Quercetin simultaneously induces G0 /G1 -phase arrest and caspase-mediated crosstalk between apoptosis and autophagy in human leukemia HL-60 cells.

Abstract

Quercetin is a plant-derived bioflavonoid with high anticancer activity in various tumors. Herein, the molecular mechanisms by which quercetin exerts its anticancer effects against HL-60 acute myeloid leukemia (AML) cells were investigated. Results showed that quercetin suppressed cell proliferation in the HL-60 cell line in vitro and in vivo. Quercetin-induced G0 /G1 -phase arrest occurred when expressions of cyclin-dependent kinase (CDK)2/4 were inhibited and the CDK inhibitors, p16 and p21, were induced. Moreover, quercetin treatment not only activated proapoptotic signaling like poly (ADP ribose) polymerase (PARP)-1 cleavage and caspase activation but also triggered autophagy events as shown by the increased expression of light chain 3 (LC3)-II, decreased expression of p62, and formation of acidic vesicular organelles. Interestingly, it was found that use of the autophagy inhibitor, 3-methyladenine, significantly enhanced quercetin-mediated apoptotic cell death as analyzed by MTS and DNA fragmentation assays. Moreover, pretreatment of HL-60 cells with the pan-caspase inhibitor, Z-VAD-fmk, dramatically reversed quercetin-mediated apoptotic and autophagic cell death. Although apoptosis and autophagy are two independent cell death pathways, our findings indicated that quercetin can activate caspases to trigger these two pathways, and both pathways played contrary roles in quercetin-mediated HL-60 cell death. In conclusion, besides promoting apoptosis, quercetin also induced cytoprotective autophagy in HL-60 cells, and inhibition of autophagy may be a novel strategy to enhance the anticancer activity of quercetin in AML.

• Authors: Junn-Liang Chang, Jyh-Ming Chow, Jer-Hwa Chang, Yu-Ching Wen, Yung-Wei Lin, Shun-Fa Yang, Wei-Jiunn Lee, Ming-Hsien Chien
• Journal: Environmental toxicology (Environ Toxicol) Vol. 32 Issue 7 Pg. 1857-1868 (Jul 2017) ISSN: 1522-7278 [Electronic] United States
• PMID: 28251795 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Amino Acid Chloromethyl Ketones
• Antineoplastic Agents, Phytogenic
• Caspase Inhibitors
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• 3-methyladenine
• Quercetin
• Poly(ADP-ribose) Polymerases
• Caspases
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Amino Acid Chloromethyl Ketones (pharmacology)
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Caspase Inhibitors (pharmacology)
• Caspases (metabolism)
• Cell Proliferation (drug effects)
• Enzyme Activation
• G1 Phase Cell Cycle Checkpoints (drug effects)
• HL-60 Cells
• Humans
• Poly(ADP-ribose) Polymerases (metabolism)
• Quercetin (pharmacology)
• Resting Phase, Cell Cycle (drug effects)
• Signal Transduction