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Enhanced cell growth inhibition by thiacremonone in paclitaxel-treated lung cancer cells

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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.

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Acknowledgments

This work was supported by National Research Foundation of Korea (NRF) Grant by the Korea government (MEST; MRC, 2008-0062275) and by the research grant of Chungbuk National University in 2014.

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The authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. College of Pharmacy and Medical Research Center, Chungbuk National University, 52, Naesudong-ro, Heungdeok-gu, Cheongju, Chungbuk, 361-763, Republic of Korea

    Jung Ok Ban, Chul Ju Hwang, Mi Hee Park, Hee Pom Lee, Byoung Kook Hyun, Ji Young Kim, Hae Suk Youn, Sang-Bae Han & Jin Tae Hong

  2. Agriculture, Life and Environments Sciences, Chungbuk National University, 52, Naesudong-ro, Heungdeok-gu, Cheongju, Chungbuk, 361-763, Republic of Korea

    In-Kook Hwang & Heon-Sang Jeong

  3. Deparment of Chemistry and Biochemistry, Brigham Young University, C409 BNSN, Provo, UT, 84602, USA

    Young Wan Ham

  4. Department of Bioscience and Biotechnology Bio/Molecular Informatics Center, Konkuk University, Hwayang-dong 1, Gwangjin-gu, Seoul, 143-701, Korea

    Do Young Yoon

  5. Department of Obstetrics and Gynecology, Daejeon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 64, Daeheung-ro, Jung-gu, Daejeon, 301-723, Republic of Korea

    Min Jong Song

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Fig. S1

Effect of the combination treatment of thiacremonone and other chemotherapeutics on cell viability. A, NCI-H460 and A549 lung cancer cells were treated with various concentration of paclitaxel, doxorubicin, cisplatin and docetaxel for 48 h. Cell viability was determined by cell counting using trypan blue exclusion as described in Materials and methods” section, and the results were expressed as percentage of dead cells. Quantification of synergism for thiacremonone and paclitaxel was calculated described in material methods. The type of interaction that occured at each particular drug combination was determined by the calculation of combination indices (CI). Values are each the mean ± SD of three experiments, each performed in triplicate (TIFF 599 kb)

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Ban, J.O., Hwang, C.J., Park, M.H. et al. Enhanced cell growth inhibition by thiacremonone in paclitaxel-treated lung cancer cells. Arch. Pharm. Res. 38, 1351–1362 (2015). https://doi.org/10.1007/s12272-015-0589-4

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