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 ce lls, 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 effect s of theophylline on macromolecule synthesis and indices of cell viability. Theophylline evoked a concentration- and time-dependent decrease in DNA sy nthesis. However, the net decrease in cell number was greater than that pre dicted solely from mitotic arrest. Assessment of protein synthesis indicate d a second effect of theophylline separable from that on DNA synthesis. Thi s was confirmed by decreased cell viability and adhesion. Exposure of the c ells to the phosphodiesterase inhibitor, IBMX, in concentrations that produ ced inhibition of DNA synthesis equivalent to that seen with theophylline, elicited a smaller reduction in cell number. Theophylline also evoked speci fic changes in the expression or function of membrane-bound adenylyl cyclas e activity, effects that are likely to contribute to sustained reactivity o f these cells to other cAMP-related inhibitors of cell proliferation, such as isoproterenol. The multiple pharmacologic properties of theophylline, pr oducing mitotic inhibition, cytotoxicity and altered signaling in MDA-MB-23 1 cells, may provide insight into novel therapeutic strategies.