title: Induction of apoptosis in non-small lung carcinoma cell line (H1299) by combination of anti-asthma drugs with gemcitabine and cisplatin.
abstract: Gemcitabine and cisplatin are commonly used in chemotherapy, however, these drugs may cause severe cytotoxic side effects. Theophylline and aminophylline are commonly used as anti-asthma drugs and can block anti-phosphodiesterase activity. We examined whether these methylxanthins could effect lung cancer cell survival and synergise with gemcitabine and cisplatin to induce apoptosis. We found that theophylline induced apoptosis in the cultured H1299 cell line already at concentrations of 30 microg/ml, reaching an ED50% at 100 microg/ml. In contrast, aminophylline induced apoptosis at concentrations of 300 microg/ml and 17% apoptosis was evident at concentrations as high as 900 microg/ml, which is a lethal dose for in vivo treatment. Cisplatin induced apoptosis with ED50% of 0.8 microg/ml, while gemcitabine induced apoptosis with ED50% of 20 ng/ml. Using a combination of 20 microg/ml of theophylline (calculated as an effective but not toxic anti-asthma drug) with 10 ng/ml gemcitabine or with 0.3 microg/ml cisplatin significantly elevated incidence of apoptosis compared to gemcitabine or cisplatin alone at similar concentrations. In contrast, an observed synergistic effect between aminophylline and gemcitabine was evident only at concentrations of 80 microg/ml and 10 ng/ml respectively. However, no effect was apparent in combination doses of aminophylline (80 microg/ml) with cisplatin (0.3 microg/ml). The combined treatments involved reduction in the intracellular level of the anti-apoptotic Bcl-2 gene product. This corresponded with the extent of apoptosis induced by the various drug combinations. Thus, theophylline is significantly more effective than aminophylline in increasing the sensitivity of the H1299 lung cancer cells to the induction of cell death by gemcitabine and cisplatin. Thus, combination of theophylline with these drugs may permit a reduction in the effective dose needed in chemotherapy treatment of lung cancer patients.
authors.affiliation: Unit of Bone and Soft Tissue Oncology, Division of Oncology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel. oferm@tasmc.health.gov.il
authors.forename: O
authors.initials: O
authors.lastname: Merimsky
authors.forename: L
authors.initials: L
authors.lastname: Hirsh
authors.forename: A
authors.initials: A
authors.lastname: Dantes
authors.forename: A
authors.initials: A
authors.lastname: Land-Bracha
authors.forename: B S
authors.initials: BS
authors.lastname: Suh
authors.forename: A
authors.initials: A
authors.lastname: Amsterdam
mesh_terms: D018927:Anti-Asthmatic Agents / Q000008:administration & dosage*; D017209:Apoptosis; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011419:Propidium / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D013806:Theophylline / Q000008:administration & dosage* / Q000494:pharmacology; D000093542:Gemcitabine
chemical_list: D018927:Anti-Asthmatic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D003841:Deoxycytidine; D011419:Propidium; D013806:Theophylline; D002945:Cisplatin; D000093542:Gemcitabine