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Current Cancer Drug Targets

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ISSN (Print): 1568-0096
ISSN (Online): 1873-5576

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Research Article

Polyphyllin VII as a Potential Drug for Targeting Stemness in Hepatocellular Cancer via STAT3 Signaling

Author(s): Liuhang Xu, Ziqi Chen, Yangbin Wang, Yulin Li, Zhongyu Wang, Fangzhou Li* and Xueyan Xi*

Volume 23, Issue 4, 2023

Published on: 10 November, 2022

Page: [325 - 331] Pages: 7

DOI: 10.2174/1568009623666221024103834

Price: $65

Abstract

Background: At present, the treatment of hepatocellular carcinoma (HCC) is disturbed by the treatment failure and recurrence caused by the residual liver cancer stem cells (CSCs). Therefore, drugs targeting HCC CSCs should be able to effectively eliminate HCC and prevent its recurrence. In this study, we demonstrated the effect of Polyphyllin VII (PP7) on HCC CSCs and explored their potential mechanism.

Methods: HepG2 and Huh7 cells were used to analyze the antitumor activity of PP7 by quantifying cell growth and metastasis as well as to study the effect on stemness.

Results: Our results demonstrated that PP7 promoted apoptosis and significantly inhibited proliferation and migration of both HepG2 and Huh7 cells. PP7 also inhibited tumor spheroid formation and induced significant changes in the expression of stemness markers (CD133 and OCT-4). These effects of PP7 were mediated by STAT3 signaling.

Conclusion: PP7 can effectively suppress tumor initiation, growth, and metastasis and inhibit stemness through regulation of STAT3 signaling pathway in liver cancer cells. Our data would add more evidence to further clarify the therapeutic effect of PP7 against HCC.

Keywords: PP7, hepatocellular carcinoma, cancer stem cells, STAT3 signaling, CD133, OCT-4.

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[1]
Chen, W.; Zheng, R.; Baade, P.D.; Zhang, S.; Zeng, H.; Bray, F.; Jemal, A.; Yu, X.Q.; He, J. Cancer statistics in China, 2015. CA Cancer J. Clin., 2016, 66(2), 115-132.
[http://dx.doi.org/10.3322/caac.21338] [PMID: 26808342]
[2]
Hernandez, G.V.; Toffanin, S.; Friedman, S.L.; Llovet, J.M. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology, 2013, 144(3), 512-527.
[http://dx.doi.org/10.1053/j.gastro.2013.01.002] [PMID: 23313965]
[3]
Garg, M. Epithelial plasticity and cancer stem cells: Major mechanisms of cancer pathogenesis and therapy resistance. World J. Stem Cells, 2017, 9(8), 118-126.
[http://dx.doi.org/10.4252/wjsc.v9.i8.118] [PMID: 28928908]
[4]
Chai, S.; Ng, K.Y.; Tong, M.; Lau, E.Y.; Lee, T.K.; Chan, K.W.; Yuan, Y.F.; Cheung, T.T.; Cheung, S.T.; Wang, X.Q.; Wong, N.; Lo, C.M.; Man, K.; Guan, X.Y.; Ma, S. Octamer 4/microRNA-1246 signaling axis drives Wnt/β-catenin activation in liver cancer stem cells. Hepatology, 2016, 64(6), 2062-2076.
[http://dx.doi.org/10.1002/hep.28821] [PMID: 27639189]
[5]
Di, J.; De Boer, D.T.; Zusterzeel, P.L.M.; Figdor, C.G.; Massuger, L.F.A.G.; Torensma, R. The stem cell markers Oct4A, Nanog and c-Myc are expressed in ascites cells and tumor tissue of ovarian cancer patients. Cell. Oncol., 2013, 36(5), 363-374.
[http://dx.doi.org/10.1007/s13402-013-0142-8] [PMID: 23928726]
[6]
Sainz, B., Jr; Alcala, S.; Garcia, E.; Sanchez, R.Y.; Azevedo, M.M.; Cioffi, M.; Tatari, M.; Miranda, L.I.; Hidalgo, M.; Gomez, L.G.; Cañamero, M.; Erkan, M.; Kleeff, J.; García, S.S.; Sancho, P.; Hermann, P.C.; Heeschen, C. Microenvironmental hCAP-18/LL-37 promotes pancreatic ductal adenocarcinoma by activating its cancer stem cell compartment. Gut, 2015, 64(12), 1921-1935.
[http://dx.doi.org/10.1136/gutjnl-2014-308935] [PMID: 25841238]
[7]
Myung, S.J.; Yoon, J.H.; Yu, S.J. STAT3 & cytochrome P450 2C9: A novel signaling pathway in liver cancer stem cells. Biomed. Pharmacother., 2012, 66(8), 612-616.
[http://dx.doi.org/10.1016/j.biopha.2012.08.011] [PMID: 23089473]
[8]
Gariboldi, M.B.; Ravizza, R.; Molteni, R.; Osella, D.; Gabano, E.; Monti, E. Inhibition of Stat3 increases doxorubicin sensitivity in a human metastatic breast cancer cell line. Cancer Lett., 2007, 258(2), 181-188.
[http://dx.doi.org/10.1016/j.canlet.2007.08.019] [PMID: 17920763]
[9]
Zhou, J.; Wulfkuhle, J.; Zhang, H.; Gu, P.; Yang, Y.; Deng, J.; Margolick, J.B.; Liotta, L.A.; Petricoin, E., III; Zhang, Y. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. Proc. Natl. Acad. Sci. USA, 2007, 104(41), 16158-16163.
[http://dx.doi.org/10.1073/pnas.0702596104] [PMID: 17911267]
[10]
Dragu, D.L.; Necula, L.G.; Bleotu, C.; Diaconu, C.C.; Chivu, E.M. Therapies targeting cancer stem cells: Current trends and future challenges. World J. Stem Cells, 2015, 7(9), 1185-1201.
[PMID: 26516409]
[11]
Wang, H.; Zhai, Z.; Li, N.; Jin, H.; Chen, J.; Yuan, S.; Wang, L.; Zhang, J.; Li, Y.; Yun, J.; Fan, J.; Yi, J.; Ling, R. Steroidal saponin of Trillium tschonoskii. Reverses multidrug resistance of hepatocellular carcinoma. Phytomedicine, 2013, 20(11), 985-991.
[http://dx.doi.org/10.1016/j.phymed.2013.04.014] [PMID: 23786867]
[12]
Li, Z.H.; Wan, J.I.A.Y.U.; Wang, G.U.I.Q.I.N.; Zhao, F.G.; Wen, J.H. Identification of compounds from Paris polyphylla (ChongLou) active against Dactylogyrus intermedius. Parasitology, 2013, 140(8), 952-958.
[http://dx.doi.org/10.1017/S0031182013000139] [PMID: 23552446]
[13]
Yin, X.; Qu, C.; Li, Z.; Zhai, Y.; Cao, S.; Lin, L.; Feng, L.; Yan, L.; Ni, J. Simultaneous determination and pharmacokinetic study of polyphyllin I, polyphyllin II, polyphyllin VI and polyphyllin VII in beagle dog plasma after oral administration of Rhizoma paridis extracts by LC-MS-MS. Biomed. Chromatogr., 2013, 27(3), 343-348.
[PMID: 22903625]
[14]
Xiao, X.H.; Yuan, Z.Q.; Li, G.K. Separation and purification of steroidal saponins from Paris polyphylla by microwave-assisted extraction coupled with countercurrent chromatography using evaporative light scattering detection. J. Sep. Sci., 2014, 37(6), 635-641.
[http://dx.doi.org/10.1002/jssc.201301341] [PMID: 24772456]
[15]
Zhang, C.; Jia, X.; Wang, K.; Bao, J.; Li, P.; Chen, M.; Wan, J.B.; Su, H.; Mei, Z.; He, C. Polyphyllin VII induces an autophagic cell death by activation of the JNK pathway and inhibition of PI3K/AKT/mTOR pathway in HepG2 cells. PLoS One, 2016, 11(1)e0147405
[http://dx.doi.org/10.1371/journal.pone.0147405] [PMID: 26808193]
[16]
He, D.X.; Li, G.H.; Gu, X.T.; Zhang, L.; Mao, A.Q.; Wei, J.; Liu, D.Q.; Shi, G.Y.; Ma, X. A new agent developed by biotransformation of polyphyllin VII inhibits chemoresistance in breast cancer. Oncotarget, 2016, 7(22), 31814-31824.
[http://dx.doi.org/10.18632/oncotarget.6674] [PMID: 26701723]
[17]
Lin, Z.; Liu, Y.; Li, F.; Wu, J.; Zhang, G.; Wang, Y.; Lu, L.; Liu, Z. Anti-lung cancer effects of polyphyllin vi and vii potentially correlate with apoptosis in vitro and in vivo. Phytother. Res., 2015, 29(10), 1568-1576.
[http://dx.doi.org/10.1002/ptr.5430] [PMID: 26272214]
[18]
Fan, X.; Zhu, M.; Qiu, F.; Li, W.; Wang, M.; Guo, Y.; Xi, X.; Du, B. Curcumin may be a potential adjuvant treatment drug for colon cancer by targeting CD44. Int. Immunopharmacol., 2020, 88106991
[http://dx.doi.org/10.1016/j.intimp.2020.106991] [PMID: 33182071]
[19]
Jordan, C.T.; Guzman, M.L.; Noble, M. Cancer stem cells. N. Engl. J. Med., 2006, 355(12), 1253-1261.
[http://dx.doi.org/10.1056/NEJMra061808] [PMID: 16990388]
[20]
Zheng, H.C. The molecular mechanisms of chemoresistance in cancers. Oncotarget, 2017, 8(35), 59950-59964.
[http://dx.doi.org/10.18632/oncotarget.19048] [PMID: 28938696]
[21]
Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer, 2005, 5(4), 275-284.
[http://dx.doi.org/10.1038/nrc1590] [PMID: 15803154]
[22]
Dallas, N.A.; Xia, L.; Fan, F.; Gray, M.J.; Gaur, P.; Van Buren, G.I.I.; Samuel, S.; Kim, M.P.; Lim, S.J.; Ellis, L.M. Chemoresistant colorectal cancer cells, the cancer stem cell phenotype, and increased sensitivity to insulin-like growth factor-I receptor inhibition. Cancer Res., 2009, 69(5), 1951-1957.
[http://dx.doi.org/10.1158/0008-5472.CAN-08-2023] [PMID: 19244128]
[23]
Lytle, N.K.; Ferguson, L.P.; Rajbhandari, N.; Gilroy, K.; Fox, R.G.; Deshpande, A.; Schürch, C.M.; Hamilton, M.; Robertson, N.; Lin, W.; Noel, P.; Wartenberg, M.; Zlobec, I.; Eichmann, M.; Galván, J.A.; Karamitopoulou, E.; Gilderman, T.; Esparza, L.A.; Shima, Y.; Spahn, P.; French, R.; Lewis, N.E.; Fisch, K.M.; Sasik, R.; Rosenthal, S.B.; Kritzik, M.; Von Hoff, D.; Han, H.; Ideker, T.; Deshpande, A.J.; Lowy, A.M.; Adams, P.D.; Reya, T. A multiscale map of the stem cell state in pancreatic adenocarcinoma. Cell, 2019, 177(3), 572-586.e22.
[http://dx.doi.org/10.1016/j.cell.2019.03.010] [PMID: 30955884]
[24]
Zhang, C.; Li, Q.; Qin, G.; Zhang, Y.; Li, C.; Han, L.; Wang, R.; Wang, S.; Chen, H.; Liu, K.; He, C. Anti-angiogenesis and anti-metastasis effects of polyphyllin VII on hepatocellular carcinoma cells in vitro and in vivo. Chin. Med., 2021, 16(1), 41.
[http://dx.doi.org/10.1186/s13020-021-00447-w] [PMID: 34059099]
[25]
Ahmad, B.; Rehman, S.U.; Azizullah, A.; Khan, M.F.; Din, S.R.U.; Ahmad, M.; Ali, A.; Tahir, N.; Azam, N.; Gamallat, Y.; Rahman, K.U.; Ali, M.; Safi, M.; Khan, I.; Qamer, S.; Oh, D.H. Molecular mechanisms of anticancer activities of polyphyllin VII. Chem. Biol. Drug Des., 2021, 97(4), 914-929.
[http://dx.doi.org/10.1111/cbdd.13818] [PMID: 33342040]
[26]
Feng, F.F.; Cheng, P.; Sun, C.; Wang, H.; Wang, W. Inhibitory effects of polyphyllins I and VII on human cisplatin-resistant NSCLC via p53 upregulation and CIP2A/AKT/mTOR signaling axis inhibition. Chin. J. Nat. Med., 2019, 17(10), 768-777.
[http://dx.doi.org/10.1016/S1875-5364(19)30093-7] [PMID: 31703757]
[27]
He, H.; Xu, C.; Zheng, L.; Wang, K.; Jin, M.; Sun, Y.; Yue, Z. Polyphyllin VII induces apoptotic cell death via inhibition of the PI3K/Akt and NF-κB pathways in A549 human lung cancer cells. Mol. Med. Rep., 2020, 21(2), 597-606.
[PMID: 31974591]
[28]
Wang, P.; Yang, Q.; Du, X.; Chen, Y.; Zhang, T. Targeted regulation of Rell2 by microRNA-18a is implicated in the anti-metastatic effect of polyphyllin VI in breast cancer cells. Eur. J. Pharmacol., 2019, 851, 161-173.
[http://dx.doi.org/10.1016/j.ejphar.2019.02.041] [PMID: 30817902]
[29]
Jove, R. Preface: STAT signaling. Oncogene, 2000, 19(21), 2466-2467.
[http://dx.doi.org/10.1038/sj.onc.1203549] [PMID: 10851044]
[30]
Lee, T.K.W.; Castilho, A.; Cheung, V.C.H.; Tang, K.H.; Ma, S.; Ng, I.O.L. CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell, 2011, 9(1), 50-63.
[http://dx.doi.org/10.1016/j.stem.2011.06.005] [PMID: 21726833]
[31]
Kasprzycka, M.; Marzec, M.; Liu, X.; Zhang, Q.; Wasik, M.A. Nucleophosmin/Anaplastic Lymphoma Kinase (NPM/ALK) oncoprotein induces the T regulatory cell phenotype by activating STAT3. Proc. Natl. Acad. Sci. USA, 2006, 103(26), 9964-9969.
[http://dx.doi.org/10.1073/pnas.0603507103] [PMID: 16766651]
[32]
Ren, D.; Lin, B.; Zhang, X.; Peng, Y.; Ye, Z.; Ma, Y.; Liang, Y.; Cao, L.; Li, X.; Li, R.; Sun, L.; Liu, Q.; Wu, J.; Zhou, K.; Zeng, J. Maintenance of cancer stemness by miR-196b-5p contributes to chemoresistance of colorectal cancer cells via activating STAT3 signaling pathway. Oncotarget, 2017, 8(30), 49807-49823.
[http://dx.doi.org/10.18632/oncotarget.17971] [PMID: 28591704]
[33]
Niwa, H.; Burdon, T.; Chambers, I.; Smith, A. Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. Genes Dev., 1998, 12(13), 2048-2060.
[http://dx.doi.org/10.1101/gad.12.13.2048] [PMID: 9649508]
[34]
Chung, Y.J.; Park, B.B.; Kang, Y.J.; Kim, T.; Eaves, C.J.; Oh, I.H. Unique effects of Stat3 on the early phase of hematopoietic stem cell regeneration. Blood, 2006, 108(4), 1208-1215.
[http://dx.doi.org/10.1182/blood-2006-01-010199] [PMID: 16614239]
[35]
Kim, E.; Kim, M.; Woo, D.H.; Shin, Y.; Shin, J.; Chang, N.; Oh, Y.T.; Kim, H.; Rheey, J.; Nakano, I.; Lee, C.; Joo, K.M.; Rich, J.N.; Nam, D.H.; Lee, J. Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell, 2013, 23(6), 839-852.
[http://dx.doi.org/10.1016/j.ccr.2013.04.008] [PMID: 23684459]
[36]
Kim, J.H.; Lee, S.C.; Ro, J.; Kang, H.S.; Kim, H.S.; Yoon, S. Jnk signaling pathway-mediated regulation of Stat3 activation is linked to the development of doxorubicin resistance in cancer cell lines. Biochem. Pharmacol., 2010, 79(3), 373-380.
[http://dx.doi.org/10.1016/j.bcp.2009.09.008] [PMID: 19766599]
[37]
Iliopoulos, D.; Hirsch, H.A.; Wang, G.; Struhl, K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc. Natl. Acad. Sci. USA, 2011, 108(4), 1397-1402.
[http://dx.doi.org/10.1073/pnas.1018898108] [PMID: 21220315]

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