Caffeine markedly sensitizes human mesothelioma cell lines to pemetrexed

• Published in: Cancer chemotherapy and pharmacology Vol. 61; no. 5; pp. 819 - 827
• Main Authors: Min, Sang Hee, Goldman, I. David, Zhao, Rongbao
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.04.2008; Springer; Springer Nature B.V
• Subjects: Antineoplastic agents; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Caffeine - administration & dosage; Caffeine - pharmacology; Cancer Research; Cell Cycle Proteins - drug effects; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Survival - drug effects; Checkpoint Kinase 1; DNA-Binding Proteins - drug effects; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Drug Administration Schedule; Folic Acid Antagonists - administration & dosage; Folic Acid Antagonists - pharmacology; Glutamates - administration & dosage; Glutamates - pharmacology; Guanine - administration & dosage; Guanine - analogs & derivatives; Guanine - pharmacology; Humans; Medical sciences; Medicine; Medicine & Public Health; Mesothelioma - drug therapy; Oncology; Original Article; Pemetrexed; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phosphorylation - drug effects; Protein Kinases - drug effects; Protein Kinases - metabolism; Protein-Serine-Threonine Kinases - drug effects; Protein-Serine-Threonine Kinases - metabolism; Theobromine - pharmacology; Tumor Suppressor Proteins - drug effects; Tumor Suppressor Proteins - metabolism; Theobromine; Mesothelioma; Pemetrexed; Caffeine; Antineoplastic agent; Antifolate; Human; Established cell line; Tumor; Xanthine derivatives; In vitro
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-007-0539-z

Pemetrexed is a new generation antifolate approved for the treatment of mesothelioma and non-small cell lung cancer. Caffeine is known to augment radiation or chemotherapeutic drug-induced cell killing. The current study addresses the impact of caffeine on the activity of pemetrexed in mesothelioma cell lines. Caffeine enhanced pemetrexed activity in all four mesothelioma cell lines tested (H2052, H2373, H28 and MSTO-211H). Caffeine sensitized H2052 cells in a dose- and schedule-dependent manner, and was associated with a markedly decreased clonogenic survival. Caffeine sensitization occurred only in cells subjected to pulse, but not continuous, exposure to pemetrexed. Similar pemetrexed sensitization was also observed with the clinically better tolerated caffeine analog, theobromine. Pemetrexed sensitization by caffeine was associated with an increase in pemetrexed-induced phosphorylation of ataxia-telangiectasia-mutated (ATM) and Chk1. These data indicate that caffeine and its analog, theobromine, may be a useful approach to enhance pemetrexed-based chemotherapy.