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Molecules 2014, 19(2), 2077-2088; doi:10.3390/molecules19022077
Article

Synergism of Cyclin-Dependent Kinase Inhibitors with Camptothecin Derivatives in Small Cell Lung Cancer Cell Lines

1,2,* , 1,3
, 1
 and 3
Received: 31 October 2013; in revised form: 21 January 2014 / Accepted: 29 January 2014 / Published: 17 February 2014
(This article belongs to the Special Issue Bioactivity-focused Semi-synthesis in Drug Discovery)
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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.
Keywords: small cell lung cancer; camptothecin; topotecan; rubitecan; cyclin-dependent kinase inhibitor; PD0332991; roscovitine; olomoucine; chemoresistance; MTT assay; cell cycle; topoisomerase I small cell lung cancer; camptothecin; topotecan; rubitecan; cyclin-dependent kinase inhibitor; PD0332991; roscovitine; olomoucine; chemoresistance; MTT assay; cell cycle; topoisomerase I
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Hamilton, G.; Klameth, L.; Rath, B.; Thalhammer, T. Synergism of Cyclin-Dependent Kinase Inhibitors with Camptothecin Derivatives in Small Cell Lung Cancer Cell Lines. Molecules 2014, 19, 2077-2088.

AMA Style

Hamilton G, Klameth L, Rath B, Thalhammer T. Synergism of Cyclin-Dependent Kinase Inhibitors with Camptothecin Derivatives in Small Cell Lung Cancer Cell Lines. Molecules. 2014; 19(2):2077-2088.

Chicago/Turabian Style

Hamilton, Gerhard; Klameth, Lukas; Rath, Barbara; Thalhammer, Theresia. 2014. "Synergism of Cyclin-Dependent Kinase Inhibitors with Camptothecin Derivatives in Small Cell Lung Cancer Cell Lines." Molecules 19, no. 2: 2077-2088.


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