title: 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.affiliation: Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581, Japan.
authors.forename: Motofumi
authors.initials: M
authors.lastname: Kumazoe
authors.forename: Yoonhee
authors.initials: Y
authors.lastname: Kim
authors.forename: Jaehoon
authors.initials: J
authors.lastname: Bae
authors.forename: Mika
authors.initials: M
authors.lastname: Takai
authors.forename: Motoki
authors.initials: M
authors.lastname: Murata
authors.forename: Yumi
authors.initials: Y
authors.lastname: Suemasu
authors.forename: Kaori
authors.initials: K
authors.lastname: Sugihara
authors.forename: Shuya
authors.initials: S
authors.lastname: Yamashita
authors.forename: Shuntaro
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Huang
authors.forename: Kanami
authors.initials: K
authors.lastname: Nakahara
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Tachibana
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D061251:Primary Cell Culture; D017474:Receptors, Laminin / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D017474:Receptors, Laminin; D002392:Catechin; C045651:epigallocatechin gallate; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt; D013108:Sphingomyelin Phosphodiesterase; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP
keywords: (−)-epigallocatechin-3-O-gallate; 67-kDa laminin receptor; 67LR; AML; ASM; Acid sphingomyelinase; Acute myeloid leukemia; Apoptosis; EGCG; Epigallocatechin-3-O-gallate; Laminin receptor; PDE; acid sphingomyelinase; acute myeloid leukemia; cGMP; phosphodiesterase