Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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Ginseng-derived compounds as potential anticancer agents targeting cancer stem cells

  • Ji-Sun Lee (Department of Molecular, Cell & Cancer Biology, University of Massachusetts Chan Medical School) ;
  • Ho-Young Lee (Natural Products Research Institute, College of Pharmacy, Seoul National University)
  • Received : 2023.09.20
  • Accepted : 2024.03.07
  • Published : 2024.05.01
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Abstract

Cancer stem cells (CSCs) are a rare subpopulation of cancer cells that exhibit stem cell-like characteristics, including self-renewal and differentiation in a multi-stage lineage state via symmetric or asymmetric division, causing tumor initiation, heterogeneity, progression, and recurrence and posing a major challenge to current anticancer therapy. Despite the importance of CSCs in carcinogenesis and cancer progression, currently available anticancer therapeutics have limitations for eradicating CSCs. Moreover, the efficacy and therapeutic windows of currently available anti-CSC agents are limited, suggesting the necessity to optimize and develop a novel anticancer agent targeting CSCs. Ginseng has been traditionally used for enhancing immunity and relieving fatigue. As ginseng's long history of use has demonstrated its safety, it has gained attention for its potential pharmacological properties, including anticancer effects. Several studies have identified the bioactive principles of ginseng, such as ginseng saponin (ginsenosides) and non-saponin compounds (e.g., polysaccharides, polyacetylenes, and phenolic compounds), and their pharmacological activities, including antioxidant, anticancer, antidiabetic, antifatigue, and neuroprotective effects. Notably, recent reports have shown the potential of ginseng-derived compounds as anti-CSC agents. This review investigates the biology of CSCs and efforts to utilize ginseng-derived components for cancer treatment targeting CSCs, highlighting their role in overcoming current therapeutic limitations.

Keywords

Acknowledgement

This work was supported by a grant from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (MSIT), Republic of Korea (No. NRF-2016R1A3B1908631). The illustrations in the figures were created with BioRender.com. The image of P. ginseng from Freepik (www.freepik.com) was used for the graphical abstract.

References

  1. Sung H, Ferlay J, Siegel RL, 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):209-49. https://doi.org/10.3322/caac.21660
  2. GBD 2019 Cancer Risk Factors Collaborators. The global burden of cancer attributable to risk factors 2010-19:. A systematic analysis for the Global Burden of Disease Study 2019 Lancet 2022;400(10352):563-591. https://doi.org/10.1016/S0140-6736(22)01438-6
  3. Marusyk A, Janiszewska M, Polyak K. Intratumor heterogeneity: the rosetta stone of therapy resistance. Cancer Cell 2020;37(4):471-84. https://doi.org/10.1016/j.ccell.2020.03.007
  4. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 2009;138(5):822-9. https://doi.org/10.1016/j.cell.2009.08.017
  5. Batlle E, Clevers H. Cancer stem cells revisited. Nat Med 2017;23(10):1124-34. https://doi.org/10.1038/nm.4409
  6. Sugihara E, Saya H. Complexity of cancer stem cells. Int J Cancer 2013;132(6):1249-59. https://doi.org/10.1002/ijc.27961
  7. Stenning SP, Parkinson MC, Fisher C, Mead GM, Cook PA, Fossa SD, et al. Postchemotherapy residual masses in germ cell tumor patients: content, clinical features, and prognosis. Medical Research Council Testicular Tumour Working Party. Cancer. 1998;83(7):1409-19. https://doi.org/10.1002/(SICI)1097-0142(19981001)83:7<1409::AID-CNCR19>3.0.CO;2-8
  8. Deng S, Wong CKC, Lai HC, Wong AST. Ginsenoside-Rb1 targets chemotherapyresistant ovarian cancer stem cells via simultaneous inhibition of Wnt/betacatenin signaling and epithelial-to-mesenchymal transition. Oncotarget 2017;8(16):25897-914. https://doi.org/10.18632/oncotarget.13071
  9. Wang J, Tian L, Khan MN, Zhang L, Chen Q, Zhao Y, et al. Ginsenoside Rg3 sensitizes hypoxic lung cancer cells to cisplatin via blocking of NF-kappaB mediated epithelial-mesenchymal transition and stemness. Cancer Lett 2018;415:73-85. https://doi.org/10.1016/j.canlet.2017.11.037
  10. Oh J, Yoon HJ, Jang JH, Kim DH, Surh YJ. The standardized Korean Red Ginseng extract and its ingredient ginsenoside Rg3 inhibit manifestation of breast cancer stem cell-like properties through modulation of self-renewal signaling. J Ginseng Res 2019;43(3):421-30. https://doi.org/10.1016/j.jgr.2018.05.004
  11. Song JH, Eum DY, Park SY, Jin YH, Shim JW, Park SJ, et al. Inhibitory effect of ginsenoside Rg3 on cancer stemness and mesenchymal transition in breast cancer via regulation of myeloid-derived suppressor cells. PLoS One 2020;15(10):e0240533.
  12. Ham SW, Kim JK, Jeon HY, Kim EJ, Jin X, Eun K, et al. Korean Red ginseng extract inhibits glioblastoma propagation by blocking the Wnt signaling pathway. J Ethnopharmacol 2019;236:393-400. https://doi.org/10.1016/j.jep.2019.03.031
  13. Liu S, Chen M, Li P, Wu Y, Chang C, Qiu Y, et al. Ginsenoside Rh2 inhibits cancer stem-like cells in skin squamous cell carcinoma. Cell Physiol Biochem 2015;36(2):499-508. https://doi.org/10.1159/000430115
  14. Kim H, Choi P, Kim T, Kim Y, Song BG, Park YT, et al. Ginsenosides Rk1 and Rg5 inhibit transforming growth factor-β1-induced epithelial-mesenchymal transition and suppress migration, invasion, anoikis resistance, and development of stemlike features in lung cancer. J Ginseng Res 2021;45(1):134-48. https://doi.org/10.1016/j.jgr.2020.02.005
  15. Le HT, Nguyen HT, Min HY, Hyun SY, Kwon S, Lee Y, et al. Panaxynol, a natural Hsp90 inhibitor, effectively targets both lung cancer stem and non-stem cells. Cancer Lett 2018;412:297-307. https://doi.org/10.1016/j.canlet.2017.10.013
  16. Atanasov AG, Zotchev SB, Dirsch VM, International Natural Product Sciences T, Supuran CT. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 2021;20(3):200-16. https://doi.org/10.1038/s41573-020-00114-z
  17. Newman DJ, Cragg GM. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J Nat Prod 2020;83(3):770-803. https://doi.org/10.1021/acs.jnatprod.9b01285
  18. Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. Int J Biochem Cell Biol 2012;44(12):2144-51. https://doi.org/10.1016/j.biocel.2012.08.022
  19. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 1994;367(6464):645-8. https://doi.org/10.1038/367645a0
  20. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003;100(7):3983-8. https://doi.org/10.1073/pnas.0530291100
  21. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature 2004;432(7015):396-401. https://doi.org/10.1038/nature03128
  22. Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J, Dirks PB. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63(18):5821-8.
  23. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 2008;15(3):504-14.
  24. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005;65(23):10946-51. https://doi.org/10.1158/0008-5472.CAN-05-2018
  25. Zhang S, Balch C, Chan MW, Lai HC, Matei D, Schilder JM, et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res 2008;68(11):4311-20. https://doi.org/10.1158/0008-5472.CAN-08-0364
  26. Jariyal H, Gupta C, Bhat VS, Wagh JR, Srivastava A. Advancements in cancer stem cell isolation and characterization. Stem Cell Rev Rep 2019;15(6):755-73. https://doi.org/10.1007/s12015-019-09912-4
  27. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1(5):555-67. https://doi.org/10.1016/j.stem.2007.08.014
  28. Jiang F, Qiu Q, Khanna A, Todd NW, Deepak J, Xing L, et al. Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer. Mol Cancer Res 2009;7(3):330-8.
  29. Liu S, Cong Y, Wang D, Sun Y, Deng L, Liu Y, et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Rep 2014;2(1):78-91. https://doi.org/10.1016/j.stemcr.2013.11.009
  30. Greaves M, Maley CC. Clonal evolution in cancer. Nature 2012;481(7381):306-13. https://doi.org/10.1038/nature10762
  31. Lopez de Andres J, Grinan-Lison C, Jimenez G, Marchal JA. Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol 2020;13(1):136.
  32. Chaffer CL, Weinberg RA. A perspective on cancer cell metastasis. Science 2011; 331(6024):1559-64. https://doi.org/10.1126/science.1203543
  33. Shiozawa Y, Nie B, Pienta KJ, Morgan TM, Taichman RS. Cancer stem cells and their role in metastasis. Pharmacol Ther 2013;138(2):285-93. https://doi.org/10.1016/j.pharmthera.2013.01.014
  34. Saygin C, Matei D, Majeti R, Reizes O, Lathia JD. Targeting cancer stemness in the clinic: from hype to hope. Cell Stem Cell 2019;24(1):25-40. https://doi.org/10.1016/j.stem.2018.11.017
  35. Bajaj J, Diaz E, Reya T. Stem cells in cancer initiation and progression. J Cell Biol 2020;219(1).
  36. Taipale J, Chen Jk Fau, Cooper MK, Cooper Mk Fau, Wang B, Wang B Fau, Mann RK, Mann Rk Fau, Milenkovic L, Milenkovic L Fau, Scott MP, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. 2000 Aug 31 (Print).
  37. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012;366(23):2171-9. https://doi.org/10.1056/NEJMoa1113713
  38. Dummer R, Guminski A, Gutzmer R, Dirix L, Lewis KD, Combemale P, et al. The 12-month analysis from Basal Cell Carcinoma Outcomes with LDE225 Treatment (BOLT): a phase II, randomized, double-blind study of sonidegib in patients with advanced basal cell carcinoma. J Am Acad Dermatol 2016;75(1):113-125 e5.
  39. Majumder S, Crabtree JS, Golde TE, Minter LM, Osborne BA, Miele L. Targeting Notch in oncology: the path forward. Nat Rev Drug Discov 2021;20(2):125-44. https://doi.org/10.1038/s41573-020-00091-3
  40. Schott AF, Landis Md Fau - Dontu G, Dontu G Fau - Griffith KA, Griffith Ka Fau - Layman RM, Layman Rm Fau - Krop I, Krop I Fau - Paskett LA, et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. (1557-3265 (Electronic).
  41. Hoey T, Yen Wc Fau - Axelrod F, Axelrod F Fau - Basi J, Basi J Fau - Donigian L, Donigian L Fau - Dylla S, Dylla S Fau - Fitch-Bruhns M, et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. (1875-9777 (Electronic).
  42. Fischer M, Yen Wc Fau - Kapoun AM, Kapoun Am Fau - Wang M, Wang M Fau - O'Young G, O'Young G Fau - Lewicki J, Lewicki J Fau - Gurney A, et al. Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. (1538-7445 (Electronic)).
  43. Zhou B, Lin W, Long Y, Yang Y, Zhang H, Wu K, Chu Q. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduct Targeted Ther 2022;7(1):95.
  44. Jimeno A, Gordon M, Chugh R, Messersmith W, Mendelson D, Dupont J, et al. A first-in-human phase I study of the anticancer stem cell agent ipafricept (OMP54F28), a decoy receptor for Wnt ligands, in Patients with advanced solid tumors. (1557-3265 (Electronic).
  45. Ko AH, Chiorean EG, Kwak EL, Lenz H-J, Nadler PI, Wood DL, et al. Final results of a phase Ib dose-escalation study of PRI-724, a CBP/beta-catenin modulator, plus gemcitabine (GEM) in patients with advanced pancreatic adenocarcinoma (APC) as second-line therapy after FOLFIRINOX or FOLFOX. J Clin Oncol 2016;34(15_suppl):e15721-e.
  46. Kahn M. Can we safely target the WNT pathway? (1474-1784 (Electronic).
  47. Li C, Liang Y, Cao J, Zhang N, Wei X, Tu M, et al. The delivery of a Wnt pathway inhibitor toward CSCs requires stable liposome encapsulation and delayed drug release in tumor tissues. Mol Ther 2019;27(9):1558-67. https://doi.org/10.1016/j.ymthe.2019.06.013
  48. Vora P, Venugopal C, Salim SK, Tatari N, Bakhshinyan D, Singh M, et al. The rational development of cd133-targeting immunotherapies for glioblastoma. Cell Stem Cell 2020;26(6):832-844 e6.
  49. Miyamoto S, Kochin V, Kanaseki T, Hongo A, Tokita S, Kikuchi Y, et al. The antigen ASB4 on cancer stem cells serves as a target for CTL immunotherapy of colorectal cancer. Cancer Immunol Res 2018;6(3):358-69. https://doi.org/10.1158/2326-6066.CIR-17-0518
  50. Lichota A, Gwozdzinski K. Anticancer activity of natural compounds from plant and marine environment. Int J Mol Sci 2018;19(11).
  51. Khazir J, Riley DL, Pilcher LA, De-Maayer P, Mir BA. Anticancer agents from diverse natural sources. Nat Prod Commun 2014;9(11):1655-69.
  52. Schwartsmann G, Brondani da Rocha A, Berlinck RG, Jimeno J. Marine organisms as a source of new anticancer agents. Lancet Oncol 2001;2(4):221-5. https://doi.org/10.1016/S1470-2045(00)00292-8
  53. Shaik BB, Katari NK, Jonnalagadda SB. Role of natural products in developing novel anticancer agents: a perspective. Chem Biodivers 2022;19(11):e202200535.
  54. Ahuja A, Kim JH, Kim JH, Yi YS, Cho JY. Functional role of ginseng-derived compounds in cancer. J Ginseng Res 2018;42(3):248-54. https://doi.org/10.1016/j.jgr.2017.04.009
  55. Lee JH, Leem DG, Chung KS, Kim KT, Choi SY, Lee KT. Panaxydol derived from Panax ginseng inhibits G(1) cell cycle progression in non-small cell lung cancer via upregulation of intracellular Ca(2+) levels. Biol Pharm Bull 2018;41(11):1701-7. https://doi.org/10.1248/bpb.b18-00447
  56. Kim HS, Lim JM, Kim JY, Kim Y, Park S, Sohn J. Panaxydol, a component of Panax ginseng, induces apoptosis in cancer cells through EGFR activation and ER stress and inhibits tumor growth in mouse models. Int J Cancer 2016;138(6):1432-41. https://doi.org/10.1002/ijc.29879
  57. Attele AS, Wu JA, Yuan CS. Ginseng pharmacology: multiple constituents and multiple actions. Biochem Pharmacol 1999;58(11):1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  58. Hyun SH, Kim SW, Seo HW, Youn SH, Kyung JS, Lee YY, et al. Physiological and pharmacological features of the non-saponin components in Korean Red Ginseng. J Ginseng Res 2020;44(4):527-37. https://doi.org/10.1016/j.jgr.2020.01.005
  59. Shin BK, Kwon SW, Park JH. Chemical diversity of ginseng saponins from Panax ginseng. J Ginseng Res 2015;39(4):287-98. https://doi.org/10.1016/j.jgr.2014.12.005
  60. Yu JS, Roh HS, Baek KH, Lee S, Kim S, So HM, et al. Bioactivity-guided isolation of ginsenosides from Korean Red Ginseng with cytotoxic activity against human lung adenocarcinoma cells. J Ginseng Res 2018;42(4):562-70. https://doi.org/10.1016/j.jgr.2018.02.004
  61. Chen L, Meng Y, Sun Q, Zhang Z, Guo X, Sheng X, et al. Ginsenoside compound K sensitizes human colon cancer cells to TRAIL-induced apoptosis via autophagydependent and -independent DR5 upregulation. Cell Death Dis 2016;7(8):e2334.
  62. Kim YW, Bak SB, Lee WY, Bae SJ, Lee EH, Yang JH, et al. Systemic and molecular analysis dissect the red ginseng induction of apoptosis and autophagy in HCC as mediated with AMPK. J Ginseng Res 2023;47(3):479-91. https://doi.org/10.1016/j.jgr.2023.02.002
  63. Yang J, Yuan D, Xing T, Su H, Zhang S, Wen J, et al. Ginsenoside Rh2 inhibiting HCT116 colon cancer cell proliferation through blocking PDZ-binding kinase/TLAK cell-originated protein kinase. J Ginseng Res 2016;40(4):400-8. https://doi.org/10.1016/j.jgr.2016.03.007
  64. Liu TG, Huang Y, Cui DD, Huang XB, Mao SH, Ji LL, et al. Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice. BMC Cancer 2009;9:250.
  65. Li Y, Zhou T, Ma C, Song W, Zhang J, Yu Z. Ginsenoside metabolite compound K enhances the efficacy of cisplatin in lung cancer cells. J Thorac Dis 2015;7(3):400-6.
  66. Lee YJ, Lee S, Ho JN, Byun SS, Hong SK, Lee SE, Lee E. Synergistic antitumor effect of ginsenoside Rg3 and cisplatin in cisplatin-resistant bladder tumor cell line. Oncol Rep 2014;32(5):1803-8. https://doi.org/10.3892/or.2014.3452
  67. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010;12(5):468-76. https://doi.org/10.1038/ncb2048
  68. Merlos-Suarez A, Barriga FM, Jung P, Iglesias M, Cespedes MV, Rossell D, et al. The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 2011;8(5):511-24. https://doi.org/10.1016/j.stem.2011.02.020
  69. Malanchi I, Peinado H, Kassen D, Hussenet T, Metzger D, Chambon P, et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 2008;452(7187):650-3. https://doi.org/10.1038/nature06835
  70. Chen J, Duan Z, Liu Y, Fu R, Zhu C. Ginsenoside Rh4 suppresses metastasis of esophageal cancer and expression of c-myc via targeting the wnt/β-catenin signaling pathway. Nutrients 2022;14(15).
  71. Chen Y, Liu Z-H, Xia J, Li X-P, Li KQ, Xiong W, et al. 20(S)-ginsenoside Rh2 inhibits the proliferation and induces the apoptosis of KG-1a cells through the Wnt/β-catenin signaling pathway. Oncol Rep 2016;36(1):137-46. https://doi.org/10.3892/or.2016.4774
  72. Xiang Y, Wang SH, Wang L, Wang ZL, Yao H, Chen LB, Wang YP. Effects of ginsenoside Rg1 regulating wnt/β-catenin signaling on neural stem cells to delay brain senescence. Stem Cell Int 2019;2019:5010184.
  73. Fan Q, Xi P, Tian D, Jia L, Cao Y, Zhan K, et al. Ginsenoside Rb1 facilitates browning by repressing wnt/beta-catenin signaling in 3T3-L1 adipocytes. Med Sci Mon Int Med J Exp Clin Res 2021;27:e928619.
  74. Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 2006;7(9):678-89. https://doi.org/10.1038/nrm2009
  75. Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B, Miele L. Targeting Notch to target cancer stem cells. Clin Cancer Res 2010;16(12):3141-52. https://doi.org/10.1158/1078-0432.CCR-09-2823
  76. Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, et al. IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 2007;117(12):3988-4002. https://doi.org/10.1172/JCI32533
  77. Sansone P, Storci G, Giovannini C, Pandolfi S, Pianetti S, Taffurelli M, et al. p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cell 2007;25(3):807-15. https://doi.org/10.1634/stemcells.2006-0442
  78. Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N, et al. NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cell 2010;28(1):5-16. https://doi.org/10.1002/stem.254
  79. Li N, Zhu C, Fu R, Ma X, Duan Z, Fan D. Ginsenoside Rg5 inhibits lipid accumulation and hepatocyte apoptosis via the Notch1 signaling pathway in NASH mice. Phytomedicine 2024;124:155287.
  80. Peng D, Tanikawa T, Li W, Zhao L, Vatan L, Szeliga W, et al. Myeloid-derived suppressor cells endow stem-like qualities to breast cancer cells through IL6/ STAT3 and NO/NOTCH cross-talk signaling. Cancer Res 2016;76(11):3156-65.
  81. Jiang J, Hui CC. Hedgehog signaling in development and cancer. Dev Cell 2008;15(6):801-12. https://doi.org/10.1016/j.devcel.2008.11.010
  82. Nieuwenhuis E, Hui CC. Hedgehog signaling and congenital malformations. Clin Genet 2005;67(3):193-208.
  83. Po A, Ferretti E, Miele E, De Smaele E, Paganelli A, Canettieri G, et al. Hedgehog controls neural stem cells through p53-independent regulation of Nanog. EMBO J 2010;29(15):2646-58. https://doi.org/10.1038/emboj.2010.131
  84. Liu S, Dontu G, Mantle ID, Patel S, Ahn NS, Jackson KW, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006;66(12):6063-71. https://doi.org/10.1158/0008-5472.CAN-06-0054
  85. Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci U S A 2007;104(10):4048-53. https://doi.org/10.1073/pnas.0611682104
  86. Zhang G, He L, Chen J, Xu B, Mao Z. Ginsenoside Rh2 activates alpha-catenin phosphorylation to inhibit lung cancer cell proliferation and invasion. Exp Ther Med 2020;19(4):2913-22.
  87. Cai N, Yang Q, Che DB, Jin X. 20(S)-Ginsenoside Rg3 regulates the Hedgehog signaling pathway to inhibit proliferation and epithelial-mesenchymal transition of lung cancer cells. Pharmazie 2021;76(9):431-6.
  88. Mohanan P, Subramaniyam S, Mathiyalagan R, Yang DC. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. J Ginseng Res 2018;42 (2):123-32. https://doi.org/10.1016/j.jgr.2017.01.008
  89. Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI. Tumour-initiating stemlike cells in human prostate cancer exhibit increased NF-kappaB signalling. Nat Commun 2011;2:162.
  90. Garner JM, Fan M, Yang CH, Du Z, Sims M, Davidoff AM, Pfeffer LM. Constitutive activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappaB signaling in glioblastoma cancer stem cells regulates the Notch pathway. J Biol Chem 2013;288(36):26167-76. https://doi.org/10.1074/jbc.M113.477950
  91. Birnie R, Bryce Sd Fau - Roome C, Roome C Fau - Dussupt V, Dussupt V Fau - Droop A, Droop A Fau - Lang SH, Lang Sh Fau - Berry PA, et al. Gene expression profiling of human prostate cancer stem cells reveals a pro-inflammatory phenotype and the importance of extracellular matrix interactions. (1474-760X (Electronic).
  92. Zhou J, Wulfkuhle J Fau - Zhang H, Zhang H Fau - Gu P, Gu P Fau - Yang Y, Yang Y Fau - Deng J, Deng J Fau - Margolick JB, et al. Activation of the PTEN/mTOR/STAT3 pathway in breast cancer stem-like cells is required for viability and maintenance. (27-8424 (Print).
  93. Kim SM, Lee SY, Yuk DY, Moon DC, Choi SS, Kim Y, et al. Inhibition of NF-κB by ginsenoside Rg3 enhances the susceptibility of colon cancer cells to docetaxel. Arch Pharm Res (Seoul) 2009;32(5):755-65. https://doi.org/10.1007/s12272-009-1515-4
  94. Jin Y, Huynh DTN, Myung CS, Heo KS. Ginsenoside Rh1 prevents migration and invasion through mitochondrial ROS-mediated inhibition of STAT3/NF-κB signaling in MDA-MB-231 cells. Int J Mol Sci 2021;22(19).
  95. Karami Fath M, Ebrahimi M, Nourbakhsh E, Zia Hazara A, Mirzaei A, Shafieyari S, et al. PI3K/Akt/mTOR signaling pathway in cancer stem cells. Pathol Res Pract 2022;237:154010.
  96. Lee JS, Lero MW, Mercado-Matos J, Zhu S, Jo M, Tocheny CE, et al. The insulin and IGF signaling pathway sustains breast cancer stem cells by IRS2/PI3Kmediated regulation of MYC. Cell Rep 2022;41(10):111759.
  97. Ghafouri-Fard S, Balaei N, Shoorei H, Hasan SMF, Hussen BM, Talebi SF, et al. The effects of Ginsenosides on PI3K/AKT signaling pathway. Mol Biol Rep 2022;49(7):6701-16. https://doi.org/10.1007/s11033-022-07270-y
  98. Mathieu J, Zhang Z, Zhou W, Wang AJ, Heddleston JM, Pinna CM, et al. HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 2011;71(13):4640-52.
  99. Zhai FG, Liang QC, Wu YY, Liu JQ, Liu JW. Red ginseng polysaccharide exhibits anticancer activity through GPX4 downregulation-induced ferroptosis. Pharm Biol 2022;60(1):909-14.
  100. Kabakov A, Yakimova A, Matchuk O. Molecular chaperones in cancer stem cells: determinants of stemness and potential targets for antitumor therapy. Cells 2020;9(4).