title: Enhanced cell growth inhibition by thiacremonone in paclitaxel-treated lung cancer cells.
abstract: Activation of nuclear factor kappa-B (NF-κB) is implicated in drug resistant of lung cancer cells. Our previous data showed that thiacremonone inhibited activation of NF-κB. In the present study, we investigated whether thiacremonone enhanced susceptibility of lung cancer cells to a common anti-cancer drug paclitaxel by further inhibition of NF-κB. Thus, we used the threefold lower doses of IC50 values (50 μg/ml thiacremonone and 2.5 nM paclitaxel). We found that combination treatment with thiacremonone and paclitaxel was more susceptible (combination index; 0.40 in NCI-H460 cells and 0.46 in A549 cells) in cell growth inhibition of two types of lung cancer cell lines compared to a single agent treatment. Consistent with the combination effect on cancer cell growth inhibition, the combination treatment further induced apoptotic cell death and arrested the cancer cells in G2/M phase accompanied with a much lower expression of cdc2 and cyclin B1, and inhibited colony formation. Much more inactivation of NF-κB and greater expression of NF-κB target apoptosis regulated genes such as caspase-8 and PARPs were found by the combination treatment. Molecular model and pull down assay as well as MALDI-TOF analysis demonstrated that thiacremonone directly binds to p50. These data indicated that thiacremonone leads to increased apoptotic cell death in lung cancer cell lines through greater inhibition of NF-κB by the combination treatment with paclitaxel.
authors: College of Pharmacy and Medical Research Center, Chungbuk National University, 52, Naesudong-ro, Heungdeok-gu, Cheongju, Chungbuk, 361-763, Republic of Korea.
authors: Jung Ok
authors: JO
authors: Ban
authors: Chul Ju
authors: CJ
authors: Hwang
authors: Mi Hee
authors: MH
authors: Park
authors: In-Kook
authors: IK
authors: Hwang
authors: Heon-Sang
authors: HS
authors: Jeong
authors: Hee Pom
authors: HP
authors: Lee
authors: Byoung Kook
authors: BK
authors: Hyun
authors: Ji Young
authors: JY
authors: Kim
authors: Hae Suk
authors: HS
authors: Youn
authors: Young Wan
authors: YW
authors: Ham
authors: Do Young
authors: DY
authors: Yoon
authors: Sang-Bae
authors: SB
authors: Han
authors: Min Jong
authors: MJ
authors: Song
authors: Jin Tae
authors: JT
authors: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053181:Caspase 8 / Q000096:biosynthesis; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects; D017239:Paclitaxel / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D013876:Thiophenes; C524083:thiacremonone; D011065:Poly(ADP-ribose) Polymerases; D053181:Caspase 8; D017239:Paclitaxel