Caffeine markedly sensitizes human mesothelioma cell lines to pemetrexed.
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.
Min
Sang Hee
SH
Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Goldman
I David
ID
Zhao
Rongbao
R
D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000008:administration & dosage / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005493:Folic Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005971:Glutamates / Q000008:administration & dosage / Q000494:pharmacology*; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008654:Mesothelioma / Q000188:drug therapy*; D000068437:Pemetrexed; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D013805:Theobromine / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005493:Folic Acid Antagonists; D005971:Glutamates; D025521:Tumor Suppressor Proteins; D000068437:Pemetrexed; D002110:Caffeine; D006147:Guanine; D011494:Protein Kinases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D017346:Protein Serine-Threonine Kinases; D013805:Theobromine