Phosphodiesterase inhibitors as anti-cancer drugs.

Abstract

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.

• Authors: Liron Hirsh, Ada Dantes, Byong-Sun Suh, Yoshio Yoshida, Kumiko Hosokawa, Kimihisa Tajima, Fumikazu Kotsuji, Ofer Merimsky, Abraham Amsterdam
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 68 Issue 6 Pg. 981-8 (Sep 15 2004) ISSN: 0006-2952 [Print] England
• PMID: 15313391 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Phosphodiesterase Inhibitors
• Xanthines
• methylxanthine
• Theophylline

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Cell Division (drug effects)
• Drug Synergism
• Female
• Humans
• Lung Neoplasms (pathology)
• Male
• Ovarian Neoplasms (pathology)
• Phosphodiesterase Inhibitors (pharmacology)
• Theophylline (pharmacology)
• Tumor Cells, Cultured
• Xanthines (pharmacology)