title: Cryptotanshinone enhances TNF-α-induced apoptosis in chronic myeloid leukemia KBM-5 cells.
abstract: Cryptotanshinone is a biologically active compound from the root of Salvia miltiorrhiza. In the present study, we investigated the molecular mechanisms by which cryptotanshinone is in synergy with tumor necrosis factor-alpha (TNF-α) for the induction of apoptosis in human chronic myeloid leukemia (CML) KBM-5 cells. The co-treatment of cryptotanshinone with TNF-α reduced the viability of the cells [combination index (CI) < 1]. Concomitantly, the co-treatment of cryptotanshinone and TNF-α elicited apoptosis, manifested by enhanced the number of terminal deoxynucleotide transferase-mediated dUTP-nick-end labeling (TUNEL)-positive cells, the sub-G1 cell populations, and the activation of caspase-8 and -3, in comparison with the treatment with either drug alone. The treatment with cryptotanshinone further suppressed TNF-α-mediated expression of c-FLIP(L), Bcl-x(L), but the increased level of tBid (a caspase-8 substrate). Furthermore, cryptotanshinone activated p38 but not NF-κB in TNF-α-treated KBM-5 cells. The addition of a specific p38 MAPK inhibitor SB203580 significantly attenuated cryptotanshinone/TNF-α-induced apoptosis. The combination treatment of cryptotanshinone and TNF-α also stimulated the reactive oxygen species (ROS) generation. N-acetyl-L-cysteine (NAC, a ROS scavenger) was not only able to block cryptotanshinone/TNF-α-induced ROS production but also the activation of caspase-8 and p38 MAPK. Overall, our findings suggest that cryptotanshinone can sensitize TNF-α-induced apoptosis in human myeloid leukemia KBM-5 cells, which appears through ROS-dependent activation of caspase-8 and p38.
authors.affiliation: Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, Seoul, 130-701, South Korea. sungkim7@khu.ac.kr
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Tae-Rin
authors.initials: TR
authors.lastname: Kwon
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Minseok
authors.initials: M
authors.lastname: Kim
authors.forename: Hyo-Jung
authors.initials: HJ
authors.lastname: Lee
authors.forename: Min-Ho
authors.initials: MH
authors.lastname: Lee
authors.forename: Seong Gyu
authors.initials: SG
authors.lastname: Ko
authors.forename: Chang-Yan
authors.initials: CY
authors.lastname: Chen
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology / Q000473:pathology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010616:Phenanthrenes / Q000737:chemistry / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D010616:Phenanthrenes; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C037886:cryptotanshinone; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human