Tumor-specific cytotoxicity of 3,5-dibenzoyl-1,4-dihydropyridines.
In search of compounds which show tumor-specific cytotoxic activity, two 3,5-dibenzoyl-1, 4-dihydropyridines (GB5, GB12) were found to show one or two orders higher cytotoxic activity against human tumor cell lines (squamous cell carcinoma HSC-2, HSC-3, submandibular gland carcinoma HSG, promyelocytic leukemia HL-60) than human normal cells (gingival fibroblast HGF, pulp cells HPC, periodontal ligament fibroblasts HPLF). GB5 and GB12 weakly induced several apoptosis-associated properties, such as internucleosomal DNA fragmentation, and activation of caspases -3, -8 and -9, in both HL-60 and HSC-2 cells. Western blot analysis showed that GB5 and GB12 transiently increased the expression of both anti-apoptotic protein (Bcl-2) and proapoptotic proteins (Bax and Bad) in HL-60 cells. ESR spectroscopy showed these compounds did not produce any detectable amount of radicals, nor scavenged superoxide (generated by hypoxanthine-xanthine oxidase reaction) or nitric oxide (generated by 1-hydroxy-2-oxo-3-(N-3-methyl-3-aminopropyl)-3-methyl-1-triazene), suggesting that the induction of cytotoxic action is not via a radical-mediated reaction. The present study suggests that GB5 and GB12 may induce non-apoptotic cell death in tumor cell lines.
Morshed
Sufi Reza M D
SR
Meikai Pharmaco-Medical Laboratory (MPL), Meikai University School of Dentistry, Sakado, Saitama, Japan.
Hashimoto
Ken
K
Murotani
Yukie
Y
Kawase
Masami
M
Shah
Anamik
A
Satoh
Kazue
K
Kikuchi
Hirotaka
H
Nishikawa
Hirofumi
H
Maki
Jun
J
Sakagami
Hiroshi
H
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects; D016166:Free Radical Scavengers / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism; D013365:Submandibular Gland Neoplasms / Q000188:drug therapy; D013481:Superoxides / Q000378:metabolism
D000970:Antineoplastic Agents; D004095:Dihydropyridines; D016166:Free Radical Scavengers; D013481:Superoxides; D009569:Nitric Oxide