Induction of p16INK4a transcription and of cellular senescence by aclacinomycin-derivatives and cardiac glycosides.
Stable transformants of Saos-2 cells that contain the luciferase reporter gene under the control of the human p16INK4a transcriptional regulatory region were established, and were used to identify growth-inhibiting substances from culture broths of actinomycetes and extracts of plants. Among the active substances so far identified were an aclacinomycin-derivative, cenerubin B, and a cardiac glycoside, periplocin. These substances inhibited growth of normal human fibroblasts, and induced senescent phenotypes including a flattened morphology and increased acidic beta-galactosidase activity, although the activities of their derivatives to induce p16CDKN2 and beta-galactosidase did not coincided with each other. These results suggest that the reporter system using the p16CDKN2 transcriptional regulatory region is a useful means for screening growth inhibiting substances that are potential anti-tumor agents.
Egawa
Kiyoshi
K
Department of Microbiology, Showa University School of Pharmaceutical Sciences, Tokyo, Japan.
Kurihara
Yosuke
Y
Ito
Tatsuya
T
Matsumoto
Masahiko
M
Nose
Kiyoshi
K
D015250:Aclarubicin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019942:Genes, p16 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014407:Tumor Cells, Cultured
D002301:Cardiac Glycosides; C011157:aclacinomycins; D015250:Aclarubicin