title: Hydroxychavicol, a Piper betle leaf component, induces apoptosis of CML cells through mitochondrial reactive oxygen species-dependent JNK and endothelial nitric oxide synthase activation and overrides imatinib resistance.
abstract: Alcoholic extract of Piper betle (Piper betle L.) leaves was recently found to induce apoptosis of CML cells expressing wild type and mutated Bcr-Abl with imatinib resistance phenotype. Hydroxy-chavicol (HCH), a constituent of the alcoholic extract of Piper betle leaves, was evaluated for anti-CML activity. Here, we report that HCH and its analogues induce killing of primary cells in CML patients and leukemic cell lines expressing wild type and mutated Bcr-Abl, including the T315I mutation, with minimal toxicity to normal human peripheral blood mononuclear cells. HCH causes early but transient increase of mitochondria-derived reactive oxygen species. Reactive oxygen species-dependent persistent activation of JNK leads to an increase in endothelial nitric oxide synthase-mediated nitric oxide generation. This causes loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, cleavage of caspase 9, 3 and poly-adenosine diphosphate-ribose polymerase leading to apoptosis. One HCH analogue was also effective in vivo in SCID mice against grafts expressing the T315I mutation, although to a lesser extent than grafts expressing wild type Bcr-Abl, without showing significant bodyweight loss. Our data describe the role of JNK-dependent endothelial nitric oxide synthase-mediated nitric oxide for anti-CML activity of HCH and this molecule merits further testing in pre-clinical and clinical settings.
authors.affiliation: Department of Cancer and Cell Biology, Council of Scientific and Industrial Research, Indian Institute of Chemical Biology, Kolkata, India.
authors.forename: Jayashree B
authors.initials: JB
authors.lastname: Chakraborty
authors.forename: Sanjit K
authors.initials: SK
authors.lastname: Mahato
authors.forename: Kalpana
authors.initials: K
authors.lastname: Joshi
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Shinde
authors.forename: Srabanti
authors.initials: S
authors.lastname: Rakshit
authors.forename: Nabendu
authors.initials: N
authors.lastname: Biswas
authors.forename: Indrani
authors.initials: I
authors.lastname: Choudhury Mukherjee
authors.forename: Labanya
authors.initials: L
authors.lastname: Mandal
authors.forename: Dipyaman
authors.initials: D
authors.lastname: Ganguly
authors.forename: Avik A
authors.initials: AA
authors.lastname: Chowdhury
authors.forename: Jaydeep
authors.initials: J
authors.lastname: Chaudhuri
authors.forename: Kausik
authors.initials: K
authors.lastname: Paul
authors.forename: Bikas C
authors.initials: BC
authors.lastname: Pal
authors.forename: Jayaraman
authors.initials: J
authors.lastname: Vinayagam
authors.forename: Churala
authors.initials: C
authors.lastname: Pal
authors.forename: Anirban
authors.initials: A
authors.lastname: Manna
authors.forename: Parasuraman
authors.initials: P
authors.lastname: Jaisankar
authors.forename: Utpal
authors.initials: U
authors.lastname: Chaudhuri
authors.forename: Aditya
authors.initials: A
authors.lastname: Konar
authors.forename: Siddhartha
authors.initials: S
authors.lastname: Roy
authors.forename: Santu
authors.initials: S
authors.lastname: Bandyopadhyay
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005054:Eugenol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D031721:Piper betle / Q000737:chemistry*; D010879:Piperazines / Q000494:pharmacology; D010936:Plant Extracts / Q000494:pharmacology; D018515:Plant Leaves / Q000737:chemistry; D011743:Pyrimidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D010936:Plant Extracts; D011743:Pyrimidines; D017382:Reactive Oxygen Species; C051268:2-hydroxychavicol; D009569:Nitric Oxide; D005054:Eugenol; D000068877:Imatinib Mesylate; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D016044:Fusion Proteins, bcr-abl; D048670:MAP Kinase Kinase 4