Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Arctigenin Suppresses the Proliferation and Metastasis, and Induces Apoptosis and Cycle Arrest of Osteosarcoma Cells by inhibiting HMOX1 Expression

Author(s): Guosong Xu, Zhensen He and Yinping Liu*

Volume 23, Issue 20, 2023

Published on: 19 September, 2023

Page: [2209 - 2216] Pages: 8

DOI: 10.2174/1871520623666230913105845

Price: $65


Background: Osteosarcoma is the most common malignant bone tumor, with highly proliferative and metastatic properties. Previous studies have reported that arctigenin (Arc), a bioactive lignin compound, showed excellent anti-tumor activities in a variety of human cancers. However, its role in osteosarcoma has not been studied.

Objective: We aimed to investigate the anti-tumor effects of Arc on osteosarcoma cell proliferation, migration, invasion, apoptosis, and cell cycle.

Methods: Effects of Arc on osteosarcoma cell proliferation were detected by MTT and colony formation assay. Flow cytometry analysis was performed to assess the cell apoptosis and cycle arrest. Transwell assay was used to evaluate the capability of migration and invasion. qRT-PCR and Western blot were employed to determine the changes in mRNA and protein levels.

Results: Arc could significantly suppress the proliferation, colony formation, and induce cell apoptosis and S phase cycle arrest of MG63 and U-2 OS cells in a dose-dependent manner. In addition, we also observed an inhibitory effect of Arc treatment on osteosarcoma cell invasion, migration, and epithelial-mesenchymal transition (EMT). HMOX1, encoding enzyme heme oxygenase-1, was predicted to be a candidate target of Arc using STITCH. Arc treatment significantly reduced the mRNA and protein levels of HMOX1. Furthermore, overexpression of HMOX1 could partly reverse the inhibitory effects of Arc on osteosarcoma cell malignant phenotypes.

Conclusion: Our results suggest that Arc inhibits the proliferation, metastasis and promotes cell apoptosis and cycle arrest of osteosarcoma cells by downregulating HMOX1 expression.

Keywords: Osteosarcoma, arctigenin, proliferation, migration, apoptosis, HMOX1.

Graphical Abstract
Harrison, D.J.; Geller, D.S.; Gill, J.D.; Lewis, V.O.; Gorlick, R. Current and future therapeutic approaches for osteosarcoma. Expert Rev. Anticancer Ther., 2018, 18(1), 39-50.
[] [PMID: 29210294]
Gill, J.; Gorlick, R. Advancing therapy for osteosarcoma. Nat. Rev. Clin. Oncol., 2021, 18(10), 609-624.
[] [PMID: 34131316]
Shoaib, Z.; Fan, T.M.; Irudayaraj, J.M.K. Osteosarcoma mechanobiology and therapeutic targets. Br. J. Pharmacol., 2022, 179(2), 201-217.
[] [PMID: 34679192]
Sheng, G.; Gao, Y.; Yang, Y.; Wu, H. Osteosarcoma and metastasis. Front. Oncol., 2021, 11, 780264.
[] [PMID: 34956899]
Sun, W.J.; Sha, Z.F.; Gao, H. Determination of arctiin and arctigenin in fructus arctii by reverse-phase HPLC. Yao Xue Xue Bao, 1992, 27(7), 549-551.
[PMID: 1442089]
Zhao, F.; Wang, L.; Liu, K. In vitro anti-inflammatory effects of arctigenin, a lignan from Arctium lappa L., through inhibition on iNOS pathway. J. Ethnopharmacol., 2009, 122(3), 457-462.
[] [PMID: 19429312]
Xu, X.; Piao, H.N.; Aosai, F.; Zeng, X.Y.; Cheng, J.H.; Cui, Y.X.; Li, J.; Ma, J.; Piao, H.R.; Jin, X.; Piao, L.X. Arctigenin protects against depression by inhibiting microglial activation and neuroinflammation via HMGB1/TLR4/NF-κB and TNF-α/TNFR1/NF-κB pathways. Br. J. Pharmacol., 2020, 177(22), 5224-5245.
[] [PMID: 32964428]
Shen, Y.F.; Liu, L.; Chen, W.C.; Hu, Y.; Zhu, B.; Wang, G.X. Evaluation on the antiviral activity of arctigenin against spring viraemia of carp virus. Aquaculture, 2018, 483, 252-262.
[] [PMID: 32287458]
He, Y.; Fan, Q.; Cai, T.; Huang, W.; Xie, X.; Wen, Y.; Shi, Z. Molecular mechanisms of the action of arctigenin in cancer. Biomed. Pharmacother., 2018, 108, 403-407.
[] [PMID: 30236849]
Luo, W.; Wang, F.; Luo, H.; Liu, H. Arctigenin inhibits human breast cancer cell proliferation, migratory and invasive abilities and epithelial to mesenchymal transition by targeting 4EBP1. Exp. Ther. Med., 2021, 21(6), 547.
[] [PMID: 33850519]
Wang, Y.; Lina, L.; Xu, L.; Yang, Z.; Qian, Z.; Zhou, J.; Suoni, L. Arctigenin enhances the sensitivity of cisplatin resistant colorectal cancer cell by activating autophagy. Biochem. Biophys. Res. Commun., 2019, 520(1), 20-26.
[] [PMID: 31564411]
Shi, H.; Zhao, L.; Guo, X.; Fang, R.; Zhang, H.; Dong, G.; Fu, J.; Yan, F.; Zhang, J.; Ning, Z.; Ma, Q.; Li, Z.; Li, C.; Dai, J.; Si, C.; Xiong, H. Arctigenin attenuates breast cancer progression through decreasing GM-CSF/TSLP/STAT3/β-Catenin signaling. Int. J. Mol. Sci., 2020, 21(17), 6357.
[] [PMID: 32887217]
Yang, S.; Ma, J.; Xiao, J.; Lv, X.; Li, X.; Yang, H.; Liu, Y.; Feng, S.; Zhang, Y. Arctigenin anti-tumor activity in bladder cancer T24 cell line through induction of cell-cycle arrest and apoptosis. Anat. Rec. , 2012, 295(8), 1260-1266.
[] [PMID: 22619087]
Sun, B.; Cai, E.; Zhao, Y.; Wang, Y.; Yang, L.; Wang, J.Y. Arctigenin triggers apoptosis and autophagy via PI3K/Akt/mTOR Inhibition in PC-3M Cells. Chem. Pharm. Bull., 2021, 69(5), 472-480.
[] [PMID: 33627540]
Li, H.; Yang, C.; Lan, M.; Liao, X.; Tang, Z. Arctigenin promotes bone formation involving PI3K/Akt/PPARγ signaling pathway. Chem. Biol. Drug Des., 2020, 95(4), 451-459.
[] [PMID: 31883507]
Yamashita, T.; Uehara, S.; Udagawa, N.; Li, F.; Kadota, S.; Esumi, H.; Kobayashi, Y.; Takahashi, N. Arctigenin inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways. PLoS One, 2014, 9(1), e85878.
[] [PMID: 24465763]
Kim, A.R.; Kim, H.S.; Lee, J.M.; Choi, J.H.; Kim, S.N.; Kim, D.K.; Kim, J.H.; Mun, S.H.; Kim, J.W.; Jeon, H.S.; Kim, Y.M.; Choi, W.S. Arctigenin suppresses receptor activator of nuclear factor κB ligand (RANKL)-mediated osteoclast differentiation in bone marrow-derived macrophages. Eur. J. Pharmacol., 2012, 682(1-3), 29-36.
[] [PMID: 22387094]
Ahmad, Z.; Salim, M.; Maines, M.D. Human biliverdin reductase is a leucine zipper-like DNA-binding protein and functions in transcriptional activation of heme oxygenase-1 by oxidative stress. J. Biol. Chem., 2002, 277(11), 9226-9232.
[] [PMID: 11773068]
Kharb, S.; Halder, M.; Kundu, Z.S. Heme oxygenase-1 in osteosarcoma. J. Cancer Res. Ther., 2020, 16(4), 874-877.
[] [PMID: 32930133]
Lin, H.; Chen, X.; Zhang, C.; Yang, T.; Deng, Z.; Song, Y.; Huang, L.; Li, F.; Li, Q.; Lin, S.; Jin, D. EF24 induces ferroptosis in osteosarcoma cells through HMOX1. Biomed. Pharmacother., 2021, 136, 111202.
[] [PMID: 33453607]
Zhong, L.; Wang, Y.; Li, W.; Gu, J.; Li, X.; Wang, X.; Yue, Z.; Mu, Y.; Bai, J.; Li, R.; Zhang, H. Heme oxygenase-1 silencing increases the sensitivity of human osteosarcoma MG63 cells to arsenic trioxide. Mol. Cell. Biochem., 2014, 392(1-2), 135-144.
[] [PMID: 24676542]
Avila-Carrasco, L.; Majano, P.; Sánchez-Toméro, J.A.; Selgas, R.; López-Cabrera, M.; Aguilera, A.; González Mateo, G. Natural plants compounds as modulators of epithelial-to-mesenchymal transition. Front. Pharmacol., 2019, 10, 715.
[] [PMID: 31417401]
Babaei, G.; Aziz, S.G.G.; Jaghi, N.Z.Z. EMT, cancer stem cells and autophagy; The three main axes of metastasis. Biomed. Pharmacother., 2021, 133, 110909.
[] [PMID: 33227701]
Xu, Z.; Zhang, Y.; Dai, H.; Han, B. Epithelial–mesenchymal transition-mediated tumor therapeutic resistance. Molecules, 2022, 27(15), 4750.
[] [PMID: 35897925]
Yang, C.; Tian, Y.; Zhao, F.; Chen, Z.; Su, P.; Li, Y.; Qian, A. Bone microenvironment and osteosarcoma metastasis. Int. J. Mol. Sci., 2020, 21(19), 6985.
[] [PMID: 32977425]
Yang, Z.; Li, X.; Yang, Y.; He, Z.; Qu, X.; Zhang, Y. Long noncoding RNAs in the progression, metastasis, and prognosis of osteosarcoma. Cell Death Dis., 2016, 7(9), e2389.
[] [PMID: 27685633]
Hemmati, M.; Yousefi, B.; Bahar, A.; Eslami, M. Importance of heme oxygenase-1 in gastrointestinal cancers: Functions, inductions, regulations, and signaling. J. Gastrointest. Cancer, 2021, 52(2), 454-461.
[] [PMID: 33484436]
Krukowska, K.; Magierowski, M. Carbon monoxide (CO)/heme oxygenase (HO)-1 in gastrointestinal tumors pathophysiology and pharmacology - possible anti- and pro-cancer activities. Biochem. Pharmacol., 2022, 201, 115058.
[] [PMID: 35490732]
Sferrazzo, G.; Di Rosa, M.; Barone, E.; Li Volti, G.; Musso, N.; Tibullo, D.; Barbagallo, I. Heme oxygenase-1 in central nervous system malignancies. J. Clin. Med., 2020, 9(5), 1562.
[] [PMID: 32455831]
Zhao, Z.; Xu, Y.; Lu, J.; Xue, J.; Liu, P. High expression of HO-1 predicts poor prognosis of ovarian cancer patients and promotes proliferation and aggressiveness of ovarian cancer cells. Clin. Transl. Oncol., 2018, 20(4), 491-499.
[] [PMID: 28808929]
Andrés, N.C.; Fermento, M.E.; Gandini, N.A.; Romero, A.L.; Ferro, A.; Donna, L.G.; Curino, A.C.; Facchinetti, M.M. Heme oxygenase-1 has antitumoral effects in colorectal cancer: Involvement of p53. Exp. Mol. Pathol., 2014, 97(3), 321-331.
[] [PMID: 25236576]
Zou, C.; Zou, C.; Cheng, W.; Li, Q.; Han, Z.; Wang, X.; Jin, J.; Zou, J.; Liu, Z.; Zhou, Z.; Zhao, W.; Du, Z. Heme oxygenase-1 retards hepatocellular carcinoma progression through the microRNA pathway. Oncol. Rep., 2016, 36(5), 2715-2722.
[] [PMID: 27571925]
Gandini, N.A.; Alonso, E.N.; Fermento, M.E.; Mascaró, M.; Abba, M.C.; Coló, G.P.; Arévalo, J.; Ferronato, M.J.; Guevara, J.A.; Núñez, M.; Pichel, P.; Curino, A.C.; Facchinetti, M.M. Heme oxygenase-1 has an antitumor role in breast cancer. . Antioxid. Redox Signal., , 2019, 30(18), ars.2018.7554..
[] [PMID: 30484334]
Jiang, Y.; Liu, J.; Hong, W.; Fei, X.; Liu, R. Arctigenin inhibits glioblastoma proliferation through the AKT/mTOR pathway and induces autophagy. BioMed Res. Int., 2020, 2020, 1-13.
[] [PMID: 33015162]
Li, Q.C.; Liang, Y.; Tian, Y.; Hu, G.R. Arctigenin induces apoptosis in colon cancer cells through ROS/p38MAPK pathway. J. BUON, 2016, 21(1), 87-94.
[PMID: 27061535]
Lee, M.G.; Lee, K.S.; Nam, K.S. Anti metastatic effects of arctigenin are regulated by MAPK/AP 1 signaling in 4T 1 mouse breast cancer cells. Mol. Med. Rep., 2020, 21(3), 1374-1382.
[] [PMID: 32016480]
Lu, Z.; Chang, L.; Zhou, H.; Liu, X.; Li, Y.; Mi, T.; Tong, D. Arctigenin attenuates tumor metastasis through inhibiting epithelial–mesenchymal transition in hepatocellular carcinoma via suppressing GSK3β-Dependent Wnt/β-Catenin signaling pathway in vivo and in vitro. Front. Pharmacol., 2019, 10, 937.
[] [PMID: 31555129]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy