Faculty Collaboration Database

Reduced DNA synthesis and cell viability in small cell lung carcinoma by treatment with cyclic AMP phosphodiesterase inhibitors. Biochem Pharmacol 1998 Nov 01;56(9):1229-36

Date

11/05/1998

Pubmed ID

9802335

DOI

10.1016/s0006-2952(98)00260-3

Scopus ID

2-s2.0-0031740825 (requires institutional sign-in at Scopus site)   46 Citations

Abstract

This study investigated the effects of the adenosine 3',5'-cyclic monophosphate (cAMP) phosphodiesterase inhibitors caffeine, theophylline, and 3-isobutyl-1-methyl-xanthine (IBMX) on the proliferation and viability of the small cell lung carcinoma (SCLC) cell lines NCI-H345, NCI-H128, and SCC-9. These effects were correlated with the ability of the drugs to induce intracellular Ca2+ mobilization. Treatment of NCI-H345 cells with caffeine resulted in rapid mobilization of Ca2+, as indicated by Fura-2 fluorescence. Incubation of NCI-H345 cells with 6.25 mM caffeine resulted in a 62% inhibition of [3H]thymidine uptake after 2 hr, indicating reduced DNA synthesis. Incubation with 25 mM caffeine resulted in almost total inhibition of [3H]thymidine uptake after 2 hr. Similar effects on [3H]thymidine uptake were seen upon treatment of NCI-H128 and SCC-9 cells with caffeine; however, these cells did not exhibit caffeine-induced Ca2+ mobilization. Inhibition of DNA synthesis (66-93%) also occurred upon incubation of all cell lines with theophylline and IBMX, which did not mobilize Ca2+. Treatment of NCI-H345, NCI-H128, and SCC-9 cells with caffeine, theophylline, or IBMX markedly reduced cell viability. Levels of cAMP increased in the cells following treatment with caffeine, theophylline, or IBMX, reflecting the ability of these drugs to inhibit cAMP phosphodiesterase. These results suggest that the decrease in DNA synthesis and the subsequent cell death induced by these drugs are due to reduced cAMP phosphodiesterase activity, rather than to changes in intracellular Ca2+. These findings indicate that drugs that alter cAMP signaling pathways are potentially valuable agents to inhibit SCLC survival.

Author List

Shafer SH, Phelps SH, Williams CL

Author

Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

3',5'-Cyclic-AMP Phosphodiesterases
Caffeine
Calcium
Carcinoma, Small Cell
Cell Survival
Cyclic AMP
DNA
Humans
Lung Neoplasms
Phosphodiesterase Inhibitors
Thymidine
Tumor Cells, Cultured