Generic placeholder image

Current Cancer Drug Targets

Editor-in-Chief

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

Research Article

Polyphyllin VII is a Potential Drug Targeting CD44 Positive Colon Cancer Cells

Author(s): Ye Zhu, Fei Fu, Zhongyu Wang, Fen Qiu, Ting Deng, Boyu Du*, Yunhe Zhu* and Xueyan Xi*

Volume 22, Issue 5, 2022

Published on: 12 April, 2022

Page: [426 - 435] Pages: 10

DOI: 10.2174/1568009622666220304110222

Price: $65

Abstract

Background: Current therapies for colon cancer are hindered by treatment failure and recurrence, mainly due to colon cancer stem cells (CSCs). Thus, treatment using drugs targeting CSCs should be effective in eliminating colon cancer cells and impeding cancer recurrence.

Objective: This study aimed to test if PPVII can be a potent drug candidate for the treatment of colon cancer by targeting CD44 positive colon cancer cells.

Methods: In this study, we first demonstrated that CD44 is highly expressed in colon cancer tissues by TCGA/GTEX database analysis and immunohistochemical staining.

Results: In this study, we first demonstrated that CD44 is highly expressed in colon cancer tissues by TCGA/GTEX database analysis. CD44 had high accuracy as a diagnostic and predictive index for colorectal cancer through receiver operating characteristic curve (ROC) analysis. At the same time, survival curve analysis also showed that the high expression of CD44 was associated with poor prognosis in patients with colon cancer. CD44’s higher expression in colon cancer tissues was further confirmed by immunohistochemical staining; the positive rate of CD44 expression was 87.95%. Then, one of the constituents that derives from the root of Paris polyphylla, Polyphyllin VII (PPVII), has been confirmed to inhibit the migration of colon cancer cells. Our results also demonstrated that PPVII could inhibit the sphere-forming ability of colon cancer cells. Further experiment results showed that PPVII could downregulate the expression of CD44 in colon cancer cells. In addition, PPVII was proved to have inhibitory effects against CD44 positive colon cancer cells.

Conclusion: Therefore, PPVII might be a potent candidate reagent for the treatment of colon cancer by targeting CD44 positive colon cancer cells.

Keywords: PPVII, colon cancer, cancer stem cells, CD44, CSCs, tumors.

« Previous
Graphical Abstract

[1]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[2]
Catarinella, M.; Monestiroli, A.; Escobar, G.; Fiocchi, A.; Tran, N.L.; Aiolfi, R.; Marra, P.; Esposito, A.; Cipriani, F.; Aldrighetti, L.; Iannacone, M.; Naldini, L.; Guidotti, L.G.; Sitia, G. IFNα gene/cell therapy curbs colorectal cancer colonization of the liver by acting on the hepatic microenvironment. EMBO Mol. Med., 2016, 8(2), 155-170.
[http://dx.doi.org/10.15252/emmm.201505395] [PMID: 26769348]
[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]
Angius, A.; Scanu, A.M.; Arru, C.; Muroni, M.R.; Rallo, V.; Deiana, G.; Ninniri, M.C.; Carru, C.; Porcu, A.; Pira, G.; Uva, P.; Cossu-Rocca, P.; De Miglio, M.R. Portrait of cancer stem cells on colorectal cancer: Molecular biomarkers, signaling pathways and miRNAome. Int. J. Mol. Sci., 2021, 22(4), 1603.
[http://dx.doi.org/10.3390/ijms22041603] [PMID: 33562604]
[5]
Modarai, S.R.; Gupta, A.; Opdenaker, L.M.; Kowash, R.; Masters, G.; Viswanathan, V.; Zhang, T.; Fields, J.Z.; Boman, B.M. The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells. Oncotarget, 2018, 9(78), 34658-34669.
[http://dx.doi.org/10.18632/oncotarget.26157] [PMID: 30410666]
[6]
Dinger, T.F.; Chen, O.; Dittfeld, C.; Hetze, L.; Hüther, M.; Wondrak, M.; Löck, S.; Eicheler, W.; Breier, G.; Kunz-Schughart, L.A. Microenvironmentally-driven plasticity of CD44 isoform expression determines engraftment and stem-like phenotype in CRC cell lines. Theranostics, 2020, 10(17), 7599-7621.
[http://dx.doi.org/10.7150/thno.39893] [PMID: 32685007]
[7]
Di, J.; Duiveman-de Boer, T.; Zusterzeel, P.L.; Figdor, C.G.; Massuger, L.F.; 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. (Dordr.), 2013, 36(5), 363-374.
[http://dx.doi.org/10.1007/s13402-013-0142-8] [PMID: 23928726]
[8]
Roudi, R.; Barodabi, M.; Madjd, Z.; Roviello, G.; Corona, S.P.; Panahei, M. Expression patterns and clinical significance of the potential cancer stem cell markers OCT4 and NANOG in colorectal cancer patients. Mol. Cell. Oncol., 2020, 7(5), 1788366.
[http://dx.doi.org/10.1080/23723556.2020.1788366] [PMID: 32944642]
[9]
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]
[10]
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]
[11]
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]
[12]
Dallas, N.A.; Xia, L.; Fan, F.; Gray, M.J.; Gaur, P.; van Buren, G.II.; 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]
[13]
Frank, M.H.; Wilson, B.J.; Gold, J.S.; Frank, N.Y. Clinical implications of colorectal cancer stem cells in the age of single-cell omics and targeted therapies. Gastroenterology, 2021, 160(6), 1947-1960.
[http://dx.doi.org/10.1053/j.gastro.2020.12.080] [PMID: 33617889]
[14]
Sadeghi, A.; Roudi, R.; Mirzaei, A.; Zare Mirzaei, A.; Madjd, Z.; Abolhasani, M. CD44 epithelial isoform inversely associates with invasive characteristics of colorectal cancer. Biomarkers Med., 2019, 13(6), 419-426.
[http://dx.doi.org/10.2217/bmm-2018-0337] [PMID: 30942083]
[15]
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, 88, 106991.
[http://dx.doi.org/10.1016/j.intimp.2020.106991] [PMID: 33182071]
[16]
Du, L.; Wang, H.; He, L.; Zhang, J.; Ni, B.; Wang, X.; Jin, H.; Cahuzac, N.; Mehrpour, M.; Lu, Y.; Chen, Q. CD44 is of functional importance for colorectal cancer stem cells. Clin. Cancer Res., 2008, 14(21), 6751-6760.
[http://dx.doi.org/10.1158/1078-0432.CCR-08-1034] [PMID: 18980968]
[17]
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]
[18]
Li, Z-H.; Wan, J-Y.; Wang, G-Q.; 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]
[19]
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.
[http://dx.doi.org/10.1002/bmc.2797] [PMID: 22903625]
[20]
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]
[21]
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]
[22]
Zhang, C.; Jia, X.; Bao, J.; Chen, S.; Wang, K.; Zhang, Y.; Li, P.; Wan, J-B.; Su, H.; Wang, Y.; Mei, Z.; He, C. Polyphyllin VII induces apoptosis in HepG2 cells through ROS-mediated mitochondrial dysfunction and MAPK pathways. BMC Complement. Altern. Med., 2016, 16(1), 58.
[http://dx.doi.org/10.1186/s12906-016-1036-x] [PMID: 26861252]
[23]
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]
[24]
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]
[25]
Wang, Y.J.; Bailey, J.M.; Rovira, M.; Leach, S.D. Sphere-forming assays for assessment of benign and malignant pancreatic stem cells. Methods Mol. Biol., 2013, 980, 281-290.
[http://dx.doi.org/10.1007/978-1-62703-287-2_15] [PMID: 23359160]
[26]
Pastrana, E.; Silva-Vargas, V.; Doetsch, F. Eyes wide open: A critical review of sphere-formation as an assay for stem cells. Cell Stem Cell, 2011, 8(5), 486-498.
[http://dx.doi.org/10.1016/j.stem.2011.04.007] [PMID: 21549325]
[27]
Clara, J.A.; Monge, C.; Yang, Y.; Takebe, N. Targeting signalling pathways and the immune microenvironment of cancer stem cells - a clinical update. Nat. Rev. Clin. Oncol., 2020, 17(4), 204-232.
[http://dx.doi.org/10.1038/s41571-019-0293-2] [PMID: 31792354]
[28]
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]
[29]
Heldin, P.; Kolliopoulos, C.; Lin, C-Y.; Heldin, C-H. Involvement of hyaluronan and CD44 in cancer and viral infections. Cell. Signal., 2020, 65, 109427.
[http://dx.doi.org/10.1016/j.cellsig.2019.109427] [PMID: 31654718]
[30]
Brennan, F.R.; O’Neill, J.K.; Allen, S.J.; Butter, C.; Nuki, G.; Baker, D. CD44 is involved in selective leucocyte extravasation during inflammatory central nervous system disease. Immunology, 1999, 98(3), 427-435.
[http://dx.doi.org/10.1046/j.1365-2567.1999.00894.x] [PMID: 10583604]
[31]
Skandalis, S.S.; Karalis, T.T.; Chatzopoulos, A.; Karamanos, N.K. Hyaluronan-CD44 axis orchestrates cancer stem cell functions. Cell. Signal., 2019, 63, 109377.
[http://dx.doi.org/10.1016/j.cellsig.2019.109377] [PMID: 31362044]
[32]
Consortium, G.T. GTEx Consortium. Human genomics. The genotype-tissue expression (GTEx) pilot analysis: Multitissue gene regulation in humans. Science, 2015, 348(6235), 648-660.
[http://dx.doi.org/10.1126/science.1262110] [PMID: 25954001]
[33]
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]
[34]
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.
[http://dx.doi.org/10.3892/mmr.2019.10879] [PMID: 31974591]
[35]
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]

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