the IC50 values of the respective CPT analog (mean percentage of IC50 ± SD, n = 6).
Figure 7
Figure 7
Effects of the CDK inhibitors on topoisomerase I (TOP1) mRNA expression was assessed by qPCR in DMS153 cells which were treated with the inhibitors for four days (mean ± SD, n = 2).
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