Antitumor activity of pyrvinium pamoate, 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium pamoate salt, showing preferential cytotoxicity during glucose starvation.
An anthelminthic, pyrvinium pamoate (PP), 6-(dimethylamino)-2-[2-(2,5-dimethyl-1-phenyl-1H-pyrrol-3-yl)ethenyl]-1-methyl-quinolinium pamoate salt, has been found to be extremely toxic to PANC-1 cells in glucose-free medium, but not to be toxic to the same cells cultured in ordinary medium, Dulbecco's modified Eagle's medium (DMEM). It showed the same preferential toxicity for various cancer cell lines during glucose starvation. When 0.1 microg/ml PP was added to the medium, spheroid growth of human colon cancer cell line WiDr was strongly inhibited to a diameter of 750 microm, and this finding is consistent with the concept of anti-austerity. PP was also found to exert antitumor activity against human pancreatic cancer cell line PANC-1 in nude mice and SCID mice when it was administered subcutaneously or orally. Regarding the mechanism of PP action, inhibition of Akt phosphorylation, which has been found to be essential for the austerity mechanism, was observed in vitro and in vivo. These findings indicate that PP may be useful for anticancer therapy and that anti-austerity therapy could be a novel strategy for anticancer therapy.
Esumi
Hiroyasu
H
Investigative Treatment Division, National Cancer Center Research Institute East, Kashiwa, Chiba 277-8577, Japan. hesumi@east.ncc.go.jp
Lu
Jie
J
Kurashima
Yukiko
Y
Hanaoka
Tomoyuki
T
D000818:Animals; D018929:Cell Culture Techniques; D002455:Cell Division; D048429:Cell Size; D003110:Colonic Neoplasms / Q000473:pathology*; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011774:Pyrvinium Compounds / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D011518:Proto-Oncogene Proteins; D011774:Pyrvinium Compounds; C024631:pyrvinium; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose