Phosphodiesterase 5 inhibitor acts as a potent agent sensitizing acute myeloid leukemia cells to 67-kDa laminin receptor-dependent apoptosis.

Abstract

(-)-Epigallocatechin-3-O-gallate (EGCG), a polyphenol in green tea, induces apoptosis in acute myeloid leukemia (AML) cells without affecting normal cells. In this study, we observed that cGMP acts as a cell death mediator of the EGCG-induced anti-AML effect through acid sphingomyelinase activation. EGCG activated the Akt/eNOS axis, a well-known mechanism in vascular cGMP upregulation. We also observed that a major cGMP negative regulator, phosphodiesterase 5, was overexpressed in AML cells, and PDE5 inhibitor, an anti-erectile dysfunction drug, synergistically enhanced the anti-AML effect of EGCG. This combination regimen killed AML cells via overexpressed 67-kDa laminin receptors.

• Authors: Motofumi Kumazoe, Yoonhee Kim, Jaehoon Bae, Mika Takai, Motoki Murata, Yumi Suemasu, Kaori Sugihara, Shuya Yamashita, Shuntaro Tsukamoto, Yuhui Huang, Kanami Nakahara, Koji Yamada, Hirofumi Tachibana
• Journal: FEBS letters (FEBS Lett) Vol. 587 Issue 18 Pg. 3052-7 (Sep 17 2013) ISSN: 1873-3468 [Electronic] England
• PMID: 23916810 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Chemical References

• Phosphodiesterase 5 Inhibitors
• Receptors, Laminin
• Catechin
• epigallocatechin gallate
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• Oncogene Protein v-akt
• Sphingomyelin Phosphodiesterase
• Cyclic Nucleotide Phosphodiesterases, Type 5
• Cyclic GMP

Topics

• Apoptosis (drug effects)
• Catechin (analogs & derivatives, pharmacology)
• Cyclic GMP (metabolism)
• Cyclic Nucleotide Phosphodiesterases, Type 5 (genetics, metabolism)
• Drug Synergism
• Enzyme Activation (drug effects)
• Gene Expression Regulation, Leukemic (drug effects)
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (drug therapy, genetics, metabolism, pathology)
• Nitric Oxide Synthase Type III (genetics, metabolism)
• Oncogene Protein v-akt (genetics, metabolism)
• Phosphodiesterase 5 Inhibitors (pharmacology)
• Primary Cell Culture
• Receptors, Laminin (agonists, genetics, metabolism)
• Signal Transduction
• Sphingomyelin Phosphodiesterase (genetics, metabolism)