Effect of vesnarinone in combination with anti-cancer drugs on lung cancer cell lines.
Vesnarinone, a quinolinone derivative which is used as an oral inotropic agent in the clinic, has recently also been shown to have anti-cancer activity. We have studied the anti-cancer effect of vesnarinone in combination with cisplatin, VP-16 (etoposide) and gemcitabine, against human lung cancer cell lines (PC-9 and Lu 134A) using the MTT assay and isobologram analysis. Simultaneously, by establishing two cisplatin-resistant sublines, i.e. PC-9/CDDP and Lu 134A/CDDP, we analyzed the cross-resistance between vesnarinone and cisplatin and the resistance-reversing effect of vesnarinone. Nuclear fragmentation, as the presumed mechanism of tumor cell growth inhibition, was further studied quantitatively using flow cytometric analysis. Combination of vesnarinone with the studied anti-cancer drugs had a synergic or additive inhibitory effect on both PC-9 and Lu 134A tumor cell growth. Neither decrease of the sensitivity to vesnarinone nor cross-resistance between vesnarinone and anti-cancer drugs was observed. On the contrary, vesnarinone showed a resistance-reversing effect. Both vesnarinone and the studied anti-cancer drugs could induce tumor cell apoptosis, but a definite correlation between nuclear fragmentation and the growth inhibitory effect was not established.
Fujita
M
M
Third Department of Internal Medicine, Hyogo College of Medicine, Japan. t-ohk@hyo-med.ac.jp
Tsuchida
T
T
Higashino
K
K
D000230:Adenocarcinoma / Q000188:drug therapy*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004396:Coloring Agents / Q000737:chemistry; D053938:DNA Fragmentation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005047:Etoposide / Q000008:administration & dosage; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011719:Pyrazines; D011804:Quinolines / Q000008:administration & dosage*; D013778:Tetrazolium Salts / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D004396:Coloring Agents; D011719:Pyrazines; D011804:Quinolines; D013778:Tetrazolium Salts; D013844:Thiazoles; D003841:Deoxycytidine; C041667:vesnarinone; D005047:Etoposide; C022616:thiazolyl blue; D002945:Cisplatin; D000093542:Gemcitabine