It is well known that high intracellular levels of cAMP can effectively kill
cancer cells in vitro. Unfortunately substances elevating cAMP such as
forskolin,
8-bromo-cAMP,
8-chloro-cAMP, monobutiryl or dibutiryl cAMP are not recommended to be used as anti-
cancer drugs because of their high cytotoxicity. In contrast blockers of phosphodieterases such as
theophylline and
aminophylline, which could elevate intracellular cAMP, are commonly used as anti-
asthma drugs reaching concentrations in the blood of 10-20 microg/ml. We tested the effectiveness of
theophylline and
aminophylline to induce cell death alone or in combination with common anti-
cancer drugs such as
cisplatin and
gemcitabine (
gemzar). We examined such
drug combinations in the induction of cell death in a variety of
carcinoma cell lines derived from human ovarian, prostate and
lung cancer and in granulosa cell line transformed by SV40 and Ras oncogene. While
theophylline could induce moderate cell death alone, at 20-25 microg/ml concentrations,
aminophylline was ineffective at this concentration.
Theophylline (at 15-25 ng/ml) was found in all four representative cell lines to synergize with
gemcitabine or
cisplatin to induce programmed cell death, which permits a reduction in the effective doses of
cisplatin and
gemcitabine by 2-3-fold. The effect of
theophylline in induction of apoptosis involved reduction of intracellular levels of Bcl2. Such a reduction was proportional to the extent of apoptosis induced by
theophylline as well as by the combined
drug treatments. Therefore, we propose that
theophylline should be considered as a potential anti-
cancer drug in combination with other chemotherapeutic drugs. Screening of other
phosphodiesterase blockers, which are not severely toxic, could open a possibility to improved chemotherapeutic
cancer treatments with reduced undesired side-effects. A clinical trial, using
theophylline as an anti-
cancer drug, is currently being conducted in
lung cancer patients.