Dividing phase-dependent cytotoxicity profiling of human embryonic lung fibroblast identifies candidate anticancer reagents.
Human Embryonic Lung fibroblasts (HEL cells) are widely used as a normal cell in studies of cell biology and can be easily maintained in the resting phase. Here we aimed to discover compounds that exhibit cytotoxicity against HEL cells in the dividing phase, but not in the resting phase. The cytotoxicity of each compound against HEL cells either in the resting phase or in the dividing phase was determined by MTT assay. Ratios of the IC50 of cells in the resting phase and that of cells in the dividing phase (RRD) for these compounds were compared. We selected 44 compounds that exhibited toxic effects on HEL cells in the dividing phase from a chemical library containing 325 anticancer drugs and enzyme inhibitors. The RRD values of those compounds were widely distributed. Paclitaxel and docetaxel, which are clinically used as anticancer drugs, had RRD values larger than 2000. On the other hand, the RRD value of dimethyl sulfoxide, an organic solvent, was 1. The cytotoxic effect of paclitaxel on HEL cells in the dividing phase was attenuated by aphidicolin, hydroxyurea, and nocodazole, confirming that the cytotoxic effects of paclitaxel are dependent on cells being in the dividing phase. Thapsigargin, whose RRD value was 800, the third highest RRD value in the library, exhibited therapeutic effects in a mouse model of FM3A ascites carcinoma. We suggest that compounds with high RRD values for HEL cells are candidate anticancer chemotherapy seeds.
Laboratory of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo.
Yoshinori
Y
Inagaki
Yasuhiko
Y
Matsumoto
Wei
W
Tang
Kazuhisa
K
Sekimizu
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016590:Aphidicolin / Q000494:pharmacology; D002277:Carcinoma / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D000077143:Docetaxel; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects*; D006918:Hydroxyurea / Q000494:pharmacology; D008168:Lung / Q000166:cytology*; D051379:Mice; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010534:Peritoneal Neoplasms / Q000188:drug therapy; D016192:Resting Phase, Cell Cycle / Q000187:drug effects*; D012997:Solvents / Q000494:pharmacology; D043823:Taxoids / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D012997:Solvents; D043823:Taxoids; D000077143:Docetaxel; D016590:Aphidicolin; D019284:Thapsigargin; D017239:Paclitaxel; D015739:Nocodazole; D006918:Hydroxyurea; D004121:Dimethyl Sulfoxide