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Cancer Cell International
Published in: Cancer Cell International 1/2019

Open Access 01-12-2019 | Lymphoma | Primary research

β-Asarone increases doxorubicin sensitivity by suppressing NF-κB signaling and abolishes doxorubicin-induced enrichment of stem-like population by destabilizing Bmi1

Authors: Li-Na Lv, Xiao-Chao Wang, Li-Ju Tao, Hong-Wen Li, Shu-You Li, Fei-Meng Zheng

Published in: Cancer Cell International | Issue 1/2019

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Abstract

Background

Lymphoma is one of the most common hematologic malignancy. Drug resistance is the main obstacle faced in lymphoma treatment. Cancer stem cells are considered as the source of tumor recurrence, metastasis and drug resistance. The β-Asarone, a low-toxicity compound from the traditional medical herb Acorus calamus, has been shown to act as an anti-cancer reagent in various cancer types. However, the anti-cancer activities of β-Asarone in lymphoma have not been shown.

Methods

Cell counting assay was used to evaluate Raji cell proliferation. CCK8 assay was used to evaluate the cell viability. Annexin-V/PI staining and flow cytometry analysis were used to evaluate apoptosis. ALDEFLUOR assay was used to evaluate the stem-like population. Luciferase reporter assay was used to examine the activation of NF-κB signaling. Western blot and polymerase chain reaction (PCR) were used to determine the expression of interested genes.

Results

We showed that β-Asarone inhibited proliferation and induced apoptosis in Raji lymphoma cells in a dose-dependent manner. Additionally, β-Asarone functioned as a sensitizer of doxorubicin and resulted in synergistic effects on inhibition of proliferation and induction of apoptosis when combined with doxorubicin treatment. Interestingly, we found that β-Asarone also reduced the stem-like population of Raji lymphoma cells in a dose-dependent manner, and suppressed the expression of c-Myc and Bmi1. Importantly, β-Asarone abolished doxorubicin-induced enrichment of the stem-like population. In the mechanism study, we revealed that β-Asarone suppressed not only basal NF-κB activity but also Tumor necrosis factor α (TNF-α) induced NF-κB activity. Moreover, blocking NF-κB signaling inactivation was critical for β-Asarone induced apoptosis and inhibition of proliferation, but not for the effect on β-Asarone reduced stem-like population. In fact, β-Asarone suppressed stem-like population by destabilizing Bmi1 via a proteasome-mediated mechanism.

Conclusions

Our data suggested the application of β-Asarone to lower the toxic effect of doxorubicin and increase the sensitivity of doxorubicin in clinical treatment. More importantly, our data revealed a novel role of β-Asarone which could be used to eliminate stem-like population in lymphoma, implying that β-Asarone might reduce relapse and drug resistance.
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Literature
1.
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440–6.PubMedPubMedCentralCrossRef
2.
3.
Bhattacharya S, Muhammad N, Steele R, Peng G, Ray RB. Immunomodulatory role of bitter melon extract in inhibition of head and neck squamous cell carcinoma growth. Oncotarget. 2016;7(22):33202–9.PubMedPubMedCentralCrossRef
4.
Bhattacharya S, Muhammad N, Steele R, Kornbluth J, Ray RB. Bitter melon enhances natural killer-mediated toxicity against head and neck cancer cells. Cancer Prev Res. 2017;10(6):337–44.CrossRef
5.
Muhammad N, Steele R, Isbell TS, Philips N, Ray RB. Bitter melon extract inhibits breast cancer growth in preclinical model by inducing autophagic cell death. Oncotarget. 2017;8(39):66226–36.PubMedPubMedCentralCrossRef
6.
Lin JP, Yang JS, Lee JH, Hsieh WT, Chung JG. Berberine induces cell cycle arrest and apoptosis in human gastric carcinoma SNU-5 cell line. World J Gastroenterol. 2006;12(1):21–8.PubMedPubMedCentralCrossRef
7.
Constantinou A, Mehta R, Runyan C, Rao K, Vaughan A, Moon R. Flavonoids as DNA topoisomerase antagonists and poisons: structure–activity relationships. J Nat Prod. 1995;58(2):217–25.PubMedCrossRef
8.
Ribeiro D, Freitas M, Tome SM, Silva AM, Laufer S, Lima JL, Fernandes E. Flavonoids inhibit COX-1 and COX-2 enzymes and cytokine/chemokine production in human whole blood. Inflammation. 2015;38(2):858–70.PubMedCrossRef
9.
Chellian R, Pandy V, Mohamed Z. Pharmacology and toxicology of alpha- and beta-Asarone: a review of preclinical evidence. Phytomedicine. 2017;32:41–58.PubMedCrossRef
10.
Lim HW, Kumar H, Kim BW, More SV, Kim IW, Park JI, Park SY, Kim SK, Choi DK. β-Asarone (cis-2,4,5-trimethoxy-1-allyl phenyl), attenuates pro-inflammatory mediators by inhibiting NF-kappaB signaling and the JNK pathway in LPS activated BV-2 microglia cells. Food Chem Toxicol. 2014;72:265–72.PubMedCrossRef
11.
Lee JY, Lee JY, Yun BS, Hwang BK. Antifungal activity of beta-asarone from rhizomes of Acorus gramineus. J Agric Food Chem. 2004;52(4):776–80.PubMedCrossRef
12.
Fang YQ, Fang RM, Fang GL, Jiang Y, Fu SY. Effects of beta-asarone on expression of c-fos in kindling epilepsy rat brain. Zhongguo Zhong Yao Za Zhi. 2008;33(5):534–6.PubMed
13.
Dong H, Gao Z, Rong H, Jin M, Zhang X. β-Asarone reverses chronic unpredictable mild stress-induced depression-like behavior and promotes hippocampal neurogenesis in rats. Molecules. 2014;19(5):5634–49.PubMedPubMedCentralCrossRef
14.
Liu L, Wang J, Shi L, Zhang W, Du X, Wang Z, Zhang Y. β-Asarone induces senescence in colorectal cancer cells by inducing lamin B1 expression. Phytomedicine. 2013;20(6):512–20.PubMedCrossRef
15.
Wu J, Zhang XX, Sun QM, Chen M, Liu SL, Zhang X, Zhou JY, Zou X. β-Asarone inhibits gastric cancer cell proliferation. Oncol Rep. 2015;34(6):3043–50.PubMedCrossRef
16.
Wang TL, Ouyang CS, Lin LZ. β-Asarone suppresses Wnt/beta-catenin signaling to reduce viability, inhibit migration/invasion/adhesion and induce mitochondria-related apoptosis in lung cancer cells. Biomed Pharmacother. 2018;106:821–30.PubMedCrossRef
17.
18.
19.
Jost PJ, Ruland J. Aberrant NF-kappaB signaling in lymphoma: mechanisms, consequences, and therapeutic implications. Blood. 2007;109(7):2700–7.PubMed
20.
Lee TI, Jenner RG, Boyer LA, Guenther MG, Levine SS, Kumar RM, Chevalier B, Johnstone SE, Cole MF, Isono K, et al. Control of developmental regulators by polycomb in human embryonic stem cells. Cell. 2006;125(2):301–13.PubMedPubMedCentralCrossRef
21.
Ringrose L, Paro R. Polycomb/trithorax response elements and epigenetic memory of cell identity. Development. 2007;134(2):223–32.PubMedCrossRef
22.
Siddique HR, Saleem M. Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences. Stem Cells. 2012;30(3):372–8.PubMedCrossRef
23.
Zheng FM, Long ZJ, Hou ZJ, Luo Y, Xu LZ, Xia JL, Lai XJ, Liu JW, Wang X, Kamran M, et al. A novel small molecule aurora kinase inhibitor attenuates breast tumor-initiating cells and overcomes drug resistance. Mol Cancer Ther. 2014;13(8):1991–2003.PubMedCrossRef
24.
Zheng F, Yue C, Li G, He B, Cheng W, Wang X, Yan M, Long Z, Qiu W, Yuan Z, et al. Nuclear AURKA acquires kinase-independent transactivating function to enhance breast cancer stem cell phenotype. Nat Commun. 2016;7:10180.PubMedPubMedCentralCrossRef
25.
Chou TC, Motzer RJ, Tong Y, Bosl GJ. Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst. 1994;86(20):1517–24.PubMedCrossRef
26.
Mohammad N, Singh SV, Malvi P, Chaube B, Athavale D, Vanuopadath M, Nair SS, Nair B, Bhat MK. Strategy to enhance efficacy of doxorubicin in solid tumor cells by methyl-beta-cyclodextrin: involvement of p53 and Fas receptor ligand complex. Sci Rep. 2015;5:11853.PubMedPubMedCentralCrossRef
27.
28.
Matthews GM, de Matos Simoes R, Dhimolea E, Sheffer M, Gandolfi S, Dashevsky O, Sorrell JD, Mitsiades CS. NF-kappaB dysregulation in multiple myeloma. Semin Cancer Biol. 2016;39:68–76.PubMedCrossRef
29.
30.
Kumar A, Negi G, Sharma SS. JSH-23 targets nuclear factor-kappa B and reverses various deficits in experimental diabetic neuropathy: effect on neuroinflammation and antioxidant defence. Diabetes Obes Metab. 2011;13(8):750–8.PubMedCrossRef
31.
Annett S, Robson T. Targeting cancer stem cells in the clinic: current status and perspectives. Pharmacol Ther. 2018;187:13–30.PubMedCrossRef
32.
Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69(19):7507–11.PubMedPubMedCentralCrossRef
33.
Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA, Lander ES. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009;138(4):645–59.PubMedPubMedCentralCrossRef
34.
Li Y, Zhang T, Korkaya H, Liu S, Lee HF, Newman B, Yu Y, Clouthier SG, Schwartz SJ, Wicha MS, et al. Sulforaphane, a dietary component of broccoli/broccoli sprouts, inhibits breast cancer stem cells. Clin Cancer Res. 2010;16(9):2580–90.PubMedPubMedCentralCrossRef
35.
Zhou W, Kallifatidis G, Baumann B, Rausch V, Mattern J, Gladkich J, Giese N, Moldenhauer G, Wirth T, Buchler MW, et al. Dietary polyphenol quercetin targets pancreatic cancer stem cells. Int J Oncol. 2010;37(3):551–61.PubMed
36.
Wang W, Qin JJ, Voruganti S, Nag S, Zhou J, Zhang R. Polycomb group (PcG) proteins and human cancers: multifaceted functions and therapeutic implications. Med Res Rev. 2015;35(6):1220–67.PubMedPubMedCentralCrossRef
37.
Schuettengruber B, Bourbon HM, Di Croce L, Cavalli G. Genome regulation by polycomb and trithorax: 70 years and counting. Cell. 2017;171(1):34–57.PubMedCrossRef
38.
Cui H, Hu B, Li T, Ma J, Alam G, Gunning WT, Ding HF. Bmi-1 is essential for the tumorigenicity of neuroblastoma cells. Am J Pathol. 2007;170(4):1370–8.PubMedPubMedCentralCrossRef
39.
Dimri GP, Martinez JL, Jacobs JJ, Keblusek P, Itahana K, Van Lohuizen M, Campisi J, Wazer DE, Band V. The Bmi-1 oncogene induces telomerase activity and immortalizes human mammary epithelial cells. Cancer Res. 2002;62(16):4736–45.PubMed
40.
Wang X, Venugopal C, Manoranjan B, McFarlane N, O’Farrell E, Nolte S, Gunnarsson T, Hollenberg R, Kwiecien J, Northcott P, et al. Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells. Oncogene. 2012;31(2):187–99.PubMedCrossRef
41.
Wang X, Wang C, Zhang X, Hua R, Gan L, Huang M, Zhao L, Ni S, Guo W. Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. J Hematol Oncol. 2016;9(1):90.PubMedPubMedCentralCrossRef
42.
Nagamitsu A, Greish K, Maeda H. Elevating blood pressure as a strategy to increase tumor-targeted delivery of macromolecular drug SMANCS: cases of advanced solid tumors. Jpn J Clin Oncol. 2009;39(11):756–66.PubMedCrossRef
43.
Curnis F, Sacchi A, Corti A. Improving chemotherapeutic drug penetration in tumors by vascular targeting and barrier alteration. J Clin Investig. 2002;110(4):475–82.PubMedCrossRef
44.
Stohrer M, Boucher Y, Stangassinger M, Jain RK. Oncotic pressure in solid tumors is elevated. Cancer Res. 2000;60(15):4251–5.PubMed
45.
Morris ME, Zhang S. Flavonoid–drug interactions: effects of flavonoids on ABC transporters. Life Sci. 2006;78(18):2116–30.PubMedCrossRef
46.
Mohammad N, Malvi P, Meena AS, Singh SV, Chaube B, Vannuruswamy G, Kulkarni MJ, Bhat MK. Cholesterol depletion by methyl-beta-cyclodextrin augments tamoxifen induced cell death by enhancing its uptake in melanoma. Mol Cancer. 2014;13:204.PubMedPubMedCentralCrossRef
47.
Paranjape AN, Balaji SA, Mandal T, Krushik EV, Nagaraj P, Mukherjee G, Rangarajan A. Bmi1 regulates self-renewal and epithelial to mesenchymal transition in breast cancer cells through Nanog. BMC Cancer. 2014;14:785.PubMedPubMedCentralCrossRef
Metadata
Title
β-Asarone increases doxorubicin sensitivity by suppressing NF-κB signaling and abolishes doxorubicin-induced enrichment of stem-like population by destabilizing Bmi1
Authors
Li-Na Lv
Xiao-Chao Wang
Li-Ju Tao
Hong-Wen Li
Shu-You Li
Fei-Meng Zheng
Publication date
01-12-2019
Publisher
BioMed Central
Keyword
Lymphoma
Published in
Cancer Cell International / Issue 1/2019
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-019-0873-3

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