title: (6)-Gingerolinduced myeloid leukemia cell death is initiated by reactive oxygen species and activation of miR-27b expression.
abstract: The natural polyphenolic alkanone (6)-gingerol (6G) has established anti-inflammatory and antitumoral properties. However, its precise mechanism of action in myeloid leukemia cells is unclear. In this study, we investigated the effects of 6G on myeloid leukemia cells in vitro and in vivo. The results of this study showed that 6G inhibited proliferation of myeloid leukemia cell lines and primary myeloid leukemia cells while sparing the normal peripheral blood mononuclear cells, in a concentration- and time-dependent manner. Mechanistic studies using U937 and K562 cell lines revealed that 6G treatment induced reactive oxygen species (ROS) generation by inhibiting mitochondrial respiratory complex I (MRC I), which in turn increased the expression of the oxidative stress response-associated microRNA miR-27b and DNA damage. Elevated miR-27b expression inhibited PPARγ, with subsequent inhibition of the inflammatory cytokine gene expression associated with the oncogenic NF-κB pathway, whereas the increased DNA damage led to G2/M cell cycle arrest. The 6G induced effects were abolished in the presence of anti-miR-27b or the ROS scavenger N-acetylcysteine. In addition, the results of the in vivo xenograft experiments in mice indicated that 6G treatment inhibited tumor cell proliferation and induced apoptosis, in agreement with the in vitro studies. Our data provide new evidence that 6G-induced myeloid leukemia cell death is initiated by reactive oxygen species and mediated through an increase in miR-27b expression and DNA damage. The dual induction of increased miR-27b expression and DNA damage-associated cell cycle arrest by 6G may have implications for myeloid leukemia treatment.
authors.affiliation: Endocrinology Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
authors.forename: Namrata
authors.initials: N
authors.lastname: Rastogi
authors.affiliation: Endocrinology Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
authors.forename: Rishi Kumar
authors.initials: RK
authors.lastname: Gara
authors.affiliation: Endocrinology Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
authors.forename: Rachana
authors.initials: R
authors.lastname: Trivedi
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Singh
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
authors.forename: Preety
authors.initials: P
authors.lastname: Dixit
authors.affiliation: Medicinal and Process Chemistry Division, Central Drug Research Institute, Uttar Pradesh 226021, India.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Maurya
authors.affiliation: Department of Radiotherapy, CSM Medical University, Lucknow, Uttar Pradesh 226003, India.
authors.forename: Shivali
authors.initials: S
authors.lastname: Duggal
authors.affiliation: Department of Radiotherapy, CSM Medical University, Lucknow, Uttar Pradesh 226003, India.
authors.forename: M L B
authors.initials: ML
authors.lastname: Bhatt
authors.affiliation: Toxicology Division, Central Drug Research Institute, Lucknow, Uttar Pradesh 226001, India.
authors.forename: Sarika
authors.initials: S
authors.lastname: Singh
authors.affiliation: Endocrinology Division, Central Drug Research Institute, Uttar Pradesh 226021, India. Electronic address: dpm@cdri.res.in.
authors.forename: Durga Prasad
authors.initials: DP
authors.lastname: Mishra
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002396:Catechols / Q000008:administration & dosage; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D005233:Fatty Alcohols / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology*; D007963:Leukocytes, Mononuclear; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D002396:Catechols; D005233:Fatty Alcohols; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D017382:Reactive Oxygen Species; C007845:gingerol
keywords: (6)-Gingerol; Apoptosis; DNA damage; Free radicals; G2/M arrest; Myeloid leukemia; ROS; miR-27b