Quinoxaline 1,4-dioxides induce G2/M cell cycle arrest and apoptosis in human colon cancer cells.
We have recently shown that quinoxaline 1,4-dioxide (QdNO) derivatives, namely 2-benzoyl-3-phenyl-6,7-dichloroquinoxaline 1,4-dioxide (DCQ), 2-benzoyl-3-phenyl-quinoxaline 1,4-dioxide (BPQ) and 2-acetyl-3-methyl-quinoxaline 1,4-dioxide (AMQ), suppress the growth of T-84 human colon cancer cells. Here we show that the growth-suppressive effects of QdNOs are due to their ability to induce cell cycle arrest and/or apoptosis. While AMQ blocked more than 60% of cells at the G2/M phase without inducing apoptosis, DCQ caused a significant increase in apoptotic cells with no noticeable effects on the cycling of cells. Treatment with BPQ resulted in G2/M cell cycle arrest and induction of apoptosis. With regard to the effects of QdNOs on molecules that regulate apoptosis and the G2 to M transition, both BPQ and AMQ inhibited the expression of cyclin B, while DCQ significantly decreased the levels of Bcl-2 and increased Bax expression. Next, we investigated whether transforming growth factor-beta1 (TGF-beta1) and/or extracellular signal-regulated kinase (ERK) mediate the antiproliferative and apoptotic effects of QdNOs in colon cancer cells. Interestingly, the above QdNOs increased differentially total TGF beta1 mRNA expression and decreased TGF alpha mRNA and ERK phosphorylation. None of these QdNOs induced changes in TGF beta-2 mRNA expression. The addition of a specific inhibitor of MEK greatly enhanced apoptosis in cells treated with DCQ, suggesting that the inhibition of ERK phosphorylation may explain, to an extent, the apoptogenic effects of this compound. Taken together, these findings provide insights into possible molecular mechanisms of growth inhibition by QdNOs that could aid in their evaluation for anticancer therapy.
Gali-Muhtasib
Hala U
HU
Department of Biology, American University of Beirut, Beirut, Lebanon. amro@aub.edu.lb.
Diab-Assaf
Mona
M
Department of Biology, American University of Beirut, Beirut, Lebanon.
Haddadin
Makhluf J
MJ
Department of Chemistry, American University of Beirut, Beirut, Lebanon.
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy*; D019926:Cyclin B / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D019926:Cyclin B; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; C003282:quindoxin; D048049:Extracellular Signal-Regulated MAP Kinases