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image of Targeting Chemical-induced Hepatocellular Carcinoma: Ameliorative Potential of Natural Compounds with Focus on Beta-carbolines

Abstract

Introduction

Hepatocellular carcinoma (HCC), the predominant form of primary liver malignancy, remains a major global health concern owing to its aggressive progression, limited therapeutic efficacy, and high fatality rate. A significant proportion of HCC arises from chronic exposure to chemical carcinogens, which trigger hepatocarcinogenesis through oxidative stress, DNA damage, and dysregulation of signalling networks. Natural compounds, particularly beta-carboline alkaloids, are emerging as safer, multi-targeted candidates with promising hepatoprotective and anticancer potential. This review has critically evaluated chemical-induced hepatocarcinogenesis and the therapeutic relevance of beta-carbolines in HCC.

Methods

A systematic literature survey was conducted using PubMed, Scopus, and Web of Science databases, emphasizing studies on chemical-induced HCC, natural hepatoprotective compounds, and beta-carboline derivatives. Mechanistic, pharmacological, and preclinical data were extracted and analyzed.

Results

Carcinogens, such as diethylnitrosamine (DEN), aflatoxin B1, and carbon tetrachloride (CCl), promote HCC by inducing oxidative stress, genotoxicity, and perturbations in signalling cascades, including PI3K/AKT, Wnt/β-catenin, and NF-κB. Beta-carbolines display antioxidant, pro-apoptotic, anti-inflammatory, and anti-metastatic activities, with evidence of direct modulation of oncogenic pathways and tumor microenvironment.

Discussion

The accumulating evidence highlights beta-carbolines as versatile natural agents with multi-faceted mechanisms against chemical-induced hepatocarcinogenesis. Nonetheless, gaps remain in understanding their pharmacokinetics, bioavailability, and long-term safety. Preclinical data are encouraging, but translational studies and clinical validations are limited, underscoring the need for further research.

Conclusion

Beta-carboline alkaloids hold significant promise as therapeutic candidates for chemical-induced HCC. Addressing challenges related to safety, bioavailability, and clinical applicability can prove to be crucial for their future development.

© 2025 Bentham Science Publishers
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2025-10-08
2025-11-06

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References

  1. Yang J.D. Hainaut P. Gores G.J. Amadou A. Plymoth A. Roberts L.R. A global view of hepatocellular carcinoma: Trends, risk, prevention and management. Nat. Rev. Gastroenterol. Hepatol. 2019 16 10 589 604 10.1038/s41575‑019‑0186‑y 31439937
    [Google Scholar]
  2. Gu X. Manautou J.E. Molecular mechanisms underlying chemical liver injury. Expert Rev. Mol. Med. 2012 14 e4 10.1017/S1462399411002110 22306029
    [Google Scholar]
  3. 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]
  4. Singal A.G. Lampertico P. Nahon P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J. Hepatol. 2020 72 2 250 261 10.1016/j.jhep.2019.08.025 31954490
    [Google Scholar]
  5. Cancer impact: New cervical cancer elimination planning tool now available. 2025 Available from: https://gco.iarc.fr/
  6. Liu Z. Xu K. Jiang Y. Cai N. Fan J. Mao X. Suo C. Jin L. Zhang T. Chen X. Global trend of aetiology-based primary liver cancer incidence from 1990 to 2030: A modelling study. Int. J. Epidemiol. 2021 50 1 128 142 10.1093/ije/dyaa196 33349860
    [Google Scholar]
  7. Schinzari V. Barnaba V. Piconese S. Chronic hepatitis B virus and hepatitis C virus infections and cancer: Synergy between viral and host factors. Clin. Microbiol. Infect. 2015 21 11 969 974 10.1016/j.cmi.2015.06.026 26163104
    [Google Scholar]
  8. Barsouk A. Thandra K.C. Saginala K. Rawla P. Barsouk A. Chemical risk factors of primary liver cancer: An update. Hepat. Med. 2021 12 179 188 10.2147/HMER.S278070 33447099
    [Google Scholar]
  9. Wu H.C. Wang Q. Wang L.W. Yang H.I. Ahsan H. Tsai W.Y. Wang L.Y. Chen S.Y. Chen C.J. Santella R.M. Polycyclic aromatic hydrocarbon- and aflatoxin-albumin adducts, hepatitis B virus infection and hepatocellular carcinoma in Taiwan. Cancer Lett. 2007 252 1 104 114 10.1016/j.canlet.2006.12.010 17250958
    [Google Scholar]
  10. Hamid A.S. Tesfamariam I.G. Zhang Y. Zhang Z.G. Aflatoxin B1-induced hepatocellular carcinoma in developing countries: Geographical distribution, mechanism of action and prevention. Oncol. Lett. 2013 5 4 1087 1092 10.3892/ol.2013.1169 23599745
    [Google Scholar]
  11. Memon A. Pyao Y. Jung Y. Lee J.I. Lee W.K. A modified protocol of diethylnitrosamine administration in mice to model hepatocellular carcinoma. Int. J. Mol. Sci. 2020 21 15 5461 10.3390/ijms21155461 32751728
    [Google Scholar]
  12. Stickel F. Schuppan D. Hahn E.G. Seitz H.K. Cocarcinogenic effects of alcohol in hepatocarcinogenesis. Gut 2002 51 1 132 139 10.1136/gut.51.1.132 12077107
    [Google Scholar]
  13. Elshaarawy O. Aman A. Zakaria H.M. Zakareya T. Gomaa A. Elshimi E. Abdelsameea E. Outcomes of curative liver resection for hepatocellular carcinoma in patients with cirrhosis. World J. Gastrointest. Oncol. 2021 13 5 424 439 10.4251/wjgo.v13.i5.424 34040703
    [Google Scholar]
  14. Poon R.T.P. Fan S.T. Tsang F.H.F. Wong J. Locoregional therapies for hepatocellular carcinoma: A critical review from the surgeon’s perspective. Ann. Surg. 2002 235 4 466 486 10.1097/00000658‑200204000‑00004 11923602
    [Google Scholar]
  15. Ntellas P. Chau I. Updates on systemic therapy for hepatocellular carcinoma. Am. Soc. Clin. Oncol. Educ. Book 2024 44 1 e430028 10.1200/EDBK_430028 38175973
    [Google Scholar]
  16. Shen K.Y. Zhu Y. Xie S.Z. Qin L.X. Immunosuppressive tumor microenvironment and immunotherapy of hepatocellular carcinoma: Current status and prospectives. J. Hematol. Oncol. 2024 17 1 25 10.1186/s13045‑024‑01549‑2 38679698
    [Google Scholar]
  17. Jain D. Murti Y. Khan W.U. Hossain R. Hossain M.N. Agrawal K.K. Ashraf R.A. Islam M.T. Janmeda P. Taheri Y. Alshehri M.M. Daştan S.D. Yeskaliyeva B. Kipchakbayeva A. Sharifi-Rad J. Cho W.C. Roles of therapeutic bioactive compounds in hepatocellular carcinoma. Oxid. Med. Cell. Longev. 2021 2021 1 9068850 10.1155/2021/9068850 34754365
    [Google Scholar]
  18. George B.P. Chandran R. Abrahamse H. Role of phytochemicals in cancer chemoprevention: Insights. Antioxidants 2021 10 9 1455 10.3390/antiox10091455 34573087
    [Google Scholar]
  19. Naeem A. Hu P. Yang M. Zhang J. Liu Y. Zhu W. Zheng Q. Natural products as anticancer agents: Current status and future perspectives. Molecules 2022 27 23 8367 10.3390/molecules27238367 36500466
    [Google Scholar]
  20. Hao M.J. Chen P.N. Li H.J. Wu F. Zhang G.Y. Shao Z.Z. Liu X.P. Ma W.Z. Xu J. Mahmud T. Lan W.J. β-carboline alkaloids from the deep-sea fungus Trichoderma sp. MCCC 3A01244 as a new type of anti-pulmonary fibrosis agent that inhibits TGF-β/Smad signaling pathway. Front. Microbiol. 2022 13 947226 10.3389/fmicb.2022.947226 35966687
    [Google Scholar]
  21. Ayipo Y.O. Mordi M.N. Mustapha M. Damodaran T. Neuropharmacological potentials of β-carboline alkaloids for neuropsychiatric disorders. Eur. J. Pharmacol. 2021 893 173837 10.1016/j.ejphar.2020.173837 33359647
    [Google Scholar]
  22. Zhang M. Sun D. Recent advances of natural and synthetic β-carbolines as anticancer agents. Anticancer. Agents Med. Chem. 2015 15 5 537 547 10.2174/1871520614666141128121812 25430895
    [Google Scholar]
  23. Nafisi S. Bonsaii M. Maali P. Khalilzadeh M.A. Manouchehri F. β-Carboline alkaloids bind DNA. J. Photochem. Photobiol. B 2010 100 2 84 91 10.1016/j.jphotobiol.2010.05.005 20541950
    [Google Scholar]
  24. Bhattacharjee P. Ghosh T. Sarkar S. Pandya P. Bhadra K. Binding affinity and in vitro cytotoxicity of harmaline targeting different motifs of nucleic acids: An ultimate drug designing approach. J. Mol. Recognit. 2018 31 4 e2687 10.1002/jmr.2687 29243872
    [Google Scholar]
  25. Sarkar S. Bhadra K. Therapeutic role of harmalol targeting nucleic acids: Biophysical perspective and in vitro cytotoxicity. Mini Rev. Med. Chem. 2018 18 19 1624 1639 10.2174/1389557518666171211164830 29231137
    [Google Scholar]
  26. Qin R. You F.M. Zhao Q. Xie X. Peng C. Zhan G. Han B. Naturally derived indole alkaloids targeting regulated cell death (RCD) for cancer therapy: From molecular mechanisms to potential therapeutic targets. J. Hematol. Oncol. 2022 15 1 133 10.1186/s13045‑022‑01350‑z 36104717
    [Google Scholar]
  27. Suresh D. Srinivas A.N. Kumar D.P. Etiology of hepatocellular carcinoma: Special focus on fatty liver disease. Front. Oncol. 2020 10 601710 10.3389/fonc.2020.601710 33330100
    [Google Scholar]
  28. Casey S.C. Vaccari M. Al-Mulla F. Al-Temaimi R. Amedei A. Barcellos-Hoff M.H. Brown D.G. Chapellier M. Christopher J. Curran C.S. Forte S. Hamid R.A. Heneberg P. Koch D.C. Krishnakumar P.K. Laconi E. Maguer-Satta V. Marongiu F. Memeo L. Mondello C. Raju J. Roman J. Roy R. Ryan E.P. Ryeom S. Salem H.K. Scovassi A.I. Singh N. Soucek L. Vermeulen L. Whitfield J.R. Woodrick J. Colacci A.M. Bisson W.H. Felsher D.W. The effect of environmental chemicals on the tumor microenvironment. Carcinogenesis 2015 36 Suppl. 1 S160 S183 10.1093/carcin/bgv035 26106136
    [Google Scholar]
  29. Esteves F. Rueff J. Kranendonk M. The central role of cytochrome P450 in xenobiotic metabolism—A brief review on a fascinating enzyme family. J. Xenobiot. 2021 11 3 94 114 10.3390/jox11030007 34206277
    [Google Scholar]
  30. Farazi P.A. DePinho R.A. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat. Rev. Cancer 2006 6 9 674 687 10.1038/nrc1934 16929323
    [Google Scholar]
  31. Uehara T. Pogribny I.P. Rusyn I. The DEN and CCl4‐Induced mouse model of fibrosis and inflammation‐associated hepatocellular carcinoma. Curr. Protoc. 2021 1 8 e211 10.1002/cpz1.211 34370903
    [Google Scholar]
  32. Arboatti A.S. Lambertucci F. Sedlmeier M.G. Pisani G. Monti J. Álvarez M.L. Francés D.E.A. Ronco M.T. Carnovale C.E. Diethylnitrosamine increases proliferation in early stages of hepatic carcinogenesis in insulin-treated type 1 diabetic mice. BioMed Res. Int. 2018 2018 1 10 10.1155/2018/9472939 29850590
    [Google Scholar]
  33. Márquez-Quiroga L.V. Arellanes-Robledo J. Vásquez-Garzón V.R. Villa-Treviño S. Muriel P. Models of nonalcoholic steatohepatitis potentiated by chemical inducers leading to hepatocellular carcinoma. Biochem. Pharmacol. 2022 195 114845 10.1016/j.bcp.2021.114845 34801522
    [Google Scholar]
  34. Ledda C. Loreto C. Zammit C. Marconi A. Fago L. Matera S. Costanzo V. Sanzà G.F. Palmucci S. Ferrante M. Costa C. Fenga C. Biondi A. Pomara C. Rapisarda V. Non-infective occupational risk factors for hepatocellular carcinoma: A review. Mol. Med. Rep. 2017 15 2 511 533 10.3892/mmr.2016.6046 28000892
    [Google Scholar]
  35. Romualdo G.R. Heidor R. Bacil G.P. Moreno F.S. Barbisan L.F. Past, present, and future of chemically induced hepatocarcinogenesis rodent models: Perspectives concerning classic and new cancer hallmarks. Life Sci. 2023 330 121994 10.1016/j.lfs.2023.121994 37543357
    [Google Scholar]
  36. Dey P. Gut microbiota in phytopharmacology: A comprehensive overview of concepts, reciprocal interactions, biotransformations and mode of actions. Pharmacol. Res. 2019 147 104367 10.1016/j.phrs.2019.104367 31344423
    [Google Scholar]
  37. Margison G.P. Curtin N.J. Snell K. Craig A.W. Effect of chronic N,N-diethylnitrosamine on the excision of O6-ethylguanine from rat liver DNA. Br. J. Cancer 1979 40 5 809 813 10.1038/bjc.1979.266 508583
    [Google Scholar]
  38. Connor F. Rayner T.F. Aitken S.J. Feig C. Lukk M. Santoyo-Lopez J. Odom D.T. Mutational landscape of a chemically-induced mouse model of liver cancer. J. Hepatol. 2018 69 4 840 850 10.1016/j.jhep.2018.06.009 29958939
    [Google Scholar]
  39. Arul D. Subramanian P. Inhibitory effect of naringenin (citrus flavonone) on N-nitrosodiethylamine induced hepatocarcinogenesis in rats. Biochem. Biophys. Res. Commun. 2013 434 2 203 209 10.1016/j.bbrc.2013.03.039 23523793
    [Google Scholar]
  40. Unsal V. Belge-KurutaÅŸ, E.Ã. Experimental hepatic carcinogenesis: Oxidative stress and natural antioxidants. Open Access Maced. J. Med. Sci. 2017 5 5 686 691 10.3889/oamjms.2017.101 28932315
    [Google Scholar]
  41. Fahrer J. Christmann M. DNA alkylation damage by nitrosamines and relevant dna repair pathways. Int. J. Mol. Sci. 2023 24 5 4684 10.3390/ijms24054684 36902118
    [Google Scholar]
  42. Sheweita S.A. Mostafa M.H. N-Nitrosamines and their effects on the level of glutathione, glutathione reductase and glutathione S-transferase activities in the liver of male mice. Cancer Lett. 1996 99 1 29 34 10.1016/0304‑3835(95)04034‑X 8564926
    [Google Scholar]
  43. Yang Y. Kim S. Seki E. Inflammation and liver cancer: Molecular mechanisms and therapeutic targets. Semin. Liver Dis. 2019 39 1 26 42 10.1055/s‑0038‑1676806
    [Google Scholar]
  44. Berasain C. Castillo J. Perugorria M.J. Latasa M.U. Prieto J. Avila M.A. Inflammation and liver cancer: New molecular links. Ann. N. Y. Acad. Sci. 2009 1155 1 206 221 10.1111/j.1749‑6632.2009.03704.x 19250206
    [Google Scholar]
  45. Zhao Z. Cui T. Wei F. Zhou Z. Sun Y. Gao C. Xu X. Zhang H. Wnt/β-Catenin signaling pathway in hepatocellular carcinoma: Pathogenic role and therapeutic target. Front. Oncol. 2024 14 1367364 10.3389/fonc.2024.1367364 38634048
    [Google Scholar]
  46. Hsu S. Wang B. Kutay H. Bid H. Shreve J. Zhang X. Costinean S. Bratasz A. Houghton P. Ghoshal K. Hepatic loss of miR-122 predisposes mice to hepatobiliary cyst and hepatocellular carcinoma upon diethylnitrosamine exposure. Am. J. Pathol. 2013 183 6 1719 1730 10.1016/j.ajpath.2013.08.004 24113455
    [Google Scholar]
  47. Callegari E. Elamin B.K. Giannone F. Milazzo M. Altavilla G. Fornari F. Giacomelli L. D’Abundo L. Ferracin M. Bassi C. Zagatti B. Corrà F. Miotto E. Lupini L. Bolondi L. Gramantieri L. Croce C.M. Sabbioni S. Negrini M. Liver tumorigenicity promoted by microRNA-221 in a mouse transgenic model. Hepatology 2012 56 3 1025 1033 10.1002/hep.25747 22473819
    [Google Scholar]
  48. Perumal N. Perumal M. Halagowder D. Sivasithamparam N. Morin attenuates diethylnitrosamine-induced rat liver fibrosis and hepatic stellate cell activation by co-ordinated regulation of Hippo/Yap and TGF-β1/Smad signaling. Biochimie 2017 140 10 19 10.1016/j.biochi.2017.05.017 28552397
    [Google Scholar]
  49. Zhang C.Y. Liu S. Yang M. Regulatory T. Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy. World J. Gastroenterol. 2022 28 27 3346 3358 10.3748/wjg.v28.i27.3346 36158267
    [Google Scholar]
  50. Newell P. Villanueva A. Friedman S.L. Koike K. Llovet J.M. Experimental models of hepatocellular carcinoma. J. Hepatol. 2008 48 5 858 879 10.1016/j.jhep.2008.01.008 18314222
    [Google Scholar]
  51. Liu S. Huang F. Ru G. Wang Y. Zhang B. Chen X. Chu L. Mouse models of hepatocellular carcinoma: Classification, advancement, and application. Front. Oncol. 2022 12 902820 10.3389/fonc.2022.902820 35847898
    [Google Scholar]
  52. Weber L.W.D. Boll M. Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: Carbon tetrachloride as a toxicological model. Crit. Rev. Toxicol. 2003 33 2 105 136 10.1080/713611034 12708612
    [Google Scholar]
  53. Wahlang B. Beier J.I. Clair H.B. Bellis-Jones H.J. Falkner K.C. McClain C.J. Cave M.C. Toxicant-associated steatohepatitis. Toxicol. Pathol. 2013 41 2 343 360 10.1177/0192623312468517 23262638
    [Google Scholar]
  54. Sheweita S.A. Abd El-Gabar M. Bastawy M. Carbon tetrachloride changes the activity of cytochrome P450 system in the liver of male rats: Role of antioxidants. Toxicology 2001 169 2 83 92 10.1016/S0300‑483X(01)00473‑5 11718950
    [Google Scholar]
  55. Al Amin A.S.M. Menezes, Ritesh G. Carbon tetrachloride toxicity. In: StatPearls. Treasure Island StatPearls Publishing 2025 32965851
    [Google Scholar]
  56. Khan R.A. Khan M.R. Sahreen S. CCl4-induced hepatotoxicity: Protective effect of rutin on p53, CYP2E1 and the antioxidative status in rat. BMC Complement. Altern. Med. 2012 12 1 178 10.1186/1472‑6882‑12‑178 23043521
    [Google Scholar]
  57. Hartley D.P. Kolaja K.L. Reichard J. Petersen D.R. 4-Hydroxynonenal and malondialdehyde hepatic protein adducts in rats treated with carbon tetrachloride: Immunochemical detection and lobular localization. Toxicol. Appl. Pharmacol. 1999 161 1 23 33 10.1006/taap.1999.8788 10558920
    [Google Scholar]
  58. Lee Y.S. Seki E. In vivo and in vitro models to study liver fibrosis: Mechanisms and limitations. Cell. Mol. Gastroenterol. Hepatol. 2023 16 3 355 367 10.1016/j.jcmgh.2023.05.010 37270060
    [Google Scholar]
  59. Roehlen N. Crouchet E. Baumert T.F. Liver fibrosis: Mechanistic concepts and therapeutic perspectives. Cells 2020 9 4 875 10.3390/cells9040875 32260126
    [Google Scholar]
  60. Li R. Yang W. Yin Y. Ma X. Zhang P. Tao K. 4-OI attenuates carbon tetrachloride-induced hepatic injury via regulating oxidative stress and the inflammatory response. Front. Pharmacol. 2021 12 651444 10.3389/fphar.2021.651444 34113251
    [Google Scholar]
  61. Gandhi C.R. Hepatic stellate cell activation and pro-fibrogenic signals. J. Hepatol. 2017 67 5 1104 1105 10.1016/j.jhep.2017.06.001 28939135
    [Google Scholar]
  62. Khomich O. Ivanov A.V. Bartosch B. Metabolic hallmarks of hepatic stellate cells in liver fibrosis. Cells 2019 9 1 24 10.3390/cells9010024 31861818
    [Google Scholar]
  63. Unsal V. Cicek M. Sabancilar İ. Toxicity of carbon tetrachloride, free radicals and role of antioxidants. Rev. Environ. Health 2021 36 2 279 295 10.1515/reveh‑2020‑0048 32970608
    [Google Scholar]
  64. LeFort K.R. Rungratanawanich W. Song B.J. Contributing roles of mitochondrial dysfunction and hepatocyte apoptosis in liver diseases through oxidative stress, post-translational modifications, inflammation, and intestinal barrier dysfunction. Cell. Mol. Life Sci. 2024 81 1 34 10.1007/s00018‑023‑05061‑7 38214802
    [Google Scholar]
  65. Bardallo G. R.; Panisello-Roselló, A.; Sanchez-Nuno, S.; Alva, N.; Roselló-Catafau, J.; Carbonell, T. Nrf2 and oxidative stress in liver ischemia/reperfusion injury. FEBS J. 2022 289 18 5463 5479 10.1111/febs.16336 34967991
    [Google Scholar]
  66. Jaganjac M. Milkovic L. Sunjic S.B. Zarkovic N. The NRF2, Thioredoxin, and glutathione system in tumorigenesis and anticancer therapies. Antioxidants 2020 9 11 1151 10.3390/antiox9111151 33228209
    [Google Scholar]
  67. Tak P.P. Firestein G.S. NF-κB: A key role in inflammatory diseases. J. Clin. Invest. 2001 107 1 7 11 10.1172/JCI11830 11134171
    [Google Scholar]
  68. Munakarmi S. Gurau Y. Shrestha J. Chand L. Park H.S. Lee G.H. Jeong Y.J. trans-chalcone ameliorates CCl4-induced acute liver injury by suppressing endoplasmic reticulum stress, oxidative stress and inflammation. Pathol. Res. Pract. 2024 263 155663 10.1016/j.prp.2024.155663 39437640
    [Google Scholar]
  69. Borkham-Kamphorst E. Haas U. Van de Leur E. Trevanich A. Weiskirchen R. Chronic carbon tetrachloride applications induced hepatocyte apoptosis in lipocalin 2 null mice through endoplasmic reticulum stress and unfolded protein response. Int. J. Mol. Sci. 2020 21 15 5230 10.3390/ijms21155230 32718038
    [Google Scholar]
  70. Callegari E. Domenicali M. Shankaraiah R.C. D’Abundo L. Guerriero P. Giannone F. Baldassarre M. Bassi C. Elamin B.K. Zagatti B. Ferracin M. Fornari F. Altavilla G. Blandamura S. Silini E.M. Gramantieri L. Sabbioni S. Negrini M. MicroRNA-based prophylaxis in a mouse model of cirrhosis and liver cancer. Mol. Ther. Nucleic Acids 2019 14 239 250 10.1016/j.omtn.2018.11.018 30641476
    [Google Scholar]
  71. Li J. Cheng X. Huang D. Cui R. The regulatory role of mitotic catastrophe in hepatocellular carcinoma drug resistance mechanisms and its therapeutic potential. Biomed. Pharmacother. 2024 180 117598 10.1016/j.biopha.2024.117598 39461015
    [Google Scholar]
  72. Beer S. Komatsubara K. Bellovin D.I. Kurobe M. Sylvester K. Felsher D.W. Hepatotoxin-induced changes in the adult murine liver promote MYC-induced tumorigenesis. PLoS One 2008 3 6 e2493 10.1371/journal.pone.0002493 18560566
    [Google Scholar]
  73. Chappell G. Kutanzi K. Uehara T. Tryndyak V. Hong H.H. Hoenerhoff M. Beland F.A. Rusyn I. Pogribny I.P. Genetic and epigenetic changes in fibrosis‐associated hepatocarcinogenesis in mice. Int. J. Cancer 2014 134 12 2778 2788 10.1002/ijc.28610 24242335
    [Google Scholar]
  74. Lu L. Ma Y. Tao Q. Xie J. Liu X. Wu Y. Zhang Y. Xie X. Liu M. Jin Y. Hypoxia-inducible factor-1 alpha (HIF-1α) inhibitor AMSP-30 m attenuates CCl4-induced liver fibrosis in mice by inhibiting the sonic hedgehog pathway. Chem. Biol. Interact. 2025 413 111480 10.1016/j.cbi.2025.111480 40113123
    [Google Scholar]
  75. Ikeno Y. Ohara D. Takeuchi Y. Watanabe H. Kondoh G. Taura K. Uemoto S. Hirota K. Foxp3+ regulatory T cells inhibit CCl4-induced liver inflammation and fibrosis by regulating tissue cellular immunity. Front. Immunol. 2020 11 584048 10.3389/fimmu.2020.584048 33178216
    [Google Scholar]
  76. Environmental exposures and hepatocellular carcinoma. J. Clin. Transl. Hepatol. 2016 1 2 10.14218/JCTH.2013.008XX
    [Google Scholar]
  77. Wu X. Zhang X. Yu X. Liang H. Tang S. Wang Y. Exploring the association between air pollution and the incidence of liver cancers. Ecotoxicol. Environ. Saf. 2025 290 117437 10.1016/j.ecoenv.2024.117437 39671760
    [Google Scholar]
  78. Shabeer S. Asad S. Jamal A. Ali A. Aflatoxin contamination, its impact and management strategies: An updated review. Toxins 2022 14 5 307 10.3390/toxins14050307 35622554
    [Google Scholar]
  79. Smela M.E. Currier S.S. Bailey E.A. Essigmann J.M. The chemistry and biology of aflatoxin B1: From mutational spectrometry to carcinogenesis. Carcinogenesis 2001 22 4 535 545 10.1093/carcin/22.4.535 11285186
    [Google Scholar]
  80. Kew M.C. Synergistic interaction between aflatoxin B1 and hepatitis B virus in hepatocarcinogenesis. Liver Int. 2003 23 6 405 409 10.1111/j.1478‑3231.2003.00869.x 14986813
    [Google Scholar]
  81. Moloi T.P. Ziqubu K. Mazibuko-Mbeje S.E. Mabaso N.H. Ndlovu Z. Aflatoxin B1-induced hepatotoxicity through mitochondrial dysfunction, oxidative stress, and inflammation as central pathological mechanisms: A review of experimental evidence. Toxicology 2024 509 153983 10.1016/j.tox.2024.153983 39491743
    [Google Scholar]
  82. Han J. Xian Z. Zhang Y. Liu J. Liang A. Systematic overview of aristolochic acids: Nephrotoxicity, carcinogenicity, and underlying mechanisms. Front. Pharmacol. 2019 10 648 10.3389/fphar.2019.00648 31244661
    [Google Scholar]
  83. Stiborová M. Frei E. Breuer A. Bieler C.A. Schmeiser H.H. Aristolactam I a metabolite of aristolochic acid I upon activation forms an adduct found in DNA of patients with Chinese herbs nephropathy. Exp. Toxicol. Pathol. 1999 51 4-5 421 427 10.1016/S0940‑2993(99)80033‑5 10445409
    [Google Scholar]
  84. Jelaković B. Karanović S. Vuković-Lela I. Miller F. Edwards K.L. Nikolić J. Tomić K. Slade N. Brdar B. Turesky R.J. Stipančić Ž. Dittrich D. Grollman A.P. Dickman K.G. Aristolactam-DNA adducts are a biomarker of environmental exposure to aristolochic acid. Kidney Int. 2012 81 6 559 567 10.1038/ki.2011.371 22071594
    [Google Scholar]
  85. Brandt-Rauf P. Long C. Kovvali G. Li Y. Monaco R. Marion M.J. Plastics and carcinogenesis: The example of vinyl chloride. J. Carcinog. 2012 11 1 5 10.4103/1477‑3163.93700 22529741
    [Google Scholar]
  86. Fedeli U. Girardi P. Mastrangelo G. Occupational exposure to vinyl chloride and liver diseases. World J. Gastroenterol. 2019 25 33 4885 4891 10.3748/wjg.v25.i33.4885 31543680
    [Google Scholar]
  87. Eti N.A. Flor S. Iqbal K. Scott R.L. Klenov V.E. Gibson-Corley K.N. Soares M.J. Ludewig G. Robertson L.W. PCB126 induced toxic actions on liver energy metabolism is mediated by AhR in rats. Toxicology 2022 466 153054 10.1016/j.tox.2021.153054 34848246
    [Google Scholar]
  88. Gährs M. Roos R. Andersson P.L. Schrenk D. Role of the nuclear xenobiotic receptors CAR and PXR in induction of cytochromes P450 by non-dioxinlike polychlorinated biphenyls in cultured rat hepatocytes. Toxicol. Appl. Pharmacol. 2013 272 1 77 85 10.1016/j.taap.2013.05.034 23770461
    [Google Scholar]
  89. Ramírez Carnero A. Lestido-Cardama A. Vazquez Loureiro P. Barbosa-Pereira L. Rodríguez Bernaldo de Quirós A. Sendón R. Presence of perfluoroalkyl and polyfluoroalkyl substances (PFAS) in food contact materials (FCM) and its migration to food. Foods 2021 10 7 1443 10.3390/foods10071443 34206351
    [Google Scholar]
  90. Choi M.A. Rose S. Langouët S. Per- and polyfluoroalkyl substances as potentiators of hepatotoxicity in an exposome framework: Current challenges of environmental toxicology. Toxicology 2025 515 154167 10.1016/j.tox.2025.154167 40300710
    [Google Scholar]
  91. Costello E. Rock S. Stratakis N. Eckel S.P. Walker D.I. Valvi D. Cserbik D. Jenkins T. Xanthakos S.A. Kohli R. Sisley S. Vasiliou V. La Merrill M.A. Rosen H. Conti D.V. McConnell R. Chatzi L. Exposure to per- and polyfluoroalkyl substances and markers of liver injury: A systematic review and meta-analysis. Environ. Health Perspect. 2022 130 4 046001 10.1289/EHP10092 35475652
    [Google Scholar]
  92. Bhatti J.S. Bhatti G.K. Reddy P.H. Mitochondrial dysfunction and oxidative stress in metabolic disorders — A step towards mitochondria based therapeutic strategies. Biochim. Biophys. Acta Mol. Basis Dis. 2017 1863 5 1066 1077 10.1016/j.bbadis.2016.11.010 27836629
    [Google Scholar]
  93. Khaleda L. Alam M.M. Tasnim Z. Ezaj M.M.A. Apu M.A.R. Akter R. Bakar M.A. Alam M.J. Chowdhury R.H. Datta A. Shawon I.I. Rahman M.Z. Al-Forkan M. Detrimental effects of chronic arsenic exposure through daily diet on hepatic and renal health: An animal model study. Toxicol. Rep. 2025 14 101993 10.1016/j.toxrep.2025.101993 40166734
    [Google Scholar]
  94. Reichard J.F. Puga A. Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics 2010 2 1 87 104 10.2217/epi.09.45 20514360
    [Google Scholar]
  95. Takekawa S. Ueda Y. Hiramatsu Y. Komiyama K. Munechika, H. History note: Tragedy of thorotrast. Jpn. J. Radiol. 2015 33 11 718 722 10.1007/s11604‑015‑0479‑1 26416314
    [Google Scholar]
  96. Liu D. Momoi H. Li L. Ishikawa Y. Fukumoto M. Microsatellite instability in thorotrast‐induced human intrahepatic cholangiocarcinoma. Int. J. Cancer 2002 102 4 366 371 10.1002/ijc.10726 12402306
    [Google Scholar]
  97. Ishikawa Y. Wada I. Fukumoto M. Cancers induced by alpha particles from thorotrast. Int. Congr. Ser. 2002 1236 191 194 10.1016/S0531‑5131(01)00756‑7
    [Google Scholar]
  98. Teschke R. Alcoholic liver disease: Alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects. Biomedicines 2018 6 4 106 10.3390/biomedicines6040106 30424581
    [Google Scholar]
  99. Setshedi M. Wands J.R. de la Monte S.M. Acetaldehyde adducts in alcoholic liver disease. Oxid. Med. Cell. Longev. 2010 3 3 178 185 10.4161/oxim.3.3.12288 20716942
    [Google Scholar]
  100. Ceni E. Mello T. Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism. World J. Gastroenterol. 2014 20 47 17756 17772 10.3748/wjg.v20.i47.17756 25548474
    [Google Scholar]
  101. Gao B. Bataller R. Alcoholic liver disease: Pathogenesis and new therapeutic targets. Gastroenterology 2011 141 5 1572 1585 10.1053/j.gastro.2011.09.002 21920463
    [Google Scholar]
  102. Shimada T. Fujii-Kuriyama Y. Metabolic activation of polycyclic aromatic hydrocarbons to carcinogens by cytochromes P450 1A1 and1B1. Cancer Sci. 2004 95 1 1 6 10.1111/j.1349‑7006.2004.tb03162.x 14720319
    [Google Scholar]
  103. Ba Q. Li J. Huang C. Qiu H. Li J. Chu R. Zhang W. Xie D. Wu Y. Wang H. Effects of benzo[a]pyrene exposure on human hepatocellular carcinoma cell angiogenesis, metastasis, and NF-κB signaling. Environ. Health Perspect. 2015 123 3 246 254 10.1289/ehp.1408524 25325763
    [Google Scholar]
  104. Muhammad N. Usmani D. Tarique M. Naz H. Ashraf M. Raliya R. Tabrez S. Zughaibi T.A. Alsaieedi A. Hakeem I.J. Suhail M. The role of natural products and their multitargeted approach to treat solid cancer. Cells 2022 11 14 2209 10.3390/cells11142209 35883653
    [Google Scholar]
  105. Asma S.T. Acaroz U. Imre K. Morar A. Shah S.R.A. Hussain S.Z. Arslan-Acaroz D. Demirbas H. Hajrulai-Musliu Z. Istanbullugil F.R. Soleimanzadeh A. Morozov D. Zhu K. Herman V. Ayad A. Athanassiou C. Ince S. Natural products/bioactive compounds as a source of anticancer drugs. Cancers 2022 14 24 6203 10.3390/cancers14246203 36551687
    [Google Scholar]
  106. Tungmunnithum D. Thongboonyou A. Pholboon A. Yangsabai A. Flavonoids and other phenolic compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines 2018 5 3 93 10.3390/medicines5030093 30149600
    [Google Scholar]
  107. Wang Y. Li J. Xia L. Plant-derived natural products and combination therapy in liver cancer. Front. Oncol. 2023 13 1116532 10.3389/fonc.2023.1116532 36865794
    [Google Scholar]
  108. Reyes-Gordillo K. Shah R. Lakshman M.R. Flores-Beltrán R.E. Muriel P. Hepatoprotective properties of curcumin. In: Liver Pathophysiology. Elsevier 2017 687 704 10.1016/B978‑0‑12‑804274‑8.00049‑7
    [Google Scholar]
  109. Wang J. Wang C. Bu G. Curcumin inhibits the growth of liver cancer stem cells through the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway. Exp. Ther. Med. 2018 15 4 3650 3658 10.3892/etm.2018.5805 29545895
    [Google Scholar]
  110. Jang J.Y. Im E. Kim N.D. Mechanism of resveratrol-induced programmed cell death and new drug discovery against cancer: A review. Int. J. Mol. Sci. 2022 23 22 13689 10.3390/ijms232213689
    [Google Scholar]
  111. Xiong F. Zhang Y. Li T. Tang Y. Song S.Y. Zhou Q. Wang Y. A detailed overview of quercetin: Implications for cell death and liver fibrosis mechanisms. Front. Pharmacol. 2024 15 1389179 10.3389/fphar.2024.1389179 38855739
    [Google Scholar]
  112. Vargas-Mendoza N. Madrigal-Santillán E. Morales-González A. Esquivel-Soto J. Esquivel-Chirino C. García-Luna Y. González-Rubio, M.; Gayosso-de-Lucio, J.A.; Morales-González, J.A. Hepatoprotective effect of silymarin. World J. Hepatol. 2014 6 3 144 149 10.4254/wjh.v6.i3.144 24672644
    [Google Scholar]
  113. Rauf A. Wilairatana P. Joshi P.B. Ahmad Z. Olatunde A. Hafeez N. Hemeg H.A. Mubarak M.S. Revisiting luteolin: An updated review on its anticancer potential. Heliyon 2024 10 5 e26701 10.1016/j.heliyon.2024.e26701 38455556
    [Google Scholar]
  114. Rahmani A.H. Alsahli M.A. Almatroudi A. Almogbel M.A. Khan A.A. Anwar S. Almatroodi S.A. The Potential role of apigenin in cancer prevention and treatment. Molecules 2022 27 18 6051 10.3390/molecules27186051 36144783
    [Google Scholar]
  115. Yu R. Zhang Z. Wang B. Jiang H. Cheng L. Shen L. Berberine-induced apoptotic and autophagic death of HepG2 cells requires AMPK activation. Cancer Cell Int. 2014 14 1 49 10.1186/1475‑2867‑14‑49 24991192
    [Google Scholar]
  116. Yu L. Shen N. Ren J. Xin H. Cui Y. Resource distribution, pharmacological activity, toxicology and clinical drugs of β-Carboline alkaloids: An updated and systematic review. Fitoterapia 2025 180 106326 10.1016/j.fitote.2024.106326 39645053
    [Google Scholar]
  117. Nagesh N. Recent insights into β-carboline alkaloids with anticancer potential. Modern Approaches in Drug Designing 2020 3 1 10.31031/MADD.2020.03.000554
    [Google Scholar]
  118. Hu J. Li Y. Xie X. Song Y. Yan W. Luo Y. Jiang Y. The therapeutic potential of andrographolide in cancer treatment. Biomed. Pharmacother. 2024 180 117438 10.1016/j.biopha.2024.117438 39298908
    [Google Scholar]
  119. Shi J. Li J. Xu Z. Chen L. Luo R. Zhang C. Gao F. Zhang J. Fu C. Celastrol: A review of useful strategies overcoming its limitation in anticancer application. Front. Pharmacol. 2020 11 558741 10.3389/fphar.2020.558741 33364939
    [Google Scholar]
  120. Dong M. Cui Q. Li Y. Li Y. Chang Q. Bai R. Wei M. zhao, L.; Chen, Q. Ursolic acid suppresses fatty liver-associated hepatocellular carcinoma by regulating lipid metabolism. Food Biosci. 2024 60 104460 10.1016/j.fbio.2024.104460
    [Google Scholar]
  121. Zhou W. Zeng X. Wu X. Effect of Oleanolic Acid on Apoptosis and Autophagy of SMMC-7721 Hepatoma Cells. Med. Sci. Monit. 2020 26 e921606 10.12659/MSM.921606 32424110
    [Google Scholar]
  122. Zheng Y. Zhang W. Xu L. Zhou H. Yuan M. Xu H. Recent progress in understanding the action of natural compounds at novel therapeutic drug targets for the treatment of liver cancer. Front. Oncol. 2022 11 795548 10.3389/fonc.2021.795548 35155196
    [Google Scholar]
  123. Fu Y. Chung F.L. Oxidative stress and hepatocarcinogenesis. Hepatoma Res. 2018 4 8 39 10.20517/2394‑5079.2018.29 30761356
    [Google Scholar]
  124. Ibrahim S.G. El-Emam S.Z. Mohamed E.A. Abd Ellah M.F. Dimethyl fumarate and curcumin attenuate hepatic ischemia/reperfusion injury via Nrf2/HO-1 activation and anti-inflammatory properties. Int. Immunopharmacol. 2020 80 106131 10.1016/j.intimp.2019.106131 31981960
    [Google Scholar]
  125. Farzaei M.H. Zobeiri M. Parvizi F. El-Senduny F.F. Marmouzi I. Coy-Barrera E. Naseri R. Nabavi S.M. Rahimi R. Abdollahi M. Curcumin in liver diseases: A systematic review of the cellular mechanisms of oxidative stress and clinical perspective. Nutrients 2018 10 7 855 10.3390/nu10070855 29966389
    [Google Scholar]
  126. Marquardt J.U. Gomez-Quiroz L. Arreguin Camacho L.O. Pinna F. Lee Y.H. Kitade M. Domínguez M.P. Castven D. Breuhahn K. Conner E.A. Galle P.R. Andersen J.B. Factor V.M. Thorgeirsson S.S. Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. J. Hepatol. 2015 63 3 661 669 10.1016/j.jhep.2015.04.018 25937435
    [Google Scholar]
  127. Bhattacharya S. Perris A. Jawed J.J. Hoda M. Therapeutic role of resveratrol against hepatocellular carcinoma: A review on its molecular mechanisms of action. Pharmacol. Res. Mod. Chin. Med. 2023 6 100233 10.1016/j.prmcm.2023.100233
    [Google Scholar]
  128. Mbimba T. Awale P. Bhatia D. Geldenhuys W.J. Darvesh A.S. Carroll R.T. Bishayee A. Alteration of hepatic proinflammatory cytokines is involved in the resveratrol-mediated chemoprevention of chemically-induced hepatocarcinogenesis. Curr. Pharm. Biotechnol. 2012 13 1 229 234 10.2174/138920112798868575 21466437
    [Google Scholar]
  129. García-Mediavilla V. Crespo I. Collado P.S. Esteller A. Sánchez-Campos S. Tuñón M.J. González-Gallego J. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. Eur. J. Pharmacol. 2007 557 2-3 221 229 10.1016/j.ejphar.2006.11.014 17184768
    [Google Scholar]
  130. Shaharudin N.S. Surindar Singh G.K. Kek T. Sultan S. Targeting signaling pathways with andrographolide in cancer therapy.(Review). Mol. Clin. Oncol. 2024 21 5 81 10.3892/mco.2024.2779 39301125
    [Google Scholar]
  131. Bhadra K. A mini review on molecules inducing caspase-independent cell death: A new route to cancer therapy. Molecules 2022 27 19 6401 10.3390/molecules27196401 36234938
    [Google Scholar]
  132. Hu Y. Yu X. Yang L. Xue G. Wei Q. Han Z. Chen H. Research progress on the antitumor effects of harmine. Front. Oncol. 2024 14 1382142 10.3389/fonc.2024.1382142 38590646
    [Google Scholar]
  133. Xu B. Li M. Yu Y. He J. Hu S. Pan M. Lu S. Liao K. Pan Z. Zhou Y. Zhu J. Effects of harmaline on cell growth of human liver cancer through the p53/p21 and Fas/FasL signaling pathways. Oncol. Lett. 2017 10.3892/ol.2017.7495 29434892
    [Google Scholar]
  134. Meybodi S.M. Rezaei P. Faraji N. Jamehbozorg K. Ashna S. Shokri F. Goleij P. Moradi S. Kashian M. Arefnezhad R. Sahebkar A. Curcumin and its novel formulations for the treatment of hepatocellular carcinoma: New trends and future perspectives in cancer therapy. J. Funct. Foods 2023 108 105705 10.1016/j.jff.2023.105705
    [Google Scholar]
  135. Jung E.M. Lim J.H. Lee T.J. Park J.W. Choi K.S. Kwon T.K. Curcumin sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis through reactive oxygen species-mediated upregulation of death receptor 5 (DR5). Carcinogenesis 2005 26 11 1905 1913 10.1093/carcin/bgi167 15987718
    [Google Scholar]
  136. Notas G. Nifli A.P. Kampa M. Vercauteren J. Kouroumalis E. Castanas E. Resveratrol exerts its antiproliferative effect on HepG2 hepatocellular carcinoma cells, by inducing cell cycle arrest, and NOS activation. Biochim. Biophys. Acta, Gen. Subj. 2006 1760 11 1657 1666 10.1016/j.bbagen.2006.09.010 17052855
    [Google Scholar]
  137. Ren B. Liu H. Gao H. Liu S. Zhang Z. Fribley A.M. Callaghan M.U. Xu Z. Zeng Q. Li Y. Celastrol induces apoptosis in hepatocellular carcinoma cells via targeting ER-stress/UPR. Oncotarget 2017 8 54 93039 93050 10.18632/oncotarget.21750 29190976
    [Google Scholar]
  138. Wang N. Feng Y. Zhu M. Tsang C.M. Man K. Tong Y. Tsao S.W. Berberine induces autophagic cell death and mitochondrial apoptosis in liver cancer cells: The cellular mechanism. J. Cell. Biochem. 2010 111 6 1426 1436 10.1002/jcb.22869 20830746
    [Google Scholar]
  139. Yuan B. Wang R. Gao Z. Mirzeei H. Xiang A.D. Guo F. Silymarin plus doxorubicin exerts the anti-hepatocellular carcinoma effects via Wnt, apoptosis, autophagy and angiogenesis pathways. Mol. Cell. Probes 2025 81 102022 10.1016/j.mcp.2025.102022 40049299
    [Google Scholar]
  140. Zhan P. Qian Q. Yu L-K. Prognostic significance of vascular endothelial growth factor expression in hepatocellular carcinoma tissue: A meta-analysis. Hepatobiliary Surg. Nutr. 2013 2 3 148 155 10.3978/j.issn.2304‑3881.2013.06.06 24570933
    [Google Scholar]
  141. Wang X. Tian Y. Lin H. Cao X. Zhang Z. Curcumin induces apoptosis in human hepatocellular carcinoma cells by decreasing the expression of STAT3/VEGF/HIF-1α signaling. Open Life Sci. 2023 18 1 20220618 10.1515/biol‑2022‑0618 37333486
    [Google Scholar]
  142. Izzo C. Annunziata M. Melara G. Sciorio R. Dallio M. Masarone M. Federico A. Persico M. The role of resveratrol in liver disease: A comprehensive review from in vitro to clinical trials. Nutrients 2021 13 3 933 10.3390/nu13030933 33805795
    [Google Scholar]
  143. Yu L. Li T. Zhang H. Ma Z. Wu S. Silymarin suppresses proliferation of human hepatocellular carcinoma cells under hypoxia through downregulation of the HIF-1α/VEGF pathway. Am. J. Transl. Res. 2023 15 7 4521 4532 37560243
    [Google Scholar]
  144. Ming T. Tao Q. Tang S. Zhao H. Yang H. Liu M. Ren S. Xu H. Curcumin: An epigenetic regulator and its application in cancer. Biomed. Pharmacother. 2022 156 113956 10.1016/j.biopha.2022.113956 36411666
    [Google Scholar]
  145. Mota S.R.S. Kviecinski M.R. Felipe K.B. Grinevicius M.A.S.V. Siminski T. Almeida G.M. Zeferino R.C. Pich C.T. Filho D.W. Pedrosa, RC β-Carboline alkaloid harmine induces DNA damage and triggers apoptosis by a mitochondrial pathway: Study in silico, in vitro and in vivo. Int. J. Funct. Nutr. 2020 1 1 10.3892/ijfn.2020.1
    [Google Scholar]
  146. Shankaraiah N. Jadala C. Nekkanti S. Senwar K.R. Nagesh N. Shrivastava S. Naidu V.G.M. Sathish M. Kamal A. Design and synthesis of C3-tethered 1,2,3-triazolo-β-carboline derivatives: Anticancer activity, DNA-binding ability, viscosity and molecular modeling studies. Bioorg. Chem. 2016 64 42 50 10.1016/j.bioorg.2015.11.005 26657602
    [Google Scholar]
  147. Chen Z. Huang C. Ma T. Jiang L. Tang L. Shi T. Zhang S. Zhang L. Zhu P. Li J. Shen A. Reversal effect of quercetin on multidrug resistance via FZD7/β-catenin pathway in hepatocellular carcinoma cells. Phytomedicine 2018 43 37 45 10.1016/j.phymed.2018.03.040 29747752
    [Google Scholar]
  148. Asgharian P. Tazekand A.P. Hosseini K. Forouhandeh H. Ghasemnejad T. Ranjbar M. Hasan M. Kumar M. Beirami S.M. Tarhriz V. Soofiyani S.R. Kozhamzharova L. Sharifi-Rad J. Calina D. Cho W.C. Potential mechanisms of quercetin in cancer prevention: Focus on cellular and molecular targets. Cancer Cell Int. 2022 22 1 257 10.1186/s12935‑022‑02677‑w 35971151
    [Google Scholar]
  149. Tong K. Wang P. Li Y. Tong Y. li, X.; Yan, S.; Hu, P. Resveratrol inhibits hepatocellular carcinoma progression through regulating exosome secretion. Curr. Med. Chem. 2024 31 15 2107 2118 10.2174/0929867331666230914090053 37711128
    [Google Scholar]
  150. Chu Y.L. Ho C.T. Chung J.G. Raghu R. Lo Y.C. Sheen L.Y. Allicin induces anti-human liver cancer cells through the p53 gene modulating apoptosis and autophagy. J. Agric. Food Chem. 2013 61 41 9839 9848 10.1021/jf403241s 24059278
    [Google Scholar]
  151. Liu W. Huang X.F. Qi Q. Dai Q.S. Yang L. Nie F.F. Lu N. Gong D.D. Kong L.Y. Guo Q.L. Asparanin A induces G2/M cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Biochem. Biophys. Res. Commun. 2009 381 4 700 705 10.1016/j.bbrc.2009.02.124 19254688
    [Google Scholar]
  152. Manivannan H.P. Veeraraghavan V.P. Francis A.P. Prediction of multi-targeting pharmacological activity of bioactive compounds from medicinal plants against hepatocellular carcinoma through advanced network pharmacology and bioinformatics-based investigation. Appl. Biochem. Biotechnol. 2025 197 5 2979 3007 10.1007/s12010‑024‑05150‑8 39820926
    [Google Scholar]
  153. Cao Y. Cao J. Yu B. Wang S. Liu L. Tao L. Sun W. Berbamine induces SMMC-7721 cell apoptosis via upregulating p53, downregulating survivin expression and activating mitochondria signaling pathway. Exp. Ther. Med. 2017 10.3892/etm.2017.5637 29434780
    [Google Scholar]
  154. Zhou M. Deng Y. Liu M. Liao L. Dai X. Guo C. Zhao X. He L. Peng C. Li Y. The pharmacological activity of berberine, a review for liver protection. Eur. J. Pharmacol. 2021 890 173655 10.1016/j.ejphar.2020.173655 33068590
    [Google Scholar]
  155. Li Z.F. Wang Z.D. Ji Y.Y. Zhang S. Huang C. Li J. Xia X.M. Induction of apoptosis and cell cycle arrest in human HCC MHCC97H cells with Chrysanthemum indicum extract. World J. Gastroenterol. 2009 15 36 4538 4546 10.3748/wjg.15.4538 19777612
    [Google Scholar]
  156. Ku C.Y. Wang Y.R. Lin H.Y. Lu S.C. Lin J.Y. Corosolic acid inhibits hepatocellular carcinoma cell migration by targeting the VEGFR2/SRC/FAK pathway. PLoS One 2015 10 5 e0126725 10.1371/journal.pone.0126725 25978354
    [Google Scholar]
  157. Jin M. Kong L. Han Y. Zhang S. Gut microbiota enhances the chemosensitivity of hepatocellular carcinoma to 5‐fluorouracil in vivo by increasing curcumin bioavailability. Phytother. Res. 2021 35 10 5823 5837 10.1002/ptr.7240 34374130
    [Google Scholar]
  158. Ashwaq A.A. Al-Qubaisi M. Rasedee A. Abdul A. Taufiq-Yap Y. Yeap S. Inducing G2/M cell cycle arrest and apoptosis through generation reactive oxygen species (ROS)-mediated mitochondria pathway in HT-29 cells by dentatin (DEN) and dentatin incorporated in Hydroxypropyl-β-Cyclodextrin (DEN-HPβCD). Int. J. Mol. Sci. 2016 17 10 1653 10.3390/ijms17101653 27763535
    [Google Scholar]
  159. Gao J. Yin Z. Wu Z. Sheng Z. Ma C. Chen R. Zhang X. Tang K. Fei J. Cao Z. Probing synergistic targets by natural compounds for hepatocellular carcinoma. Front. Cell Dev. Biol. 2021 9 715762 10.3389/fcell.2021.715762 34395446
    [Google Scholar]
  160. Xiao Y. Feng-Qing Y. Shao-Ping L. Jian-Li G. Guang H. Sin-Cheng L. Emilia C.L. Kwok-Pui F. Yi-Tao W. Simon L.M-Y. Furanodiene induces G2/M cell cycle arrest and apoptosis through MAPK signaling and mitochondria-caspase pathway in human hepatocellular carcinoma cells. Cancer Biol. Ther. 2007 6 7 1044 1050 10.4161/cbt.6.7.4317 17611410
    [Google Scholar]
  161. Chien S.T. Shi M.D. Lee Y.C. Te C.C. Shih Y.W. Galangin, a novel dietary flavonoid, attenuates metastatic feature via PKC/ERK signaling pathway in TPA-treated liver cancer HepG2 cells. Cancer Cell Int. 2015 15 1 15 10.1186/s12935‑015‑0168‑2 25698902
    [Google Scholar]
  162. Huang G.J. Deng J.S. Huang S.S. Hu M.L. Hispolon induces apoptosis and cell cycle arrest of human hepatocellular carcinoma Hep3B cells by modulating ERK phosphorylation. J. Agric. Food Chem. 2011 59 13 7104 7113 10.1021/jf201289e 21630638
    [Google Scholar]
  163. Zhao Z. Jin G. Ge Y. Guo Z. Naringenin inhibits migration of breast cancer cells via inflammatory and apoptosis cell signaling pathways. Inflammopharmacology 2019 27 5 1021 1036 10.1007/s10787‑018‑00556‑3 30941613
    [Google Scholar]
  164. Li T. Xu W.S. Wu G.S. Chen X.P. Wang Y.T. Lu J.J. Platycodin D. Platycodin D induces apoptosis, and inhibits adhesion, migration and invasion in HepG2 hepatocellular carcinoma cells. Asian Pac. J. Cancer Prev. 2014 15 4 1745 1749 10.7314/APJCP.2014.15.4.1745 24641402
    [Google Scholar]
  165. Zhou R. Wu K. Su M. Li R. Bioinformatic and experimental data decipher the pharmacological targets and mechanisms of plumbagin against hepatocellular carcinoma. Environ. Toxicol. Pharmacol. 2019 70 103200 10.1016/j.etap.2019.103200 31158732
    [Google Scholar]
  166. Jiang Z. Xiong J. Induction of apoptosis in human hepatocarcinoma SMMC-7721 cells in vitro by psoralen from Psoralea corylifolia. Cell Biochem. Biophys. 2014 70 2 1075 1081 10.1007/s12013‑014‑0025‑2 24845152
    [Google Scholar]
  167. Sethi G. Rath P. Chauhan A. Ranjan A. Choudhary R. Ramniwas S. Sak K. Aggarwal D. Rani I. Tuli H.S. Apoptotic mechanisms of quercetin in liver cancer: Recent trends and advancements. Pharmaceutics 2023 15 2 712 10.3390/pharmaceutics15020712 36840034
    [Google Scholar]
  168. Wani N.A. Zhang B. Teng K. Barajas J.M. Motiwala T. Hu P. Yu L. Brüschweiler R. Ghoshal K. Jacob S.T. Reprogramming of glucose metabolism by zerumbone suppresses hepatocarcinogenesis. Mol. Cancer Res. 2018 16 2 256 268 10.1158/1541‑7786.MCR‑17‑0304 29187559
    [Google Scholar]
  169. Luo B. Song X. A comprehensive overview of β-carbolines and its derivatives as anticancer agents. Eur. J. Med. Chem. 2021 224 113688 10.1016/j.ejmech.2021.113688 34332400
    [Google Scholar]
  170. Aaghaz S. Sharma K. Jain R. Kamal A. β-Carbolines as potential anticancer agents. Eur. J. Med. Chem. 2021 216 113321 10.1016/j.ejmech.2021.113321 33684825
    [Google Scholar]
  171. Miao J. Meng C. Wu H. Shan W. Wang H. Ling C. Zhang J. Yang T. Novel hybrid chc from β-carboline and n-hydroxyacrylamide overcomes drug-resistant hepatocellular carcinoma by promoting apoptosis, dna damage, and cell cycle arrest. Front. Pharmacol. 2021 11 626065 10.3389/fphar.2020.626065 33536926
    [Google Scholar]
  172. Abdelsalam M.A. AboulWafa, O.M.; Badawey, E.S.A.M.; El-Shoukrofy, M.S.; El-Miligy, M.M.; Gouda, N. Design and synthesis of some β-carboline derivatives as multi-target anticancer agents. Future Med. Chem. 2018 10 24 2791 2814 10.4155/fmc‑2018‑0226 30539666
    [Google Scholar]
  173. Szabó T. Volk B. Milen M. Recent advances in the synthesis of β-carboline alkaloids. Molecules 2021 26 3 663 10.3390/molecules26030663 33513936
    [Google Scholar]
  174. Thatikayala M. Wadhwa P. Kaur P. Singh P.K. Yadav A. Kaushik M. Sahu S.K. Beta-carboline as a promising heterocyclic nucleus: Synthetic aspects, pharmacological potential and structure activity relationship. Eur. J. Med. Chem. Rep. 2022 6 100096 10.1016/j.ejmcr.2022.100096
    [Google Scholar]
  175. Dai J. Dan W. Schneider U. Wang J. β-Carboline alkaloid monomers and dimers: Occurrence, structural diversity, and biological activities. Eur. J. Med. Chem. 2018 157 622 656 10.1016/j.ejmech.2018.08.027 30125723
    [Google Scholar]
  176. Taylor W.I. The Complex Tetrahydro-B-Carboline Alkaloids. In: ndole Alkaloids. Elsevier 1966 52 72 10.1016/B978‑1‑4831‑9671‑8.50012‑8
    [Google Scholar]
  177. Kushwaha P. Kumar V. Saha B. Current development of β-carboline derived potential antimalarial scaffolds. Eur. J. Med. Chem. 2023 252 115247 10.1016/j.ejmech.2023.115247 36931118
    [Google Scholar]
  178. Moloudizargari M. Mikaili P. Aghajanshakeri S. Asghari M. Shayegh J. Pharmacological and therapeutic effects of Peganum harmala and its main alkaloids. Pharmacogn. Rev. 2013 7 14 199 212 10.4103/0973‑7847.120524 24347928
    [Google Scholar]
  179. Rehman M.U. Zuo Y. Tu N. Guo J. Liu Z. Cao S. Long S. Diverse pharmacological activities of β-carbolines: Substitution patterns, SARs and mechanisms of action. Eur. J. Med. Chem. 2025 287 117350 10.1016/j.ejmech.2025.117350 39933403
    [Google Scholar]
  180. Won T.H. Jeon J. Lee S.H. Rho B.J. Oh K.B. Shin J. Beta-carboline alkaloids derived from the ascidian Synoicum sp. Bioorg. Med. Chem. 2012 20 13 4082 4087 10.1016/j.bmc.2012.05.002 22652254
    [Google Scholar]
  181. Li X.L. Sun Y. Yin Y. Zhan S. Wang C. A bacterial-like Pictet–Spenglerase drives the evolution of fungi to produce β-carboline glycosides together with separate genes. Proc. Natl. Acad. Sci. USA 2023 120 30 e2303327120 10.1073/pnas.2303327120 37467272
    [Google Scholar]
  182. Kim H. Sablin S.O. Ramsay R.R. Inhibition of monoamine oxidase A by β-carboline derivatives. Arch. Biochem. Biophys. 1997 337 1 137 142 10.1006/abbi.1996.9771 8990278
    [Google Scholar]
  183. Roy S. Mohammad T. Gupta P. Dahiya R. Parveen S. Luqman S. Hasan G.M. Hassan M.I. Discovery of harmaline as a potent inhibitor of sphingosine kinase-1: A chemopreventive role in lung cancer. ACS Omega 2020 5 34 21550 21560 10.1021/acsomega.0c02165 32905276
    [Google Scholar]
  184. Pfau W. Skog K. Exposure to β-carbolines norharman and harman. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 2004 802 1 115 126 10.1016/j.jchromb.2003.10.044 15036003
    [Google Scholar]
  185. Jinous Asgarpanah Chemistry, pharmacology and medicinal properties of Peganum harmala L. Afr. J. Pharm. Pharmacol. 2012 6 22 10.5897/AJPP11.876
    [Google Scholar]
  186. Chourasiya R. Agrawal R. Vaidya A. promising anticancer activity of β-carboline derivatives: Design, Synthesis, and Pharmacological Evaluation. Chemistry 2022 4 4 1395 1406 10.3390/chemistry4040091
    [Google Scholar]
  187. Otto R. Penzis R. Gaube F. Winckler T. Appenroth D. Fleck C. Tränkle C. Lehmann J. Enzensperger C. Beta and gamma carboline derivatives as potential anti-Alzheimer agents: A comparison. Eur. J. Med. Chem. 2014 87 63 70 10.1016/j.ejmech.2014.09.048 25240096
    [Google Scholar]
  188. Cain M. Weber R.W. Guzman F. Cook J.M. Barker S.A. Rice K.C. Crawley J.N. Paul S.M. Skolnick P. beta.-Carbolines: Synthesis and neurochemical and pharmacological actions on brain benzodiazepine receptors. J. Med. Chem. 1982 25 9 1081 1091 10.1021/jm00351a015 6127411
    [Google Scholar]
  189. Tshikhudo P.P. Mabhaudhi T. Koorbanally N.A. Mudau F.N. Avendaño Caceres E.O. Popa D. Calina D. Sharifi-Rad J. Anticancer potential of β‐carboline alkaloids: An updated mechanistic overview. Chem. Biodivers. 2024 21 2 e202301263 10.1002/cbdv.202301263 38108650
    [Google Scholar]
  190. Yu A.M. Idle J.R. Krausz K.W. Küpfer A. Gonzalez F.J. Contribution of individual cytochrome P450 isozymes to the O-demethylation of the psychotropic β-carboline alkaloids harmaline and harmine. J. Pharmacol. Exp. Ther. 2003 305 1 315 322 10.1124/jpet.102.047050 12649384
    [Google Scholar]
  191. Chen Z.Y. Li J. Zhu S.D. Li Z.D. Yu J.L. Wu J. Zhang C. Zeng L.H. Harmine reinforces the effects of regorafenib on suppressing cell proliferation and inducing apoptosis in liver cancer cells. Exp. Ther. Med. 2022 23 3 209 10.3892/etm.2022.11132 35126712
    [Google Scholar]
  192. Zhang L. Zhang F. Zhang W. Chen L. Gao N. Men Y. Xu X. Jiang Y. Harmine suppresses homologous recombination repair and inhibits proliferation of hepatoma cells. Cancer Biol. Ther. 2015 16 11 1585 1592 10.1080/15384047.2015.1078021 26382920
    [Google Scholar]
  193. Kim G.D. Harmine hydrochloride induces g2/m cell cycle arrest and apoptosis in sk-hep1 hepatocellular carcinoma cells by regulating mitogen-activated protein kinases and the pi3k/akt pathway. Prev. Nutr. Food Sci. 2023 28 4 436 443 10.3746/pnf.2023.28.4.436 38188092
    [Google Scholar]
  194. Sarkar S. Bhattacharjee P. Bhadra K. DNA binding and apoptotic induction ability of harmalol in HepG2: Biophysical and biochemical approaches. Chem. Biol. Interact. 2016 258 142 152 10.1016/j.cbi.2016.08.024 27590872
    [Google Scholar]
  195. Su H. Kang Q. Wang H. Yin H. Duan L. Liu Y. Fan R. Changes in expression of P53 and inflammatory factors in patients with ulcerative colitis. Exp. Ther. Med. 2019 17 4 2451 2456 10.3892/etm.2019.7253 30906432
    [Google Scholar]
  196. Sarkar S. Bhattacharjee P. Ghosh T. Bhadra K. Pharmaceutical efficacy of harmalol in inhibiting hepatocellular carcinoma. Future J. Pharm. Sci. 2020 6 1 29 10.1186/s43094‑020‑00045‑x
    [Google Scholar]
  197. Zhang C. Wu L.W. Li Z.D. Zhang M.M. Wu J. Du F.H. Zeng L.H. Li Y.L. DYRK1A suppression attenuates HIF 1α accumulation and enhances the anti liver cancer effects of regorafenib and sorafenib under hypoxic conditions. Int. J. Oncol. 2022 60 4 45 10.3892/ijo.2022.5335 35244188
    [Google Scholar]
  198. Mishra S. Gupta A. Jain S. Vaidya A. Anticancer mechanisms of β‐carbolines. Chem. Biol. Drug Des. 2024 103 4 e14521 10.1111/cbdd.14521 38653576
    [Google Scholar]
  199. Timbilla A.A. Vrabec R. Havelek R. Rezacova M. Chlebek J. Blunden G. Cahlikova L. The anticancer properties of harmine and its derivatives. Phytochem. Rev. 2024 10.1007/s11101‑024‑09978‑0
    [Google Scholar]
  200. Chen X. Wang J. Zhao P. Dang B. Liang T. Steimbach R.R. Miller A.K. Liu J. Wang X. Zhang T. Luan X. Hu J. Gao J. Tetrahydro-β-carboline derivatives as potent histone deacetylase 6 inhibitors with broad-spectrum antiproliferative activity. Eur. J. Med. Chem. 2023 260 115776 10.1016/j.ejmech.2023.115776 37660484
    [Google Scholar]
  201. Ayipo Y.O. Osunniran W.A. Mordi M.N. Metal complexes of β-carboline: Advances in anticancer therapeutics. Coord. Chem. Rev. 2021 432 213746 10.1016/j.ccr.2020.213746
    [Google Scholar]
  202. Brahma M.K. Gilglioni E.H. Zhou L. Trépo E. Chen P. Gurzov E.N. Oxidative stress in obesity-associated hepatocellular carcinoma: Sources, signaling and therapeutic challenges. Oncogene 2021 40 33 5155 5167 10.1038/s41388‑021‑01950‑y 34290399
    [Google Scholar]
  203. Ma Y. Li W. Yao Q. Liu Y. Yu J. Zang L. Wang S. Zhou L. Wen S. Luo Y. Li W. Niu X. Harmine ameliorates CCl4-induced acute liver injury through suppression of autophagy and inflammation. Int. Immunopharmacol. 2024 129 111538 10.1016/j.intimp.2024.111538 38306830
    [Google Scholar]
  204. Sugiura S. Asamoto M. Hokaiwado N. Hirose M. Shirai T. Harman and Norharman Suppressed but NaNO2 Enhanced the Development of Preneoplastic Liver Cell Foci in 2-Amino-3,8-Dimethylimidazo[4,5-f]Quinoxaline (MeIQx)-. Treated Rats. J. Toxicol. Pathol. 2005 18 2 99 104 10.1293/tox.18.99
    [Google Scholar]
  205. El Gendy M.A.M. Soshilov A.A. Denison M.S. El-Kadi A.O.S. Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms. Food Chem. Toxicol. 2012 50 2 353 362 10.1016/j.fct.2011.10.052 22037238
    [Google Scholar]
  206. Beltagy D.M. Abdelsalam K.G. Mohamed T.M. El-Keey M.M. Role of harmaline as adiponectin modulator in defeating liver cirrhosis induced by thioacetamide in mice. Biomed. Pharmacol. J. 2021 14 1 123 131 10.13005/bpj/2106
    [Google Scholar]
  207. Cao M.R. Li Q. Liu Z.L. Liu H.H. Wang W. Liao X.L. Pan Y.L. Jiang J.W. Harmine induces apoptosis in HepG2 cells via mitochondrial signaling pathway. Hepatobiliary Pancreat. Dis. Int. 2011 10 6 599 604 10.1016/S1499‑3872(11)60102‑1 22146623
    [Google Scholar]
  208. Hafiz I. Li Z. Wang Z. He H. Tang X. Wang M. Improving the antitumor efficiency against hepatocellular carcinoma by harmine-loaded liposomes with mitochondria targeting and legumain response. J. Drug Deliv. Sci. Technol. 2022 75 103623 10.1016/j.jddst.2022.103623
    [Google Scholar]
  209. Nagaraju G.P. Dariya B. Kasa P. Peela S. El-Rayes B.F. Epigenetics in hepatocellular carcinoma. Semin. Cancer Biol. 2022 86 Pt 3 622 632 10.1016/j.semcancer.2021.07.017 34324953
    [Google Scholar]
  210. Liu J. Wang T. Wang X. Luo L. Guo J. Peng Y. Xu Q. Miao J. Zhang Y. Ling Y. Development of novel β-carboline-based hydroxamate derivatives as HDAC inhibitors with DNA damage and apoptosis inducing abilities. MedChemComm 2017 8 6 1213 1219 10.1039/C6MD00681G 30108831
    [Google Scholar]
  211. Cho C.C. Lin C.J. Huang H.H. Yang W.Z. Fei C.Y. Lin H.Y. Lee M.S. Yuan H.S. Mechanistic insights into harmine-mediated inhibition of human dna methyltransferases and prostate cancer cell growth. ACS Chem. Biol. 2023 18 6 1335 1350 10.1021/acschembio.3c00065 37188336
    [Google Scholar]
  212. Joshi H. Bhushan S. Dimri T. Sharma D. Sak K. Chauhan A. Chauhan R. Haque S. Ahmad F. Kumar M. Tuli H.S. Kaur D. Anti-tumor potential of Harmine and its derivatives: Recent trends and advancements. Discov. Oncol. 2025 16 1 189 10.1007/s12672‑025‑01893‑w 39954215
    [Google Scholar]
  213. Chou A.H. Lee H.C. Liao C.C. Yu H.P. Liu F.C. ERK/NF-kB/COX-2 signaling pathway plays a key role in curcumin protection against acetaminophen-induced liver injury. Life 2023 13 11 2150 10.3390/life13112150 38004290
    [Google Scholar]
  214. Xie D.P. Gong Y.X. Lee J. Jeong E.M. Ren C.X. Guo X.Y. Han Y.H. Cui Y.D. Lee S.J. Kwon T. Sun H.N. Peroxiredoxin 5 protects HepG2 cells from ethyl β-carboline-3-carboxylate-induced cell death via ROS-dependent MAPK signalling pathways. J. Cancer 2022 13 11 3258 3267 10.7150/jca.76663 36118528
    [Google Scholar]
  215. Zhang P. Huang C. Wang W. Zhang X. Chen J. Wang J. Lin C. Jiang J. Harmine hydrochloride triggers g2 phase arrest and apoptosis in mgc-803 cells and smmc-7721 cells by upregulating p21, activating caspase-8/bid, and downregulating erk/bad pathway. Phytother. Res. 2016 30 1 31 40 10.1002/ptr.5497 26549417
    [Google Scholar]
  216. El Gendy M.A.M. Soshilov A.A. Denison M.S. El-Kadi A.O.S. Transcriptional and posttranslational inhibition of dioxin-mediated induction of CYP1A1 by harmine and harmol. Toxicol. Lett. 2012 208 1 51 61 10.1016/j.toxlet.2011.09.030 22001777
    [Google Scholar]
  217. Prasad Kushwaha J. Baidya D. Patil S. Harmine-loaded galactosylated pluronic F68-gelucire 44/14 mixed micelles for liver targeting. Drug Dev. Ind. Pharm. 2019 45 8 1361 1368 10.1080/03639045.2019.1620267 31096800
    [Google Scholar]
  218. Bei Y.Y. Yuan Z.Q. Zhang L. Zhou X.F. Chen W.L. Xia P. Liu Y. You B.G. Hu X.J. Zhu Q.L. Zhang C.G. Zhang X.N. Jin Y. Novel self-assembled micelles based on palmitoyl-trimethyl-chitosan for efficient delivery of harmine to liver cancer. Expert Opin. Drug Deliv. 2014 11 6 843 854 10.1517/17425247.2014.893292 24655139
    [Google Scholar]
  219. Li S. Wang A. Gu F. Wang Z. Tian C. Qian Z. Tang L. Gu Y. Novel harmine derivatives for tumor targeted therapy. Oncotarget 2015 6 11 8988 9001 10.18632/oncotarget.3276 25940702
    [Google Scholar]
  220. El Gendy M.A.M. El-Kadi A.O.S. Harmine and harmaline downregulate TCDD-induced Cyp1a1 in the livers and lungs of C57BL/6 mice. BioMed Res. Int. 2013 2013 1 9 10.1155/2013/258095 23509697
    [Google Scholar]
  221. Mohammadi F. Ghaleh navi, N.; Karimi, E.; Homayouni-Tabrizi, M.; Oskoueian, E. Nanoparticle-based delivery of harmine: A comprehensive study on synthesis, characterization, anticancer activity, angiogenesis and toxicity Evaluation. Heliyon 2024 10 11 e31678 10.1016/j.heliyon.2024.e31678 38832286
    [Google Scholar]
  222. Herraiz T. González D. Ancín-Azpilicueta C. Arán V.J. Guillén H. β-Carboline alkaloids in Peganum harmala and inhibition of human monoamine oxidase (MAO). Food Chem. Toxicol. 2010 48 3 839 845 10.1016/j.fct.2009.12.019 20036304
    [Google Scholar]
  223. Sarkar P. Gopi P. Pandya P. Paria S. Hossain M. Siddiqui M.H. Alamri S. Bhadra K. Insights on the comparative affinity of ribonucleic acids with plant-based beta carboline alkaloid, harmine: Spectroscopic, calorimetric and computational evaluation. Heliyon 2024 10 14 e34183 10.1016/j.heliyon.2024.e34183 39100473
    [Google Scholar]
  224. Bhadra K. Maiti M. Kumar G.S. DNA-binding cytotoxic alkaloids: Comparative study of the energetics of binding of berberine, palmatine, and coralyne. DNA Cell Biol. 2008 27 12 675 685 10.1089/dna.2008.0779 18788977
    [Google Scholar]
  225. Bhadra K. Maiti M. Kumar G.S. Molecular recognition of DNA by small molecules: AT base pair specific intercalative binding of cytotoxic plant alkaloid palmatine. Biochim. Biophys. Acta, Gen. Subj. 2007 1770 7 1071 1080 10.1016/j.bbagen.2007.03.001 17434677
    [Google Scholar]
  226. Zhang L. Lou W. Wang J. Advances in nucleic acid therapeutics: Structures, delivery systems, and future perspectives in cancer treatment. Clin. Exp. Med. 2024 24 1 200 10.1007/s10238‑024‑01463‑4 39196428
    [Google Scholar]
  227. Hawner M. Ducho C. Cellular targeting of oligonucleotides by conjugation with small molecules. Molecules 2020 25 24 5963 10.3390/molecules25245963 33339365
    [Google Scholar]
  228. Dhyani P. Quispe C. Sharma E. Bahukhandi A. Sati P. Attri D.C. Szopa A. Sharifi-Rad J. Docea A.O. Mardare I. Calina D. Cho W.C. Anticancer potential of alkaloids: A key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine. Cancer Cell Int. 2022 22 1 206 10.1186/s12935‑022‑02624‑9 35655306
    [Google Scholar]
  229. Jarošová P. Hannig P. Kolková K. Mazzini S. Táborská E. Gargallo R. Borgonovo G. Artali R. Táborský P. Alkaloid escholidine and its interaction with DNA structures. Biology 2021 10 12 1225 10.3390/biology10121225 34943140
    [Google Scholar]
  230. Duportail G. Linear and circular dichroism of harmine and harmaline interacting with DNA. Int. J. Biol. Macromol. 1981 3 3 188 192 10.1016/0141‑8130(81)90062‑3
    [Google Scholar]
  231. Sarkar S. Bhadra K. Binding of alkaloid harmalol to DNA: Photophysical and calorimetric approach. J. Photochem. Photobiol. B 2014 130 272 280 10.1016/j.jphotobiol.2013.11.021 24368411
    [Google Scholar]
  232. Hayashi K. Nagao M. Sugimura T. Interactions of norharman and harman with DNA. Nucleic Acids Res. 1977 4 11 3679 3686 10.1093/nar/4.11.3679 593881
    [Google Scholar]
  233. Levitt R.C. Legraverend C. Nebert D.W. Pelkonen O. Effects of harman and norharman on the mutagenicity and binding to DNA of benzo[a]pyrene metabolites in vitro and on aryl hydrocarbon hydroxylase induction in cell culture. Biochem. Biophys. Res. Commun. 1977 79 4 1167 1175 10.1016/0006‑291X(77)91129‑9 603652
    [Google Scholar]
  234. Pagano B. Caterino M. Filosa R. Giancola C. Binding of harmine derivatives to DNA: A spectroscopic investigation. Molecules 2017 22 11 1831 10.3390/molecules22111831 29077046
    [Google Scholar]
  235. Cao R. Peng W. Chen H. Ma Y. Liu X. Hou X. Guan H. Xu A. DNA binding properties of 9-substituted harmine derivatives. Biochem. Biophys. Res. Commun. 2005 338 3 1557 1563 10.1016/j.bbrc.2005.10.121 16288723
    [Google Scholar]
  236. Nafisi S. Malekabady Z.M. Khalilzadeh M.A. Interaction of β-Carboline Alkaloids with RNA. DNA Cell Biol. 2010 29 12 753 761 10.1089/dna.2010.1087 20731607
    [Google Scholar]
  237. Silva M.M. Savariz F.C. Silva-Júnior E.F. Aquino T.M. Sarragiotto M.H. Santos J.C.C. Figueiredo I.M. interaction Of B-Carbolines With DNA: Spectroscopic Studies, Correlation With Biological Activity And Molecular Docking. J. Braz. Chem. Soc. 2016 10.5935/0103‑5053.20160035
    [Google Scholar]
  238. Sharma S. Yadav M. Gupta S.P. Pandav K. Kumar S. Spectroscopic and structural studies on the interaction of an anticancer β–carboline alkaloid, harmine with GC and AT specific DNA oligonucleotides. Chem. Biol. Interact. 2016 260 256 262 10.1016/j.cbi.2016.08.025 27590873
    [Google Scholar]
  239. Sarkar S. Tribedi P. Bhadra K. Structure-activity insights of harmine targeting DNA, ROS inducing cytotoxicity with PARP mediated apoptosis against cervical cancer, anti-biofilm formation and in vivo therapeutic study. J. Biomol. Struct. Dyn. 2022 40 13 5880 5902 10.1080/07391102.2021.1874533 33480316
    [Google Scholar]
  240. Vaishnav N. Khare N. Katariya P.K. Jha A.K. To study the effect of harmine against DNMT1 for the treatment of cervical cancer through molecular docking studies. IJPBS 2020 10 3 125 132
    [Google Scholar]
  241. Du W. Wang B. Li Z. Interaction of harmine with oligonucleotide d(GTGCAC)2. Thermochim. Acta 2004 416 1-2 59 63 10.1016/j.tca.2003.11.025
    [Google Scholar]
  242. Paul B.K. Ghosh N. Mukherjee S. Binding of norharmane with RNA reveals two thermodynamically different binding modes with opposing heat capacity changes. J. Colloid Interface Sci. 2019 538 587 596 10.1016/j.jcis.2018.12.011 30553091
    [Google Scholar]
  243. Sarkar S. Pandya P. Bhadra K. Sequence specific binding of beta carboline alkaloid harmalol with deoxyribonucleotides: Binding heterogeneity, conformational, thermodynamic and cytotoxic aspects. PLoS One 2014 9 9 e108022 10.1371/journal.pone.0108022 25247695
    [Google Scholar]
  244. Bhattacharjee P. Sarkar S. Pandya P. Bhadra K. Targeting different RNA motifs by beta carboline alkaloid, harmalol: A comparative photophysical, calorimetric, and molecular docking approach. J. Biomol. Struct. Dyn. 2016 34 12 1 19 10.1080/07391102.2015.1126694 26629671
    [Google Scholar]
  245. Xiao S. Lin W. Wang C. Yang M. Synthesis and biological evaluation of DNA targeting flexible side-chain substituted β-carboline derivatives. Bioorg. Med. Chem. Lett. 2001 11 4 437 441 10.1016/S0960‑894X(00)00679‑X 11229742
    [Google Scholar]
  246. Li S. Zhang Y. Deng G. Wang Y. Qi S. Cheng X. Ma Y. Xie Y. Wang C. Exposure characteristics of the analogous β-carboline alkaloids harmaline and harmine based on the efflux transporter of multidrug resistance protein 2. Front. Pharmacol. 2017 8 541 10.3389/fphar.2017.00541 28871225
    [Google Scholar]
  247. Jiménez J. Riverón-Negrete L. Abdullaev F. Espinosa-Aguirre J. Rodríguez-Arnaiz R. Cytotoxicity of the β-carboline alkaloids harmine and harmaline in human cell assays in vitro. Exp. Toxicol. Pathol. 2008 60 4-5 381 389 10.1016/j.etp.2007.12.003 18430551
    [Google Scholar]
  248. Li S. Cheng X. Wang C. A review on traditional uses, phytochemistry, pharmacology, pharmacokinetics and toxicology of the genus Peganum. J. Ethnopharmacol. 2017 203 127 162 10.1016/j.jep.2017.03.049 28359849
    [Google Scholar]
  249. Salehi H. Karimi M. Rezaie N. Raofie F. Extraction of β-Carboline alkaloids and preparation of extract nanoparticles from Peganum harmala L. capsules using supercritical fluid technique. J. Drug Deliv. Sci. Technol. 2020 56 101515 10.1016/j.jddst.2020.101515
    [Google Scholar]
  250. Arslan F.B. Ozturk K. Calis S. Antibody-mediated drug delivery. Int. J. Pharm. 2021 596 120268 10.1016/j.ijpharm.2021.120268 33486037
    [Google Scholar]
  251. Sun Q. Liu C. Jiang K. Fang Y. Kong C. Fu J. Liu Y. A preliminary study on the neurotoxic mechanism of harmine in Caenorhabditis elegans. Comp. Biochem. Physiol. C Toxicol. Pharmacol. 2021 245 109038 10.1016/j.cbpc.2021.109038 33794375
    [Google Scholar]
  252. Elumalai K. Srinivasan S. Shanmugam A. Review of the efficacy of nanoparticle-based drug delivery systems for cancer treatment. Biomedical Technology 2024 5 109 122 10.1016/j.bmt.2023.09.001
    [Google Scholar]
  253. Liu G. Yang L. Chen G. Xu F. Yang F. Yu H. Li L. Dong X. Han J. Cao C. Qi J. Su J. Xu X. Li X. Li B. A Review on Drug Delivery System for Tumor Therapy. Front. Pharmacol. 2021 12 735446 10.3389/fphar.2021.735446 34675807
    [Google Scholar]
  254. Lotan Y. Role of biomarkers to predict outcomes and response to therapy. Urol. Oncol. 2010 28 1 97 101 10.1016/j.urolonc.2009.03.017 20123357
    [Google Scholar]
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Targeting Chemical-induced Hepatocellular Carcinoma: Ameliorative Potential of Natural Compounds with Focus on Beta-carbolines
Bentham Science Publishers ; https://doi.org/10.2174/0113895575415295250922074231
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  • Article Type:     Review Article
Keywords: apoptosis induction ; natural compounds ; beta-carbolines ; oxidative stress ; chemical carcinogenesis ; Hepatocellular carcinoma

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