Skip to content
2000
image of Regulation of the PI3K/AKT/mTOR cascade in Hepatocellular Carcinoma Using Flavonoid Molecules

Abstract

Introduction

Hepatocellular carcinoma (HCC) is one of the leading causes of global cancer death. The phosphatidylinositol-3-kinase/ protein kinase B/ mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is one of the highly regulated signalling transduction pathways in cells promoting cell survival, growth, motility, metabolism, and proliferation. This signalling axis is aberrantly activated in a wide variety of tumours, such as breast, cervical, colon, gastric, liver, lung, ovarian, and prostate. The PI3K/AKT/mTOR (PAM) signalling axis is the most pivotal and overactivated signalling pathway in ⁓50% of HCC cases. Phytochemicals, such as flavonoids, have been identified and isolated to date and are reported to have anticancer, cardioprotective, anti-inflammatory, anti-oxidant, and hepatoprotective properties.

Methods

Studies discussed in this review were obtained from PubMed, Scopus, and Google Scholar databases using combinations of the terms related to HCC and flavonoids.

Results

This review summarizes the mechanism of action of flavonoids to get a better understanding of their role in HCC. It also discusses mechanistic approaches for targeting the PAM pathway using various flavonoid moieties.

Discussion

The scientific literature describes the pharmacological aspect of various flavonoids in targeting the “PAM axis” to manage hepatocarcinogenesis. These flavonoids chemosensitize the target, thus reducing the chance of resistance towards the chemotherapy, and also act as direct antioxidants, indirect antioxidants, or pro-oxidants.

Conclusion

Further studies are required to investigate the pharmacokinetic profile of flavonoids as they hold immense potential to inhibit the PAM pathway in the management of hepatocellular carcinoma.

© 2025 Bentham Science publishers
Loading

Article metrics loading...

/content/journals/ccdt/10.2174/0115680096389157250917055438
2025-10-02
2025-12-13

  • From This Site

    /content/journals/ccdt/10.2174/0115680096389157250917055438
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Bray F. Laversanne M. Sung H. Ferlay J. Siegel R.L. Soerjomataram I. Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2024 74 3 229 263 10.3322/caac.21834 38572751
    [Google Scholar]
  2. Rodriguez S. Skeet K. Mehmetoglu-Gurbuz T. Goldfarb M. Karri S. Rocha J. Shahinian M. Yazadi A. Poudel S. Subramani R. Phytochemicals as an alternative or integrative option, in conjunction with conventional treatments for hepatocellular carcinoma. Cancers 2021 13 22 5753 10.3390/cancers13225753 34830907
    [Google Scholar]
  3. Basu A. Namporn T. Ruenraroengsak P. Critical review in designing plant-based anticancer nanoparticles against hepatocellular carcinoma. Pharmaceutics 2023 15 6 1611 10.3390/pharmaceutics15061611 37376061
    [Google Scholar]
  4. Rao C.V. Asch A.S. Yamada H.Y. Frequently mutated genes/pathways and genomic instability as prevention targets in liver cancer. Carcinogenesis 2017 38 1 2 11 10.1093/carcin/bgw118 27838634
    [Google Scholar]
  5. Schlachterman A. Craft W.W. Hilgenfeldt E. Mitra A. Cabrera R. Current and future treatments for hepatocellular carcinoma. World J. Gastroenterol. 2015 21 28 8478 8491 10.3748/wjg.v21.i28.8478 26229392
    [Google Scholar]
  6. Jadlowiec C.C. Taner T. Liver transplantation: Current status and challenges. World J. Gastroenterol. 2016 22 18 4438 4445 10.3748/wjg.v22.i18.4438 27182155
    [Google Scholar]
  7. Kollmann D. Selzner N. Selzner M. Bridging to liver transplantation in HCC patients. Langenbecks Arch. Surg. 2017 402 6 863 871 10.1007/s00423‑017‑1609‑2 28755240
    [Google Scholar]
  8. Abou Baker D.H. An ethnopharmacological review on the therapeutical properties of flavonoids and their mechanisms of actions: A comprehensive review based on up to date knowledge. Toxicol. Rep. 2022 9 445 469 10.1016/j.toxrep.2022.03.011 35340621
    [Google Scholar]
  9. Seror O. Ablative therapies: Advantages and disadvantages of radiofrequency, cryotherapy, microwave and electroporation methods, or how to choose the right method for an individual patient? Diagn. Interv. Imaging 2015 96 6 617 624 10.1016/j.diii.2015.04.007 25981214
    [Google Scholar]
  10. Sacco R. Tapete G. Simonetti N. Sellitri R. Natali V. Melissari S. Cabibbo G. Biscaglia L. Bresci G. Giacomelli L. Transarterial chemoembolization for the treatment of hepatocellular carcinoma: A review. J. Hepatocell. Carcinoma 2017 4 105 110 10.2147/JHC.S103661 28795053
    [Google Scholar]
  11. Ebeling Barbier C. Heindryckx F. Lennernäs H. Limitations and possibilities of transarterial chemotherapeutic treatment of hepatocellular carcinoma. Int. J. Mol. Sci. 2021 22 23 13051 10.3390/ijms222313051 34884853
    [Google Scholar]
  12. Zheng A. Chevalier N. Calderoni M. Dubuis G. Dormond O. Ziros P.G. Sykiotis G.P. Widmann C. CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma. Oncotarget 2019 10 66 7058 7070 10.18632/oncotarget.27361 31903165
    [Google Scholar]
  13. Waidmann O. Recent developments with immunotherapy for hepatocellular carcinoma. Expert Opin. Biol. Ther. 2018 18 8 905 910 10.1080/14712598.2018.1499722 29995439
    [Google Scholar]
  14. Gupta S. Shukla S. Limitations of immunotherapy in cancer. Cureus 2022 14 10 30856 10.7759/cureus.30856 36465776
    [Google Scholar]
  15. Bang A. Dawson L.A. Radiotherapy for HCC: Ready for prime time? JHEP Rep Innov. Hepatol. 2019 1 2 131 137 10.1016/j.jhepr.2019.05.004 32039361
    [Google Scholar]
  16. Deng G.L. Zeng S. Shen H. Chemotherapy and target therapy for hepatocellular carcinoma: New advances and challenges. World J. Hepatol. 2015 7 5 787 798 10.4254/wjh.v7.i5.787 25914779
    [Google Scholar]
  17. Chen S. Wang X. Cheng Y. Gao H. Chen X. A review of classification, biosynthesis, biological activities and potential applications of flavonoids. Molecules 2023 28 13 4982 10.3390/molecules28134982 37446644
    [Google Scholar]
  18. Manning B.D. Cantley L.C. AKT/PKB signaling: Navigating downstream. Cell 2007 129 7 1261 1274 10.1016/j.cell.2007.06.009 17604717
    [Google Scholar]
  19. Janku F. Yap T.A. Meric-Bernstam F. Targeting the PI3K pathway in cancer: Are we making headway? Nat. Rev. Clin. Oncol. 2018 15 5 273 291 10.1038/nrclinonc.2018.28 29508857
    [Google Scholar]
  20. Glaviano A. Foo A.S.C. Lam H.Y. Yap K.C.H. Jacot W. Jones R.H. Eng H. Nair M.G. Makvandi P. Geoerger B. Kulke M.H. Baird R.D. Prabhu J.S. Carbone D. Pecoraro C. Teh D.B.L. Sethi G. Cavalieri V. Lin K.H. Javidi-Sharifi N.R. Toska E. Davids M.S. Brown J.R. Diana P. Stebbing J. Fruman D.A. Kumar A.P. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer. Mol. Cancer 2023 22 1 138 10.1186/s12943‑023‑01827‑6 37596643
    [Google Scholar]
  21. Porta C. Paglino C. Mosca A. Targeting PI3K/Akt/mTOR signaling in cancer. Front. Oncol. 2014 4 64 10.3389/fonc.2014.00064 24782981
    [Google Scholar]
  22. Sirico M. D’Angelo A. Gianni C. Casadei C. Merloni F. De Giorgi U. Current state and future challenges for pi3k inhibitors in cancer therapy. Cancers 2023 15 3 703 10.3390/cancers15030703 36765661
    [Google Scholar]
  23. Naqi A. Ara S.A. Khan M.A. Ahmad J. An insight on PI3K/AKT/MTOR inhibitors in cancer: Opportunity and translational perspectives. In:Protein Kinase Inhibitors; Hassan, Md. Im-taiyaz. Chapter 4 Noor S. United States Academic Press 2022 97 127.9780323912877 10.1016/B978‑0‑323‑91287‑7.00020‑X
    [Google Scholar]
  24. Panwar V. Singh A. Bhatt M. Tonk R.K. Azizov S. Raza A.S. Sengupta S. Kumar D. Garg M. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease. Signal Transduct. Target. Ther. 2023 8 1 375 10.1038/s41392‑023‑01608‑z 37779156
    [Google Scholar]
  25. He Y. Sun M.M. Zhang G.G. Yang J. Chen K.S. Xu W.W. Li B. Targeting PI3K/Akt signal transduction for cancer therapy. Signal Transduct. Target. Ther. 2021 6 1 425 10.1038/s41392‑021‑00828‑5 34916492
    [Google Scholar]
  26. Hoxhaj G. Manning B.D. The PI3K–AKT network at the interface of oncogenic signalling and cancer metabolism. Nat. Rev. Cancer 2020 20 2 74 88 10.1038/s41568‑019‑0216‑7 31686003
    [Google Scholar]
  27. Yang J. Nie J. Ma X. Wei Y. Peng Y. Wei X. Targeting PI3K in cancer: Mechanisms and advances in clinical trials. Mol. Cancer 2019 18 1 26 10.1186/s12943‑019‑0954‑x 30782187
    [Google Scholar]
  28. Dimri M. Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers 2020 12 2 491 10.3390/cancers12020491 32093152
    [Google Scholar]
  29. Zhao C. Wang B. Liu E. Zhang Z. Loss of PTEN expression is associated with PI3K pathway-dependent metabolic reprogramming in hepatocellular carcinoma. Cell Commun. Signal. 2020 18 1 131 10.1186/s12964‑020‑00622‑w 32831114
    [Google Scholar]
  30. Chen D. Li Z. Cheng Q. Wang Y. Qian L. Gao J. Zhu J.Y. Genetic alterations and expression of PTEN and its relationship with cancer stem cell markers to investigate pathogenesis and to evaluate prognosis in hepatocellular carcinoma. J. Clin. Pathol. 2019 72 9 588 596 10.1136/jclinpath‑2019‑205769 31126975
    [Google Scholar]
  31. Khemlina G. Ikeda S. Kurzrock R. The biology of Hepatocellular carcinoma: Implications for genomic and immune therapies. Mol. Cancer 2017 16 1 149 10.1186/s12943‑017‑0712‑x 28854942
    [Google Scholar]
  32. Xu Z. Hu J. Cao H. Pilo M.G. Cigliano A. Shao Z. Xu M. Ribback S. Dombrowski F. Calvisi D.F. Chen X. Loss of Pten synergizes with c-Met to promote hepatocellular carcinoma development via mTORC2 pathway. Exp. Mol. Med. 2018 50 1 e417 e417 10.1038/emm.2017.158 29303510
    [Google Scholar]
  33. Tian L.Y. Smit D.J. Jücker M. The role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism. Int. J. Mol. Sci. 2023 24 3 2652 10.3390/ijms24032652 36768977
    [Google Scholar]
  34. Lee J.W. Soung Y.H. Kim S.Y. Lee H.W. Park W.S. Nam S.W. Kim S.H. Lee J.Y. Yoo N.J. Lee S.H. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 2005 24 8 1477 1480 10.1038/sj.onc.1208304 15608678
    [Google Scholar]
  35. Liskova A. Koklesova L. Samec M. Smejkal K. Samuel S.M. Varghese E. Abotaleb M. Biringer K. Kudela E. Danko J. Shakibaei M. Kwon T.K. Büsselberg D. Kubatka P. Flavonoids in cancer metastasis. Cancers 2020 12 6 1498 10.3390/cancers12061498 32521759
    [Google Scholar]
  36. Safe S. Jayaraman A. Chapkin R.S. Howard M. Mohankumar K. Shrestha R. Flavonoids: Structure–function and mechanisms of action and opportunities for drug development. Toxicol. Res. 2021 37 2 147 162 10.1007/s43188‑020‑00080‑z 33868973
    [Google Scholar]
  37. Kopustinskiene D.M. Jakstas V. Savickas A. Bernatoniene J. Flavonoids as anticancer agents. Nutrients 2020 12 2 457 10.3390/nu12020457 32059369
    [Google Scholar]
  38. de Luna F.C.F. Ferreira W.A.S. Casseb S.M.M. de Oliveira E.H.C. Anticancer potential of flavonoids: An overview with an emphasis on tangeretin. Pharmaceuticals 2023 16 9 1229 10.3390/ph16091229 37765037
    [Google Scholar]
  39. Tuli H.S. Garg V.K. Bhushan S. Uttam V. Sharma U. Jain A. Sak K. Yadav V. Lorenzo J.M. Dhama K. Behl T. Sethi G. Natural flavonoids exhibit potent anticancer activity by targeting microRNAs in cancer: A signature step hinting towards clinical perfection. Transl. Oncol. 2023 27 101596 10.1016/j.tranon.2022.101596 36473401
    [Google Scholar]
  40. Mazurakova A. Koklesova L. Csizmár S.H. Samec M. Brockmueller A. Šudomová M. Biringer K. Kudela E. Pec M. Samuel S.M. Kassayova M. Hassan S.T.S. Smejkal K. Shakibaei M. Büsselberg D. Saso L. Kubatka P. Golubnitschaja O. Significance of flavonoids targeting PI3K/Akt/HIF-1α signaling pathway in therapy-resistant cancer cells – A potential contribution to the predictive, preventive, and personalized medicine. J. Adv. Res. 2024 55 103 118 10.1016/j.jare.2023.02.015 36871616
    [Google Scholar]
  41. Zughaibi T.A. Suhail M. Tarique M. Tabrez S. Targeting PI3K/Akt/mTOR Pathway by Different Flavonoids: A Cancer Chemopreventive Approach. Int. J. Mol. Sci. 2021 22 22 12455 10.3390/ijms222212455 34830339
    [Google Scholar]
  42. Rahmani A.H. Almatroudi A. Khan A.A. Babiker A.Y. Alanezi M. Allemailem K.S. The multifaceted role of baicalein in cancer management through modulation of cell signalling pathways. Molecules 2022 27 22 8023 10.3390/molecules27228023 36432119
    [Google Scholar]
  43. Lee W.J. Wu L.F. Chen W.K. Wang C.J. Tseng T.H. Inhibitory effect of luteolin on hepatocyte growth factor/scatter factor-induced HepG2 cell invasion involving both MAPK/ERKs and PI3K–Akt pathways. Chem. Biol. Interact. 2006 160 2 123 133 10.1016/j.cbi.2006.01.002 16458870
    [Google Scholar]
  44. Zheng Y.H. Yin L.H. Grahn T.H.M. Ye A.F. Zhao Y.R. Zhang Q.Y. Anticancer effects of baicalein on hepatocellular carcinoma cells. Phytother. Res. 2014 28 9 1342 1348 10.1002/ptr.5135 24596136
    [Google Scholar]
  45. Oh J.W. Muthu M. Pushparaj S.S.C. Gopal J. Anticancer therapeutic effects of green tea catechins (GTCs) when integrated with antioxidant natural components. Molecules 2023 28 5 2151 10.3390/molecules28052151 36903395
    [Google Scholar]
  46. Wen S. An R. Li D. Cao J. Li Z. Zhang W. Chen R. Li Q. Lai X. Sun L. Sun S. Tea and Citrus maxima complex induces apoptosis of human liver cancer cells via PI3K/AKT/mTOR pathway in vitro. Chin. Herb. Med. 2022 14 3 449 458 10.1016/j.chmed.2021.09.015 36118010
    [Google Scholar]
  47. Talib W.H. Awajan D. Alqudah A. Alsawwaf R. Althunibat R. Abu AlRoos M. Al Safadi A. Abu Asab S. Hadi R.W. Al Kury L.T. Targeting cancer hallmarks with epigallocatechin gallate (EGCG): Mechanistic basis and therapeutic targets. Molecules 2024 29 6 1373 10.3390/molecules29061373 38543009
    [Google Scholar]
  48. Zhang Q. Tang X. Lu Q. Zhang Z. Rao J. Le A.D. Green tea extract and (−)-epigallocatechin-3-gallate inhibit hypoxia- and serum-induced HIF-1α protein accumulation and VEGF expression in human cervical carcinoma and hepatoma cells. Mol. Cancer Ther. 2006 5 5 1227 1238 10.1158/1535‑7163.MCT‑05‑0490 16731755
    [Google Scholar]
  49. Shimizu M. Shirakami Y. Sakai H. Tatebe H. Nakagawa T. Hara Y. Weinstein I.B. Moriwaki H. EGCG inhibits activation of the insulin-like growth factor (IGF)/IGF-1 receptor axis in human hepatocellular carcinoma cells. Cancer Lett. 2008 262 1 10 18 10.1016/j.canlet.2007.11.026 18164805
    [Google Scholar]
  50. Huang C.H. Tsai S.J. Wang Y.J. Pan M.H. Kao J.Y. Way T.D. EGCG inhibits protein synthesis, lipogenesis, and cell cycle progression through activation of AMPK in p53 positive and negative human hepatoma cells. Mol. Nutr. Food Res. 2009 53 9 1156 1165 10.1002/mnfr.200800592 19662644
    [Google Scholar]
  51. Yang X.W. Wang X.L. Cao L.Q. Jiang X.F. Peng H.P. Lin S.M. Xue P. Chen D. Green tea polyphenol epigallocatechin‐3‐gallate enhances 5‐fluorouracil‐induced cell growth inhibition of hepatocellular carcinoma cells. Hepatol. Res. 2012 42 5 494 501 10.1111/j.1872‑034X.2011.00947.x 22221825
    [Google Scholar]
  52. Shen X. Zhang Y. Feng Y. Zhang L. Li J. Xie Y. Luo X. Epigallocatechin-3-gallate inhibits cell growth, induces apoptosis and causes S phase arrest in hepatocellular carcinoma by suppressing the AKT pathway. Int. J. Oncol. 2014 44 3 791 796 10.3892/ijo.2014.2251 24402647
    [Google Scholar]
  53. Wubetu G.Y. Shimada M. Morine Y. Ikemoto T. Ishikawa D. Iwahashi S. Yamada S. Saito Y. Arakawa Y. Imura S. Epigallocatechin gallate hinders human hepatoma and colon cancer sphere formation. J. Gastroenterol. Hepatol. 2016 31 1 256 264 10.1111/jgh.13069 26241688
    [Google Scholar]
  54. Tuli H.S. Tuorkey M.J. Thakral F. Sak K. Kumar M. Sharma A.K. Sharma U. Jain A. Aggarwal V. Bishayee A. Molecular mechanisms of action of genistein in cancer: Recent advances. Front. Pharmacol. 2019 10 1336 10.3389/fphar.2019.01336 31866857
    [Google Scholar]
  55. Wang S.D. Chen B.C. Kao S.T. Liu C.J. Yeh C.C. Genistein inhibits tumor invasion by suppressing multiple signal transduction pathways in human hepatocellular carcinoma cells. BMC Complement. Altern. Med. 2014 14 1 26 10.1186/1472‑6882‑14‑26 24433534
    [Google Scholar]
  56. Wang K.L. Yu Y.C. Hsia S.M. Perspectives on the role of isoliquiritigenin in cancer. Cancers 2021 13 1 115 10.3390/cancers13010115 33401375
    [Google Scholar]
  57. Song L. Luo Y. Li S. Hong M. Wang Q. Chi X. Yang C. ISL induces apoptosis and autophagy in hepatocellular carcinoma via downregulation of PI3K/AKT/mTOR pathway in vivo and in vitro. Drug Des. Devel. Ther. 2020 14 4363 4376 10.2147/DDDT.S270124 33116421
    [Google Scholar]
  58. Huang Y. Liu C. Zeng W.C. Xu G.Y. Wu J.M. Li Z.W. Huang X.Y. Lin R.J. Shi X. Isoliquiritigenin inhibits the proliferation, migration and metastasis of Hep3B cells via suppressing cyclin D1 and PI3K/AKT pathway. Biosci. Rep. 2020 40 1 BSR20192727 10.1042/BSR20192727 31840737
    [Google Scholar]
  59. Lu L. Guo Q. Zhao L. Overview of oroxylin A: A promising flavonoid compound. Phytother. Res. 2016 30 11 1765 1774 10.1002/ptr.5694 27539056
    [Google Scholar]
  60. Xu M. Lu N. Sun Z. Zhang H. Dai Q. Wei L. Li Z. You Q. Guo Q. Activation of the unfolded protein response contributed to the selective cytotoxicity of oroxylin A in human hepatocellular carcinoma HepG2 cells. Toxicol. Lett. 2012 212 2 113 125 10.1016/j.toxlet.2012.05.008 22609744
    [Google Scholar]
  61. Zou M. Lu N. Hu C. Liu W. Sun Y. Wang X. You Q. Gu C. Xi T. Guo Q. Beclin 1-mediated autophagy in hepatocellular carcinoma cells: Implication in anticancer efficiency of oroxylin A via inhibition of mTOR signaling. Cell. Signal. 2012 24 8 1722 1732 10.1016/j.cellsig.2012.04.009 22560876
    [Google Scholar]
  62. Tang S.M. Deng X.T. Zhou J. Li Q.P. Ge X.X. Miao L. Pharmacological basis and new insights of quercetin action in respect to its anti-cancer effects. Biomed. Pharmacother. 2020 121 109604 10.1016/j.biopha.2019.109604 31733570
    [Google Scholar]
  63. Granado-Serrano A.B. Martiín M.A. Bravo L. Goya L. Ramos S. Quercetin induces apoptosis via caspase activation, regulation of Bcl-2, and inhibition of PI-3-kinase/Akt and ERK pathways in a human hepatoma cell line (HepG2). J. Nutr. 2006 136 11 2715 2721 10.1093/jn/136.11.2715 17056790
    [Google Scholar]
  64. Ji Y. Li L. Ma Y.X. Li W.T. Li L. Zhu H.Z. Wu M.H. Zhou J.R. Quercetin inhibits growth of hepatocellular carcinoma by apoptosis induction in part via autophagy stimulation in mice. J. Nutr. Biochem. 2019 69 108 119 10.1016/j.jnutbio.2019.03.018 31078904
    [Google Scholar]
  65. Li-Weber M. New therapeutic aspects of flavones: The anticancer properties of Scutellaria and its main active constituents Wogonin, Baicalein and Baicalin. Cancer Treat. Rev. 2009 35 1 57 68 10.1016/j.ctrv.2008.09.005 19004559
    [Google Scholar]
  66. Xu M. Lu N. Zhang H. Dai Q. Wei L. Li Z. You Q. Guo Q. Wogonin induced cytotoxicity in human hepatocellular carcinoma cells by activation of unfolded protein response and inactivation of AKT. Hepatol. Res. 2013 43 8 890 905 10.1111/hepr.12036 23294370
    [Google Scholar]
  67. Zhao L. Sha Y.Y. Zhao Q. Yao J. Zhu B.B. Lu Z.J. You Q.D. Guo Q.L. Enhanced 5-fluorouracil cytotoxicity in high COX-2 expressing hepatocellular carcinoma cells by wogonin via the PI3K/Akt pathway. Biochem. Cell Biol. 2013 91 4 221 229 10.1139/bcb‑2012‑0077 23859016
    [Google Scholar]
  68. Liu X. Tian S. Liu M. Jian L. Zhao L. Wogonin inhibits the proliferation and invasion, and induces the apoptosis of HepG2 and Bel7402 HCC cells through NF-κB/Bcl-2, EGFR and EGFR downstream ERK/AKT signaling. Int. J. Mol. Med. 2016 38 4 1250 1256 10.3892/ijmm.2016.2700 27499272
    [Google Scholar]
  69. Li X. Zhang Z. Zhang X. Yang S. Liu D. Diao C. Wang H. Zheng F. Cyanidin inhibits EMT induced by oxaliplatin via targeting the PDK1–PI3K/Akt signaling pathway. Food Funct. 2019 10 2 592 601 10.1039/C8FO01611A 30672917
    [Google Scholar]
  70. Liao Z.H. Zhu H.Q. Chen Y.Y. Chen R.L. Fu L.X. Li L. Zhou H. Zhou J.L. Liang G. The epigallocatechin gallate derivative Y6 inhibits human hepatocellular carcinoma by inhibiting angiogenesis in MAPK/ERK1/2 and PI3K/AKT/ HIF-1α/VEGF dependent pathways. J. Ethnopharmacol. 2020 259 112852 10.1016/j.jep.2020.112852 32278759
    [Google Scholar]
  71. Granado-Serrano A.B. Martín M.A. Haegeman G. Goya L. Bravo L. Ramos S. Epicatechin induces NF-κB, activator protein-1 (AP-1) and nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2) via phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and extracellular regulated kinase (ERK) signalling in HepG2 cells. Br. J. Nutr. 2010 103 2 168 179 10.1017/S0007114509991747 20030899
    [Google Scholar]
  72. Mo’men Y.S. Hussein R.M. Kandeil M.A. Involvement of PI3K/Akt pathway in the protective effect of hesperidin against a chemically induced liver cancer in rats. J. Biochem. Mol. Toxicol. 2019 33 6 22305 10.1002/jbt.22305 30779474
    [Google Scholar]
  73. Ju P.C. Ho Y.C. Chen P.N. Lee H.L. Lai S.Y. Yang S.F. Yeh C.B. Kaempferol inhibits the cell migration of human hepatocellular carcinoma cells by suppressing MMP ‐9 and Akt signaling. Environ. Toxicol. 2021 36 10 1981 1989 10.1002/tox.23316 34156145
    [Google Scholar]
  74. Wang Y. Lin J. Tian J. Si X. Jiao X. Zhang W. Gong E. Li B. Blueberry Malvidin-3-galactoside Suppresses Hepatocellular Carcinoma by Regulating Apoptosis, Proliferation, and Metastasis Pathways In Vivo and In Vitro. J. Agric. Food Chem. 2019 67 2 625 636 10.1021/acs.jafc.8b06209 30586992
    [Google Scholar]
  75. Wu T. Dong X. Yu D. Shen Z. Yu J. Yan S. Natural product pectolinarigenin inhibits proliferation, induces apoptosis, and causes G2/M phase arrest of HCC via PI3K/AKT/mTOR/ERK signaling pathway. OncoTargets Ther. 2018 11 8633 8642 10.2147/OTT.S186186 30584322
    [Google Scholar]
  76. Liskova A. Samec M. Koklesova L. Brockmueller A. Zhai K. Abdellatif B. Siddiqui M. Biringer K. Kudela E. Pec M. Gadanec L.K. Šudomová M. Hassan S.T.S. Zulli A. Shakibaei M. Giordano F.A. Büsselberg D. Golubnitschaja O. Kubatka P. Flavonoids as an effective sensitizer for anti-cancer therapy: Insights into multi-faceted mechanisms and applicability towards individualized patient profiles. EPMA J. 2021 12 2 155 176 10.1007/s13167‑021‑00242‑5 34025826
    [Google Scholar]
  77. Thilakarathna S. Rupasinghe H. Flavonoid bioavailability and attempts for bioavailability enhancement. Nutrients 2013 5 9 3367 3387 10.3390/nu5093367 23989753
    [Google Scholar]
  78. Liga S. Paul C. Péter F. Flavonoids: Overview of biosynthesis, biological activity, and current extraction techniques. Plants 2023 12 14 2732 10.3390/plants12142732 37514347
    [Google Scholar]
  79. Chen L. Cao H. Huang Q. Xiao J. Teng H. Absorption, metabolism and bioavailability of flavonoids: A review. Crit. Rev. Food Sci. Nutr. 2022 62 28 7730 7742 10.1080/10408398.2021.1917508 34078189
    [Google Scholar]
  80. Zverev Y.F. Rykunova A.Y. Modern nanocarriers as a factor in increasing the bioavailability and pharmacological activity of flavonoids. Appl. Biochem. Microbiol. 2022 58 9 1002 1020 10.1134/S0003683822090149 36540406
    [Google Scholar]
  81. Böttger R. Pauli G. Chao P.H. Fayez A.L. N.; Hohenwarter, L.; Li, S.D. Lipid-based nanoparticle technologies for liver targeting. Adv. Drug Deliv. Rev. 2020 154-155 79 101 10.1016/j.addr.2020.06.017 32574575
    [Google Scholar]
  82. Llovet J.M. Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008 48 4 1312 1327 10.1002/hep.22506 18821591
    [Google Scholar]
  83. Yang S. Cai C. Wang H. Ma X. Shao A. Sheng J. Yu C. Drug delivery strategy in hepatocellular carcinoma therapy. Cell Commun. Signal. 2022 20 1 26 10.1186/s12964‑021‑00796‑x 35248060
    [Google Scholar]
  84. Ji G. Li Y. Zhang Z. Li H. Sun P. Recent advances of novel targeted drug delivery systems based on natural medicine monomers against hepatocellular carcinoma. Heliyon 2024 10 2 24667 10.1016/j.heliyon.2024.e24667 38312669
    [Google Scholar]
  85. Alhalmi A. Beg S. Kohli K. Waris M. Singh T. Nanotechnology based approach for hepatocellular carcinoma targeting. Curr. Drug Targets 2021 22 7 779 792 10.2174/18735592MTEycMjQp3 33302831
    [Google Scholar]
  86. Hou X.Y. Jiang G. Yang C.S. Tang J.Q. Wei Z.P. Liu Y.Q. Application of nanotechnology in the diagnosis and therapy of hepatocellular carcinoma. Recent Pat. Antican Drug Discov 2016 11 3 322 331 10.2174/1574892811666160309121035 26955964
    [Google Scholar]
  87. Yassin N.Y.S. AbouZid S.F. El-Kalaawy A.M. Ali T.M. Almehmadi M.M. Ahmed O.M. Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. Biomed. Pharmacother. 2022 145 112409 10.1016/j.biopha.2021.112409
    [Google Scholar]
  88. Sundarraj K. Raghunath A. Panneerselvam L. Perumal E. Fisetin inhibits autophagy in hepg2 cells via PI3K/Akt/mTOR and AMPK pathway. Nutr. Cancer 2021 73 11-12 2502 2514 10.1080/01635581.2020.1836241 33086879
    [Google Scholar]
  89. Gao X. Jiang Y. Xu Q. Liu F. Pang X. Wang M. Li Q. Li Z. 4-Hydroxyderricin promotes apoptosis and cell cycle arrest through regulating pi3k/akt/mtor pathway in hepatocellular cells. Foods 2021 10 9 2036 10.3390/foods10092036 34574146
    [Google Scholar]
/content/journals/ccdt/10.2174/0115680096389157250917055438
Loading
Regulation of the PI3K/AKT/mTOR cascade in Hepatocellular Carcinoma Using Flavonoid Molecules
Bentham Science Publishers ; https://doi.org/10.2174/0115680096389157250917055438
/content/journals/ccdt/10.2174/0115680096389157250917055438
/content/journals/ccdt/10.2174/0115680096389157250917055438
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: hepatocellular carcinoma ; Flavonoids ; PI3K/AKT/mTOR pathway ; bioavailability ; active targeting ; nanoparticles

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test