Cell death triggered by synthetic flavonoids in human leukemia cells is amplified by the inhibition of extracellular signal-regulated kinase signaling.

Abstract

A new class of methyl esters of flavonoids, with different substituents on the B ring were synthesized and evaluated for their antiproliferative activity against the human leukemia cell line HL-60. The presence of either a methyl group (1f) or a chlorine atom (1o) at position 2' of the B ring played an important role in affecting antiproliferative activity. The cytotoxic effects of these compounds were accompanied by the concentration- and time-dependent appearance of DNA- and nuclear-fragmentation, increase in the percentage of sub-G(1) cells, and processing of multiple caspases and poly(ADP-ribose)polymerase cleavage. Pretreatment of cells with the specific mitogen-activated extracellular kinases (MEK) 1/2 inhibitor PD98059, together with 1f and 1o, resulted in an important enhancement of cell death, which might have clinical implications for the use of both compounds in combination with MEK 1/2 inhibitors as potential therapeutic agents.

• Authors: Sara Rubio, Francisco León, José Quintana, Stephen Cutler, Francisco Estévez
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 55 Pg. 284-96 (Sep 2012) ISSN: 1768-3254 [Electronic] France
• PMID: 22867530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Masson SAS. All rights reserved.

Chemical References

• Antineoplastic Agents
• Flavones
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• Caspases

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Caspases (metabolism)
• Enzyme Activation (drug effects)
• Flavones (chemical synthesis, chemistry, pharmacology)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• HL-60 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Leukemia (pathology)
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)