Ta. Slotkin et Fj. Seidler, Antimitotic and cytotoxic effects of theophylline in MDA-MB-231 human breast cancer cells, BREAST CANC, 64(3), 2000, pp. 259-267
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.