Paeonol inhibits proliferation and induces cell apoptosis of human T24 and 5637 bladder cancer cells in vitro and in vivo.
Acetophenones
/ pharmacology
Animals
Antineoplastic Agents, Phytogenic
/ pharmacology
Apoptosis
/ drug effects
Caspase 3
/ analysis
Cell Line, Tumor
Cell Proliferation
/ drug effects
Flow Cytometry
Humans
In Situ Nick-End Labeling
In Vitro Techniques
Ki-67 Antigen
/ analysis
Mice
Mice, Nude
Neoplasm Transplantation
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphorylation
/ drug effects
Proto-Oncogene Proteins c-akt
/ metabolism
Proto-Oncogene Proteins c-bcl-2
/ analysis
Urinary Bladder Neoplasms
/ chemistry
Xenograft Model Antitumor Assays
bcl-2-Associated X Protein
/ analysis
Bladder cancer
Cell apoptosis
Cell proliferation
Paeonol
Journal
Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico
ISSN: 1699-3055
Titre abrégé: Clin Transl Oncol
Pays: Italy
ID NLM: 101247119
Informations de publication
Date de publication:
Mar 2021
Mar 2021
Historique:
received:
12
05
2020
accepted:
09
07
2020
pubmed:
22
7
2020
medline:
15
9
2021
entrez:
22
7
2020
Statut:
ppublish
Résumé
Paeonol is a natural chemical medicine derived from the bark of peony root, which has been found to inhibit tumor activity in various tumor cell lines, and can play a synergistic anti-tumor effect with chemotherapy or radiotherapy. We used paeonol to act on human bladder cancer T24 and 5637 cells, and established xenograft tumor in nude mice by subcutaneous injection of T24 cells. CCK-8 assay and plate cloning experiments showed that paeonol could inhibit the proliferation of T24 and 5637 cells in vitro. The results of flow cytometry and the detection of BAX, Bcl-2 and Caspase-3 proteins suggested that paeonol can induce apoptosis of T24 and 5637 cells in vitro. Tumor formation, TUNEL detection and immunohistochemical results of Ki67, BAX, Bcl-2 and Caspase-3 in nude mice showed that paeonol could inhibit T24 cell proliferation and induce apoptosis in vivo, thus inhibiting tumor growth. Further research revealed that paeonol could reduce phosphorylation expression of PI3K and AKT in T24 and 5637 cells. We confirmed that paeonol could inhibit proliferation and induce apoptosis of human bladder cancer T24 and 5637 cells in vitro and in vivo, inhibit the growth of T24 tumor-forming nude mice, and possibly play a role by inhibiting the PI3K/AKT signaling pathway, so as to provide a potential therapeutic drug for bladder cancer.
Identifiants
pubmed: 32691366
doi: 10.1007/s12094-020-02455-y
pii: 10.1007/s12094-020-02455-y
doi:
Substances chimiques
Acetophenones
0
Antineoplastic Agents, Phytogenic
0
BCL2 protein, human
0
Ki-67 Antigen
0
MKI67 protein, human
0
Proto-Oncogene Proteins c-bcl-2
0
bcl-2-Associated X Protein
0
paeonol
3R834EPI82
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
CASP3 protein, human
EC 3.4.22.-
Caspase 3
EC 3.4.22.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
601-611Subventions
Organisme : the medical innovation team of Jiangsu Province
ID : CXTDA2017048
Organisme : the Natural Science Foundation of the Jiangsu Higher Education Institutions of China
ID : 19KJB320008
Références
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34.
doi: 10.3322/caac.21551
Mertens LS, Neuzillet Y, Horenblas S, van Rhijn BWG. Landmarks in non-muscle-invasive bladder cancer. Nat Rev Urol. 2014;11:476–80.
doi: 10.1038/nrurol.2014.130
Fernández MI, Brausi M, Clark PE, Cookson MS, Grossman HB, Khochikar M, Kiemeney LA, Malavaud B, Sanchez-Salas R, Soloway MS, Svatek RS, Vikram R, Vrieling A, Kamat AM. Epidemiology, prevention, screening, diagnosis, and evaluation: update of the ICUD–SIU joint consultation on bladder cancer. World J Urol. 2018;37:3–13.
doi: 10.1007/s00345-018-2436-y
Griffiths TR, Action on Bladder C. Current perspectives in bladder cancer management. Int J Clin Pract. 2013;67:435–48.
doi: 10.1111/ijcp.12075
Cragg GM, Newman DJ. Plants as a source of anti-cancer agents. J Ethnopharmacol. 2005;100:72–9.
doi: 10.1016/j.jep.2005.05.011
Bai X, Zhang Y, Jiang H, Yang P, Li H, Zhang Y, He P. Effects of maslinic acid on the proliferation and apoptosis of A549 lung cancer cells. Mol Med Rep. 2016;13:117–22.
doi: 10.3892/mmr.2015.4552
Boufridi A, Quinn RJ. Harnessing the properties of natural products. Annu Rev Pharmacol Toxicol. 2018;58:451–70.
doi: 10.1146/annurev-pharmtox-010716-105029
Lei H, Wen Q, Li H, Du S, Wu JJ, Chen J, Huang H, Chen D, Li Y, Zhang S, Zhou J, Deng R, Yang Q. Paeonol inhibits lipopolysaccharide-induced HMGB1 translocation from the nucleus to the cytoplasm in RAW264.7 cells. Inflammation. 2016;39:1177–87.
pubmed: 27106477
Xu Q, Liu X, Mei L, Wen Q, Chen J, Miao J, Lei H, Huang H, Chen D, Du S, Liu A, Zhang S, Zhou J, Deng R, Li Y, Li C, Li H. Paeonol reduces the nucleocytoplasmic transportation of HMGB1 by upregulating HDAC3 in LPS-induced RAW264.7 cells. Inflammation. 2018;41:1536–45.
doi: 10.1007/s10753-018-0800-0
Kim SA, Lee HJ, Ahn KS, Lee HJ, Lee EO, Ahn KS, Choi SH, Jung SJ, Kim JY, Baek N, Kim SH. Paeonol exerts anti-angiogenic and anti-metastatic activities through downmodulation of Akt activation and inactivation of matrix metalloproteinases. Biol Pharm Bull. 2009;32:1142–7.
doi: 10.1248/bpb.32.1142
Zhang L, Li D-C, Liu L-F. Paeonol: pharmacological effects and mechanisms of action. Int Immunopharmacol. 2019;72:413–21.
doi: 10.1016/j.intimp.2019.04.033
Li N, Fan LL, Sun GP, Wan XA, Wang ZG, Wu Q, Wang H. Paeonol inhibits tumor growth in gastric cancerin vitroandin vivo. World J Gastroenterol. 2010;16:4483–90.
doi: 10.3748/wjg.v16.i35.4483
Xu Y, Zhu J-Y, Lei Z-M, Wan L-J, Zhu X-W, Ye F, Tong Y-Y. Anti-proliferative effects of paeonol on human prostate cancer cell lines DU145 and PC-3. J Physiol Biochem. 2016;73:157–65.
doi: 10.1007/s13105-016-0537-x
Ou Y, Li Q, Wang J, Li K, Zhou S. Antitumor and apoptosis induction effects of paeonol on mice bearing EMT6 breast carcinoma. Biomol Ther (Seoul). 2014;22:341–6.
doi: 10.4062/biomolther.2013.106
Lyu ZK, Li CL, Jin Y, Liu YZ, Zhang X, Zhang F, Ning LN, Liang ES, Ma M, Gao W, Zhang MX, Liu DS. Paeonol exerts potential activities to inhibit the growth, migration and invasion of human gastric cancer BGC823 cells via downregulating MMP2 and MMP9. Mol Med Rep. 2017;16:7513–9.
doi: 10.3892/mmr.2017.7576
Li M, Tan SY, Wang XF. Paeonol exerts an anticancer effect on human colorectal cancer cells through inhibition of PGE(2) synthesis and COX-2 expression. Oncol Rep. 2014;32:2845–53.
doi: 10.3892/or.2014.3543
Li M, Tan SY, Zhang J, You HX. Effects of paeonol on intracellular calcium concentration and expression of RUNX3 in LoVo human colon cancer cells. Mol Med Rep. 2013;7:1425–30.
doi: 10.3892/mmr.2013.1372
Xu SP, Sun GP, Shen YX, Peng WR, Wang H, Wei W. Synergistic effect of combining paeonol and cisplatin on apoptotic induction of human hepatoma cell lines. Acta Pharmacol Sin. 2007;28:869–78.
doi: 10.1111/j.1745-7254.2007.00564.x
Wu J, Xue X, Zhang B, Cao H, Kong F, Jiang W, Li J, Sun D, Guo R. Enhanced antitumor activity and attenuated cardiotoxicity of Epirubicin combined with Paeonol against breast cancer. Tumour Biol. 2016;37:12301–13.
doi: 10.1007/s13277-016-5088-9
Lei Y, Li HX, Jin WS, Peng WR, Zhang CJ, Bu LJ, Du YY, Ma T, Sun GP. The radiosensitizing effect of Paeonol on lung adenocarcinoma by augmentation of radiation-induced apoptosis and inhibition of the PI3K/Akt pathway. Int J Radiat Biol. 2013;89:1079–86.
doi: 10.3109/09553002.2013.825058
Lin MY, Lee YR, Chiang SY, Li YZ, Chen YS, Hsu CD, Liu YW. Cortex moutan induces bladder cancer cell death via apoptosis and retards tumor growth in mouse bladders. Evid Based Complement Alternat Med. 2013;2013:207279.
pubmed: 24282433
pmcid: 3824643
Zhang L, Tao L, Shi T, Zhang F, Sheng X, Cao Y, Zheng S, Wang A, Qian W, Jiang L, Lu Y. Paeonol inhibits B16F10 melanoma metastasis in vitro and in vivo via disrupting proinflammatory cytokines-mediated NF-kappaB and STAT3 pathways. IUBMB Life. 2015;67:778–88.
doi: 10.1002/iub.1435
Zhou HM, Sun QX, Cheng Y. Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor. Exp Ther Med. 2017;14:3213–20.
doi: 10.3892/etm.2017.4877
Malaguarnera L. Implications of apoptosis regulators in tumorigenesis. Cancer Metastasis Rev. 2004;23:367–87.
doi: 10.1023/B:CANC.0000031774.32572.df
Sun GP, Wan X, Xu SP, Wang H, Liu SH, Wang ZG. Antiproliferation and apoptosis induction of paeonol in human esophageal cancer cell lines. Dis Esophagus. 2008;21:723–9.
doi: 10.1111/j.1442-2050.2008.00840.x
Ramachandhiran D, Vinothkumar V, Babukumar S. Paeonol exhibits anti-tumor effects by apoptotic and anti-inflammatory activities in 7,12-dimethylbenz(a)anthracene induced oral carcinogenesis. Biotech Histochem. 2019;94:10–25.
doi: 10.1080/10520295.2018.1493221
Li LT, Jiang G, Chen Q, Zheng JN. Ki67 is a promising molecular target in the diagnosis of cancer. Mol Med Rep. 2015;11:1566–72 [Review].
doi: 10.3892/mmr.2014.2914
Katiyar SK, Roy AM, Baliga MS. Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. Mol Cancer Ther. 2005;4:207–16.
pubmed: 15713892
Reagan-Shaw S, Nihal M, Ahsan H, Mukhtar H, Ahmad N. Combination of vitamin E and selenium causes an induction of apoptosis of human prostate cancer cells by enhancing Bax/Bcl-2 ratio. Prostate. 2008;68:1624–34.
doi: 10.1002/pros.20824
Choudhary GS, Al-Harbi S, Almasan A. Caspase-3 activation is a critical determinant of genotoxic stress-induced apoptosis. Methods Mol Biol. 2015;1219:1–9.
doi: 10.1007/978-1-4939-1661-0_1
Skommer J, Brittain T, Raychaudhuri S. Bcl-2 inhibits apoptosis by increasing the time-to-death and intrinsic cell-to-cell variations in the mitochondrial pathway of cell death. Apoptosis. 2010;15:1223–33.
doi: 10.1007/s10495-010-0515-7
Zhao Y, Zhang CL, Zeng BF, Wu XS, Gao TT, Oda Y. Enhanced chemosensitivity of drug-resistant osteosarcoma cells by lentivirus-mediated Bcl-2 silencing. Biochem Biophys Res Commun. 2009;390:642–7.
doi: 10.1016/j.bbrc.2009.10.020
Majtnerová P, Roušar T. An overview of apoptosis assays detecting DNA fragmentation. Mol Med Rep. 2018;45:1469–78.
Martini M, De Santis MC, Braccini L, Gulluni F, Hirsch E. PI3K/AKT signaling pathway and cancer: an updated review. Ann Med. 2014;46:372–83.
doi: 10.3109/07853890.2014.912836
Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009;102:19–65.
doi: 10.1016/S0065-230X(09)02002-8
Oka N, Tanimoto S, Taue R, Nakatsuji H, Kishimoto T, Izaki H, Fukumori T, Takahashi M, Nishitani M, Kanayama HO. Role of phosphatidylinositol-3 kinase/Akt pathway in bladder cancer cell apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Cancer Sci. 2006;97:1093–8.
doi: 10.1111/j.1349-7006.2006.00294.x
Zeng SX, Zhu Y, Ma AH, Yu W, Zhang H, Lin TY, Shi W, Tepper CG, Henderson PT, Airhart S, Guo JM, Xu CL, deVere White RW, Pan CX. The phosphatidylinositol 3-kinase pathway as a potential therapeutic target in bladder cancer. Clin Cancer Res. 2017;23:6580–91.
doi: 10.1158/1078-0432.CCR-17-0033
Soler A, Figueiredo AM, Castel P, Martin L, Monelli E, Angulo-Urarte A, Milà-Guasch M, Viñals F, Baselga J, Casanovas O, Graupera M. Therapeutic benefit of selective inhibition of p110alpha PI3-kinase in pancreatic neuroendocrine tumors. Clin Cancer Res. 2016;22:5805–17.
doi: 10.1158/1078-0432.CCR-15-3051