Antimitotic and cytotoxic effects of theophylline in MDA-MB-231 human breast cancer cells.
A variety of cancer cell lines, including MDA-MB-231 human breast cancer cells, exhibit mitotic inhibition by cAMP. In earlier work, we found that the phosphodiesterase inhibitor, theophylline, reduced the number of cells and altered cellular morphology. In the current study, we evaluated the effects of theophylline on macromolecule synthesis and indices of cell viability. Theophylline evoked a concentration- and time-dependent decrease in DNA synthesis. However, the net decrease in cell number was greater than that predicted solely from mitotic arrest. Assessment of protein synthesis indicated a second effect of theophylline separable from that on DNA synthesis. This was confirmed by decreased cell viability and adhesion. Exposure of the cells to the phosphodiesterase inhibitor, IBMX, in concentrations that produced inhibition of DNA synthesis equivalent to that seen with theophylline, elicited a smaller reduction in cell number. Theophylline also evoked specific changes in the expression or function of membrane-bound adenylyl cyclase activity, effects that are likely to contribute to sustained reactivity of these cells to other cAMP-related inhibitors of cell proliferation, such as isoproterenol. The multiple pharmacologic properties of theophylline, producing mitotic inhibition, cytotoxicity and altered signaling in MDA-MB-231 cells, may provide insight into novel therapeutic strategies.
Slotkin
T A
TA
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. t.slotkin@duke.edu
Seidler
F J
FJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D004247:DNA / Q000096:biosynthesis; D004261:DNA Replication / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D013806:Theophylline / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000970:Antineoplastic Agents; D010726:Phosphodiesterase Inhibitors; D004247:DNA; D013806:Theophylline; D000262:Adenylyl Cyclases; D015056:1-Methyl-3-isobutylxanthine