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항암 활성 연구를 위한 최적의 모델로서 2-D culture 모델은 여전히 널리 사용되고 있으나, 종양 환경에 더 잘 근접할 수 있는 3D MTS 모델은 시험관 내 모델 연구와 동물 모델 연구 간의 격차를 해소하기 위한 대안이 될 수 있다. Isoalantolactone은 목향(木香: Elecampane, Inula helenium L.)을 포함한 약용 식물에서 발견되는 sesquiterpene lactone 중의 하나로서 항암 활성을 포함한 다양한 약리학적 활성을 가지고 있는 것으로 알려져 있다. 본 연구에서는 HCC Hep3B 세포에서 유래된 2D 모델에서 관찰된 isoalantolactone의 항암 활성이 3D MTS 모델에서도 재현될 수 있는지를 조사하였다. 우리들의 결과에 의하면 isoalantolactone은 처리 농도 의존적으로 MTSs 형성을 억제하였으며, ROS 생성의 증가를 동반하였다. 특히 isoalantolactone 처리 및 배양 시간이 증가하면서 증식성 세포 영역이 세포사멸이 유발된 세포로 대체되었다. 또한, MTSs에서 isoalantolactone은 DR 관련 단백질들의 발현과 caspase-3의 활성을 증가시켰고, Bax/Bcl-2 발현 비율 및 총 PARP 단백질의 발현은 감소시켰다. 그러나 ROS의 생성을 인위적으로 차단하였을 경우, isoalantolactone에 의한 이러한 변화들이 모두 차단되면서 MTSs 구성 세포들의 세포 생존율을 회복시켰다. 따라서 본 연구의 결과는 isoalantolactone에 의한 Hep3B 세포 유래 MTSs의 세포사멸 유도는 외인성 및 내인성 경로의 활성화를 통하여 이루어지며 이는 ROS 의존적임을 시사한다.

Although two-dimensional (2D) monolayer cell culture models are still widely used as the optimal models for anticancer activity research, three-dimensional (3D) multicellular tumor spheroid (3D MTS) models that can better approximate the tumor environment can offer an alternative to bridge the gap between in vitro and animal model studies. Isoalantolactone is among the sesquiterpene lactones found in medicinal plants, including the roots of Elecampane (Inula helenium L.), and is known to have various pharmacological activities, including anticancer activity. In this study, we investigated whether the anticancer activity of isoalantolactone observed in 2D models could be reproduced in a 3D MTS model derived from human hepatocellular carcinoma (HCC) Hep3B cells. According to our results, isoalantolactone inhibited the formation of MTSs in a manner dependent on the treatment concentration, which was accompanied by an increase in reactive oxygen species (ROS) generation. In particular, as isoalantolactone treatment and the culture time increased, the area of proliferating cells was replaced by cells in which apoptosis was induced. Additionally, in MTSs, isoalantolactone increased the expression of death-receptor-related proteins and the activity of caspase-3, and it decreased the expression of the Bax/Bcl-2 expression ratio and total poly(ADP-ribose) polymerase. However, when the production of ROS was artificially blocked, all these changes caused by isoalantolactone were attenuated and the cell survival rate of MTS cells was restored. Therefore, the results of this study suggest that the induction of apoptosis in Hep3B cell-derived MTSs by isoalantolactone is achieved through the activation of extrinsic and intrinsic pathways and is ROS-dependent.

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기사명 저자명 페이지 원문 목차
L-AHG-mediated suppression of M1 polarization and pro-inflammatory signaling pathways in LPS-stimulated RAW264.7 macrophages = LPS에 의해 자극된 RAW264.7 대식세포에서 L-AHG에 의한 M1 분극화 및 친염증 신호 경로의 억제 Won Young Jang, Shin Young Park, Ki Youn Kim, Do Youn Jun, Young-Seuk Bae, Young Ho Kim p. 443-452

메주의 크기에 따른 간장의 미생물 군집 변화 양상 분석 = Analysis of microbial community change in ganjang according to the size of meju 정호진, 하광수, 이란희, 정도연, 양희종 p. 453-464

Lactiplantibacillus plantarum K9 유전체 분석을 통해 필수 물질대사 경로의 탐색 = Examination of the central metabolic pathway with genomics in Lactiplantibacillus plantarum K9 김삼웅, 김영진, 최효인, 이상원, 지원재, 방우영, 김태완, 방규호, 갈상완 p. 465-475

ROS 의존적 세포사멸 유도를 통한 isoalantolactone의 인간 간세포암종 Hep3B 세포 유래 다세포 종양 spheroid 형성의 억제 = Isoalantolactone inhibits the formation of multicellular tumor spheroids derived from human hepatocellular carcinoma Hep3B cells through the induction of ROS-dependent apoptosis 김민영, 손변우, 이상엽, 박상은, 홍수현, 홍상훈, 김은정, 최영현, 황보현 p. 476-484

발효해삼의 항산화 및 면역강화 기능성 물질의 분석 = Examination of antioxidant and immune-enhancing functional substances in fermented sea cucumber 김삼웅, 김가희, 김범철, 이유빈, 이가빈, 갈상완, 김철호, 방우영, 방규호 p. 485-492

대장균에서 항균 펩타이드 stomoxyn을 생산하기 위한 형질전환 벡터 제작 = Construction of a plant chloroplast transformation vector to produce the antimicrobial peptide stomoxyn 고진규, 길현호, 김순영 p. 493-499

염촉매 전기분해 공기살균기의 효능 평가 = Efficacy and safety evaluation of an air sterilizer equipped with an electrolytic salt catalyst for the removal of indoor microbial pollutants 유선녕, 전호연, 김부경, 김애리, 정경일, 전계록, 안순철 p. 500-508

Scopolamine 유도 인지 저하 마우스 모델에서 크릴 오일의 인지 개선 효과 = Cognitive improvement effects of krill oil in a scopolamine-induced mice model 설혜민, 이정아, 황미선, 박상훈, 김형수 p. 509-519

소세포폐암의 미세환경에서 후성학적 조절인자의 역할에 대한 최신 연구 동향 = Recent findings on the role of epigenetic regulators in the small-cell lung cancer microenvironment 정민호, 김기범 p. 520-530

참고문헌 (44건) : 자료제공( 네이버학술정보 )

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번호 참고문헌 국회도서관 소장유무
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2 Cai, H., Meng, X., Li, Y., Yang, C. and Liu, Y. 2014. Growth inhibition effects of isoalantolactone on K562/A02cells: Caspase-dependent apoptotic pathways, S phase arrest, and downregulation of Bcr/Abl. Phytother. Res. 28, 1679-1686. 미소장
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5 Chen, W., Li, P., Liu, Y., Yang, Y., Ye, X., Zhang, F. and Huang, H. 2018. Isoalantolactone induces apoptosis through ROS-mediated ER stress and inhibition of STAT3in prostate cancer cells. J. Exp. Clin. Cancer Res. 37, 309. 미소장
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17 Kim, M. Y., Lee, H., Ji, S. Y., Kim, S. Y., Hwangbo, H., Park, S. H., Kim, G. Y., Park, C., Leem, S. H., Hong, S. H. and Choi, Y. H. 2021. Induction of apoptosis by isoalantolactone in human hepatocellular carcinoma Hep3B cells through activation of the ROS-dependent JNK signaling pathway. Pharmaceutics 13, 1627. 미소장
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26 Mirzayans, R. and Murray, D. 2020. Do TUNEL and other apoptosis assays detect cell death in preclinical studies? Int. J. Mol. Sci. 21, 9090. 미소장
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29 Namekawa, T., Ikeda, K., Horie-Inoue, K. and Inoue, S. 2019. Application of prostate cancer models for preclinical study: Advantages and limitations of cell lines, patient-derived xenografts, and three-dimensional culture of patient-derived cells. Cells 8, 74. 미소장
30 Park, C., Cha, H. J., Kim, D. H., Kwon, C. Y., Park, S. H., Hong, S. H., Bang, E., Cheong, J., Kim, G. Y. and Choi, Y. H. 2023. Fisetin protects C2C12 mouse myoblasts from oxidative stress-induced cytotoxicity through regulation of the Nrf2/HO-1 signaling. J. Microbiol. Biotechnol. 33, 591-599. 미소장
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32 Rasul, A., Di, J., Millimouno, F. M., Malhi, M., Tsuji, I., Ali, M., Li, J. and Li, X. 2013. Reactive oxygen species mediate isoalantolactone-induced apoptosis in human prostate cancer cells. Molecules 18, 9382-9396. 미소장
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