Top

BMC Complementary Medicine and Therapies

Published in:

01-12-2020 | Multiple Myeloma | Research article

Frankincense and myrrh and their bioactive compounds ameliorate the multiple myeloma through regulation of metabolome profiling and JAK/STAT signaling pathway based on U266 cells

Authors: Rumeng Gao, Xiaodong Miao, Chengjing Sun, Shulan Su, Yue Zhu, Dawei Qian, Zhen Ouyang, Jinao Duan

Published in: BMC Complementary Medicine and Therapies | Issue 1/2020

Abstract

Background

Frankincense and myrrh are used as traditional anti-inflammatory and analgesic medicines in China. It has been reported that frankincense and myrrh have significant anti-tumor activities. The present study was designed to investigate the inhibitory efficacy of frankincense ethanol extracts (RXC), myrrh ethanol extracts (MYC), frankincense -myrrh ethanol extracts (YDC), frankincense -myrrh water extracts (YDS) and their main compounds on U266 human multiple myeloma cell line.

Methods

The inhibition effects of cell proliferation was evaluated by MTT assays. Cell culture supernatant was collected for estimation of cytokines. Western blot analysis was designed to investigate the regulatory of JAK/STAT signal pathway. In addition, cell metabolomics based on the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) had been established to investigate the holistic efficacy of frankincense and myrrh on U266 cells. Acquired data were processed by partial least-squares discriminant analysis (PLS-DA) and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) to identify potential biomarkers.

Results

RXC, MYC significantly inhibited the proliferation of U266 cells at dose of 25–400 μg/mL, YDC and YDS at the dose of 12.5–400 μg/mL. 3-O-acetyl-α-boswellic acid, 3-acetyl-11 keto-boswellic acid and 11-keto-boswellic acid had the most significant anti- multiple myeloma activities in the 10 compounds investigated, therefore these 3 compounds were selected as representatives for Elisa assay and western blotting experiments. All the extracts and active compounds ameliorated the secretion of cytokines and down-regulated the expression of JAK/STAT signaling pathway-related proteins. Comparing RXC, MYC, YDC and YDS-treated U266 cells with vehicle control (DMSO), 13, 8, 7, 7 distinct metabolites and 2, 2, 3, 0 metabolic target pathways involved in amino acid metabolism, lipid metabolism, vitamin metabolism, arachidonic acid were identified, respectively.

Conclusions

Taken together our results suggest that the frankincense and myrrh and their bioactive compounds inhibit proliferation of U266 multiple myeloma cells by regulating JAK/STAT signaling pathway and cellular metabolic profile.

Available only for authorised users

Szudy-Szczyrek A, Szczyrek M, Soroka-Wojtaszko M, Hus M. New prognostic biomarkers in multiple myeloma. Postepy Hig Med Dosw. 2016;70:811–9.CrossRef

Su S, Duan J, Chen T, Huang X, Shang E, Yu L, Wei K, Zhu Y, Guo J, Guo S. Frankincense and myrrh suppress inflammation via regulation of the metabolic profiling and the MAPK signaling pathway. Sci Rep. 2015;5(1):13668.CrossRef

Hu D, Wang C, Li F, Su S, Yang N, Yang Y, Zhu C, Shi H, Yu L, Geng X. A combined water extract of frankincense and myrrh alleviates neuropathic pain in mice via modulation of TRPV1. Neural Plast. 2017;2017:1–11. https://doi.org/10.1155/2017/3710821.CrossRef

Ruiqi W, Yan W, Zuhua G, Xianjun Q. The comparative study of acetyl-11-keto-beta-boswellic acid (AKBA) and aspirin in the prevention of intestinal adenomatous polyposis in APC (min/+) mice. Drug Discov Ther. 2014;8(1):25–32.CrossRef

Mostafa Abbas S, Ashraf Abd-Elkhalik H. Analgesic, anti-inflammatory and anti-hyperlipidemic activities of Commiphora molmol extract (myrrh). J Intercult Ethnopharmacol. 2014;3(2):56–62.CrossRef

Chen Y, Zhou C, Ge Z, Liu Y, Liu Y, Feng W, Li S, Chen G, Wei T. Composition and potential anticancer activities of essential oils obtained from myrrh and frankincense. Oncol Lett. 2013;6(4):1140–6.CrossRef

Su S, Duan J, Tang Y, Zhang X, Yu L, Jiang F, Zhou W, Luo D, Ding A. Isolation and biological activities of neomyrrhaol and other terpenes from the resin of Commiphora myrrha. Planta Med. 2009;75(04):351–5..

Rapper S, De VSF, Van KGPP, Viljoen AM, Dagne E. The additive and synergistic antimicrobial effects of select frankincense and myrrh oils--a combination from the pharaonic pharmacopoeia. Lett Appl Microbiol. 2012;54(4):352–8.CrossRef

Baral S, Cho DH, Pariyar R, Yoon CS, Chang BY, Kim DS, Cho HK, Kim SY, Oh H, Kim YC. The ameliorating effect of myrrh on scopolamine-induced memory impairments in mice. Evid Based Complement Alternat Med. 2015;2015:1–9. https://doi.org/10.1155/2015/925432.

10.

Agrawal SS, Sarita S, Rajani M, Maneesha P. Antitumor properties of Boswellic acid against Ehrlich ascites cells bearing mouse. Food Chem Toxicol. 2011;49(9):1924–34.CrossRef

11.

Xiao-Ling W, Feng K, Tao S, Young CYF, Hong-Xiang L, Hui-Qing Y. Sesquiterpenoids from myrrh inhibit androgen receptor expression and function in human prostate cancer cells. Acta Pharmacol Sin. 2011;32(3):338–44.CrossRef

12.

Yini W, Dan G, Zhe C, Shangfu L, Chunmei G, Deliang C, Feng L, Hongxia L, Yuyang J. Acridone derivative 8a induces oxidative stress-mediated apoptosis in CCRF-CEM leukemia cells: application of metabolomics in mechanistic studies of antitumor agents. PLoS One. 2013;8(5):e63572.CrossRef

13.

Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica. 1999;29(11):1181–9.CrossRef

14.

Byoungduck P, Bokyung S, Yadav VR, Sung-Gook C, Mingyao L, Aggarwal BB. Acetyl-11-keto-β-boswellic acid suppresses invasion of pancreatic cancer cells through the downregulation of CXCR4 chemokine receptor expression. Int J Cancer. 2011;129(1):23–33.CrossRef

15.

Zhao W, Entschladen F, Liu H, Niggemann B, Fang Q, Zaenker KS, Han R. Boswellic acid acetate induces differentiation and apoptosis in highly metastatic melanoma and fibrosarcoma cells. Cancer Detect Prev. 2003;27(1):67–75.CrossRef

16.

None: PP2–038 A review of the cytokine network in multiple myeloma: Diagnostic, prognostic and therapeutic implications. 2009, 48(1–2):1. (DOI: https://doi.org/10.1016/j.cyto.2009.07.416).

17.

Abroun S, Liu S, Tsuyama N, Otsuyama KI, Ishikawa H, Zheng X, Obata M, Taniguchi O, Kawano MM, Li FJ. The Regulatory Mechanism of IL-6-dependent Proliferation of Human Myeloma Cells[J]. Nephron Clinical Practice. 2003;8(6):409–11.

18.

Puthier D, Bataille R, Amiot M. IL-6 up-regulates mcl-1 in human myeloma cells through JAK / STAT rather than ras / MAP kinase pathway. Eur J Immunol. 2015;29(12):3945–50.CrossRef

19.

Anderson K. The vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 inhibits growth and migration of multiple myeloma cells in the bone marrow microenvironment. Eur J Haematol. 2003;70(4):266–7. https://doi.org/10.1034/j.1600-0609.2003.t01-1-01067.x.CrossRef

20.

Klaus P, Anderson KC. The pathophysiologic role of VEGF in hematologic malignancies: therapeutic implications. Blood. 2005;105(4):1383–95.CrossRef

21.

Kisseleva T, Bhattacharya S, Braunstein J, Schindler CW. Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene. 2002;285(1):1–24.CrossRef

22.

Taniguchi K, Karin M. IL-6 and related cytokines as the critical lynchpins between inflammation and cancer. Semin Immunol. 2014;26(1):54–74.CrossRef

23.

Hua Y, Drew P, Richard J. STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer. 2009;9(11):798–809.CrossRef

24.

Qing C, Eirini B, Pasquale S, Marjan B, Sizhi Paul G, Laura D, Jared W, Till T, Selena G, Xinmin Z. The IL-6/JAK/Stat3 feed-forward loop drives tumorigenesis and metastasis. Neoplasia. 2013;15(7):848–IN45. https://doi.org/10.1593/neo.13706.CrossRef

25.

Al-Zaid-Siddiquee T. STAT3 as a target for inducing apoptosis in solid and hematological tumors. Cell Res. 2008;18(2):254–67.CrossRef

26.

Kunnumakkara AB, Nair AS, Sung B, Pandey MK, Aggarwal BB. Boswellic acid blocks signal transducers and activators of transcription 3 signaling, proliferation, and survival of multiple myeloma via the protein tyrosine phosphatase SHP-1. Mol Cancer Res. 2009;7(1):118.CrossRef

27.

Catala A. Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids. 2009;157(1):1–11.CrossRef

28.

Wright MM, Howe AG, Vanina Z. Cell membranes and apoptosis: role of cardiolipin, phosphatidylcholine, and anticancer lipid analogues. Biochem Cell Biol. 2004;82(1):18–26. https://doi.org/10.1139/o03-092.CrossRefPubMed

29.

Xie X, Tome ME, Gerner EW. Loss of intracellular Putrescine Pool-size regulation induces apoptosis. Exp Cell Res. 1997;230(2):386–92. https://doi.org/10.1006/excr.1996.3442.CrossRefPubMed

30.

Tome EM, Fiser MS, Payne MC, Gerner WE. Excess putrescine accumulation inhibits the formation of modified eukaryotic initiation factor 5A (eIF-5A) and induces apoptosis. Biochem J. 1997;328(Pt 3):847.CrossRef

31.

Laird PW. The power and the promise of DNA methylation markers. Nat Rev Cancer. 2003;3(4):253–66.CrossRef

32.

Benavides MA, Oelschlager DK, Huang-Ge Z, Stockard CR, Vital-Reyes VS, Katkoori VR, Upender M, Wenquan W, Bland KI, Grizzle WE. Methionine inhibits cellular growth dependent on the p53 status of cells. Am J Surg 2007, 193(2):0–283. (DOI: https://doi.org/10.1016/j.amjsurg.2006.07.016).

33.

Cheranov SY, Karpurapu M, Wang D, Zhang B, Venema RC, Rao GNL. An essential role for SRC-activated STAT-3 in 14, 15-EET-induced VEGF expression and angiogenesis. Blood. 2008;111(12):5581–91.CrossRef

34.

Shao J, Li Q, Wang H, Liu F, Jiang J, Zhu X, Chen Z, Zou P. P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells. J Huazhong Univ Sci Technol. 2011;31(5):596–601.CrossRef

Title: Frankincense and myrrh and their bioactive compounds ameliorate the multiple myeloma through regulation of metabolome profiling and JAK/STAT signaling pathway based on U266 cells
Authors: Rumeng Gao
Xiaodong Miao
Chengjing Sun
Shulan Su
Yue Zhu
Dawei Qian
Zhen Ouyang
Jinao Duan
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Multiple Myeloma
Biomarkers
Published in: BMC Complementary Medicine and Therapies / Issue 1/2020
Electronic ISSN: 2662-7671
DOI: https://doi.org/10.1186/s12906-020-2874-0

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Frankincense and myrrh and their bioactive compounds ameliorate the multiple myeloma through regulation of metabolome profiling and JAK/STAT signaling pathway based on U266 cells

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2020

Transcutaneous Neuromodulation improved inflammation and sympathovagal ratio in patients with primary biliary ssscholangitis and inadequate response to Ursodeoxycholic acid: a pilot study

Correlation between chemical composition and antibacterial activity of some Lamiaceae species essential oils from Tunisia

Effectiveness of herbal oral care products in reducing dental plaque & gingivitis – a systematic review and meta-analysis

Ginger relieves intestinal hypersensitivity of diarrhea predominant irritable bowel syndrome by inhibiting proinflammatory reaction

The selective anti-proliferative and pro-apoptotic effect of A. cherimola on MDA-MB-231 breast cancer cell line

Phyllanthus amarus prevents LPS-mediated BV2 microglial activation via MyD88 and NF-κB signaling pathways