Role of a small molecular weight phosphoprotein in the mechanism of action of CI-994 (N-acetyldinaline).
The mechanism of action of the novel anti-cancer compound CI-994 was studied in C26 murine colon tumor and HCT-8 human colon adenocarcinoma cells. Treatment of either cell line resulted in the specific loss of a 16-kDa phosphoprotein in a time- and concentration-dependent manner. Treatment with salicylanilide, CI-940, mimosine, aphidicolin, quercetin or ciclopirolxalamine, which, like CI-994, block cells in the G1-S phase of the cell cycle, did not affect the production of this protein. Loss of the 16-kDa protein preceded the block in cell proliferation induced by CI-994 treatment, and recovery of this protein was evident prior to the resumption of cell growth. Cellular fractionation studies demonstrated that the 16 kDa phosphoprotein is confined to the nuclear compartment. Our data indicate that loss the 16-kDa nuclear phosphoprotein appears to be a direct effect of CI-994 treatment and that the inhibition of this phosphoprotein may play a critical role in the mechanism of action of CI-994.
Rummel
S A
SA
Department of Cancer Research, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Co., Ann Arbor, MI 48105, USA.
Kraker
A J
AJ
Steinkampf
R W
RW
Hook
K E
KE
Klohs
W D
WD
D000230:Adenocarcinoma / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D002453:Cell Cycle / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000188:drug therapy; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008970:Molecular Weight; D010655:Phenylenediamines / Q000494:pharmacology*; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D012458:Salicylanilides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D010655:Phenylenediamines; D010750:Phosphoproteins; D012458:Salicylanilides; C034596:salicylanilide; C081895:tacedinaline