title: Disruption of the PI3K/AKT/mTOR signaling cascade and induction of apoptosis in HL-60 cells by an essential oil from Monarda citriodora.
abstract: We have isolated an essential oil from Monarda citriodora (MC) and characterized its 22 chemical constituents with thymol (82%), carvacrol (4.82%), β-myrcene (3.45%), terpinen-4-ol (2.78%) and p-cymene (1.53%) representing the major constituents. We have reported for the first time the chemotherapeutic potential of MC in human promyelocytic leukemia HL-60 cells by means of apoptosis and disruption of the PI3K/AKT/mTOR signaling cascade. MC and its major constituent, thymol, inhibit the cell proliferation in different types of cancer cell lines like HL-60, MCF-7, PC-3, A-549 and MDAMB-231. MC was found to be more cytotoxic than thymol in HL-60 cells with an IC50 value of 22 μg/ml versus 45 μg/ml for thymol. Both MC and thymol induce apoptosis in HL-60 cells, which is evident by Hoechst staining, cell cycle analysis and immuno-expression of Bcl-xL, caspase-3,-8,-9 and PARP-1 cleavage. Both induce apoptosis by extrinsic and intrinsic apoptotic pathways that were confirmed by enhanced expression of death receptors (TNF-R1, Fas), caspase-9, loss of mitochondrial membrane potential and regression of Bcl-2/Bax ratio. Interestingly, both MC and thymol inhibit the downstream and upstream signaling of PI3K/AKT/mTOR pathway. The degree of apoptosis induction and disruption of the PI3K signaling cascade by MC was significantly higher when compared to thymol.
authors.affiliation: Academy of Scientific and Innovative Research (AcSIR), Anusandhan Bhawan, 2 Rafi Marg, New Delhi, India; Cancer Pharmacology Division, Indian Institute of Integrative Medicine, CSIR, Jammu 180001, India.
authors.forename: Anup Singh
authors.initials: AS
authors.lastname: Pathania
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Guru
authors.forename: M K
authors.initials: MK
authors.lastname: Verma
authors.forename: Chetna
authors.initials: C
authors.lastname: Sharma
authors.forename: Sheikh Tasduq
authors.initials: ST
authors.lastname: Abdullah
authors.forename: Fayaz
authors.initials: F
authors.lastname: Malik
authors.forename: Suresh
authors.initials: S
authors.lastname: Chandra
authors.forename: Meenu
authors.initials: M
authors.lastname: Katoch
authors.forename: Shashi
authors.initials: S
authors.lastname: Bhushan
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D018922:HL-60 Cells / Q000187:drug effects; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D031338:Monarda / Q000737:chemistry*; D009822:Oils, Volatile / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012273:Ribulose-Bisphosphate Carboxylase / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013943:Thymol / Q000032:analysis / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D009822:Oils, Volatile; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012273:Ribulose-Bisphosphate Carboxylase; D058570:TOR Serine-Threonine Kinases; D013943:Thymol; D051028:bcl-2-Associated X Protein; C494826:BAX protein, human; C546842:MTOR protein, human; C101625:RbcL protein, plastid
keywords: 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide; Apoptosis; Essential oil; FBS; MC; MTT; Monarda citriodora; PARP; PBS; PI; PI3K/AKT/mTOR; PTP; Rh-123; Rhodamine-123; VEGF; essential oil from Monarda citriodora; fetal bovine serum; mTOR; mammalian target of rapamycin; mitochondrial membrane potential; permeability transition pore; phosphate buffer saline; poly-ADP-ribose polymerase; propidium iodide; vascular endothelial growth factor; Δψmt