Tumor specific low pH environments enhance the cytotoxicity of lovastatin and cantharidin.
In tumor cell masses, the extracellular pH decreases below 6.5. The effect of external acidic pH on the efficacy of 24 chemical compounds including molecular-targeted inhibitors and anti-tumor reagents was investigated in human cancer cells. Lovastatin showed no cytotoxicity in mesothelioma or pancreatic carcinoma cells at concentrations up to 10 μM and pH around 7.4, but 10 μM lovastatin decreased the survival of these cells below 40% at acidic pH. Lovastatin inhibits HMG-CoA reductase, resulting in a decrease in the levels of cholesterol and prenylated proteins. An inhibitor of the former pathway showed pH-independent cytotoxic activity, whereas an inhibitor of the latter pathway had stronger activity at acidic pH. The inhibitory efficacy of cantharidin also increased at acidic pH. On the other hands, no pH dependency or slightly impaired efficacy at low pH conditions was observed in other 20 reagents, and especially, the activity of aphidicolin was suppressed under acidic conditions. These results suggested that screening under acidic conditions would be useful for developing new chemotherapeutic reagents.
Fukamachi
Toshihiko
T
Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan. toshy75@p.chiba-u.ac.jp
Chiba
Yoshie
Y
Wang
Xin
X
Saito
Hiromi
H
Tagawa
Masatoshi
M
Kobayashi
Hiroshi
H
D002193:Cantharidin / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008654:Mesothelioma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D002193:Cantharidin