Synthetic retinoid CD437 induces cell-dependent cycle arrest by differential regulation of cell cycle associated proteins.
BACKGROUND
The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene (CD437) exhibits a wide spectrum antitumor activity through induction of cellular apoptosis and cell cycle arrest. We investigated the effects and mechanisms of CD437 on cell cycle arrest of gastric cancer cells.


METHODS
The activities of CD437 on cell growth were analyzed by measuring total cellular DNA. The effects of CD437 on cell cycle phase distribution were analyzed using flow cytometry. The levels of cell cycle associated proteins were analyzed by Western blot. The activities of cyclin-dependent kinases (cdks) were analyzed by phosphorylation of the histone H1 protein.


RESULTS
CD437 at concentrations between 0.1 and 10 microM profoundly suppressed the growth of all six gastric cancer cell lines. Growth suppression associated with induction of G0/G1 or G2/M arrest was cell-line-dependent. CD437 decreased levels of cdk inhibitor p21 in G2/M-arrested SC-M1 cells. However, CD437 increased p21 levels in G0/G1-arrested AGS cells. Total and activated cyclin-dependent kinases were differentially regulated by CD437 in AGS and SC-M1 cells. CD437 (1 microM) induced activity of cdk2- and p34cdc2-associated H1 kinase by 14.6- and 1.8-fold, respectively, in SC-M1 cells. In contrast, CD437 slightly increased (1.6-fold) the cdk2-associated H1 kinase activity in AGS cells.


CONCLUSIONS
CD437 profoundly suppressed the growth of gastric cancer cells, which was associated with cell-dependent induction of G0/G1 or G2/M arrest. The differential regulation of p21 that leads to alteration in the activity of cdks may play a critical role in cell-line-dependent regulation of cell cycle arrest following treatment with CD437.
Shyu
Rong-Yaun
RY
Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan, Republic of China.
Lin
Ding-Yen
DY
Reichert
Uwe
U
Jiang
Shun-Yuan
SY
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects* / Q000502:physiology; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D012176:Retinoids / Q000494:pharmacology*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C099555:CD 437; D018797:Cell Cycle Proteins; D006131:Growth Inhibitors; D012176:Retinoids