Skip to main content
SpringerLink
Log in

Emerging Roles of Phytochemicals in Hepatocellular Carcinoma

  • Chapter
  • First Online:
Phytochemicals Targeting Tumor Microenvironment in Gastrointestinal Cancers

  • 217 Accesses

Abstract

Hepatocellular cancer is the most common liver cancer and is the second most common cause of cancer mortality worldwide. Cirrhosis, secondary to viral hepatitis, remains the most common underlying cause worldwide. Surgical resection or liver transplantation is the mainstay of treatment. Various other treatment options include chemoembolization, radiofrequency ablation, and tyrosine kinase inhibitors including sorafenib. More than 30 genetic mutations have been described in peer-reviewed literature affecting multiple signaling pathways. Multiple in vitro and in vivo studies have been reported in the peer-reviewed literature demonstrating the benefit of phytochemicals in the treatment and prevention of hepatocellular cancer. In this chapter, we summarize the role of different phytochemicals including ginger, garlic, turmeric, cinnamon, saffron, coffee, and cruciferous vegetables that have been implicated in playing significant roles in the preventions and management of hepatocellular cancer. We also summarize the theorized pathways affected by these agents. This can lay a groundwork for further studies and randomized clinical trials to address the unmet needs of the topic.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AC:

Antrodia cinnamomea

ARID:

AT-rich interactive domain

AX1N1:

Ataxin-1

BCL:

B-cell lymphoma

BMI:

Body mass index

CCND:

Cyclin D2

Cdk:

Cyclin-dependent kinase

CI:

Confidence interval

COX:

Cyclo-oxygenase

CT:

Computerized tomography

CTNNB1:

Catenin B1

DAD:

Diallyl disulfide

DAS:

Diallyl sulfide

DAT:

Diallyl trisulfide

DR5:

Death receptor 5

EACG:

Ethanolic extracts of AC

EGCG:

Epigallocatechin-3-gallate

EGF:

Epidermal growth factor

FAS:

Apoptosis-stimulating fragment

5-FU:

5-Fluorouracil

FGF:

Fibroblast growth factor

GP:

Ginger polysaccharides

HAT:

Histone acetyltransferase

HBV:

Hepatitis B virus

HCC:

Hepatocellular carcinoma

HCCDB:

Human hepatocellular cancer database

HCV:

Hepatitis C virus

HGF:

Hepatocyte growth factor

IARC:

International Agency for Research on Cancer

IGF:

Insulin-like growth factor

JAK/STAT:

Janus kinase/signal transducer and activator of transcription

MAPK:

Mitogen-activated protein kinase

2-MCA:

2-Methoxycinnamaldehyde

mTOR:

Mammalian target of rapamycin

NAD:

Nicotinamide adenine dinucleotide

NAD(P)H:

Nicotinamide adenine dinucleotide phosphate

NF-kb:

Nuclear factor kappa B

NRF2:

Nuclear factor erythroid 2-related factor 2

PDGF:

Platelet-derived growth factor

PTEN:

Phosphatase and tensin homolog

RAF:

Serine/threonine protein kinase

RAS:

Retrovirus-associated DNA sequence

SAC:

S-allyl cysteine

SAMC:

S-allylmercaptocysteine

STAT3:

Signal transducer and activator of transcription 3

T2DM:

Type 2 diabetes mellitus

TERT:

Telomerase reverse transcriptase

TIMP:

Tissue inhibitor of matrix metalloproteinase

TGF-β:

Transforming growth factor-β

TRAIL:

Tumor necrosis factor-related apoptosis-inducing ligand

VEGF:

Vascular endothelial growth factor

WCRF:

World Cancer Research Fund

WNT:

Wingless/integrated

References

  1. Pocha, C., & Xie, C. (2019). Hepatocellular carcinoma in alcoholic and non-alcoholic fatty liver disease-one of a kind or two different enemies? Translational Gastroenterology and Hepatology, 4, 72.

    Google Scholar 

  2. Hartke, J., Johnson, M., & Ghabril, M. (2017). The diagnosis and treatment of hepatocellular carcinoma. Seminars in Diagnostic Pathology, 34(2), 153–159.

    Google Scholar 

  3. Singal, A. G., Lampertico, P., & Nahon, P. (2020). Epidemiology and surveillance for hepatocellular carcinoma: New trends. Journal of Hepatology, 72(2), 250–261.

    CAS  Google Scholar 

  4. Forner, A., Reig, M., & Bruix, J. (2018). Hepatocellular carcinoma. Lancet, 391(10127), 1301–1314.

    Google Scholar 

  5. International Consensus Group for Hepatocellular Neoplasia The International Consensus Group for Hepatocellular Neoplasia. (2009). Pathologic diagnosis of early hepatocellular carcinoma: A report of the international consensus group for hepatocellular neoplasia. Hepatology, 49(2), 658–664.

    Google Scholar 

  6. Braicu, C., Burz, C., Berindan-Neagoe, I., et al. (2009). Hepatocellular carcinoma: Tumorigenesis and prediction markers. Gastroenterology Research, 2(4), 191–199.

    CAS  Google Scholar 

  7. Gomaa, A. I., Khan, S. A., Leen, E. L., Waked, I., & Taylor-Robinson, S. D. (2009). Diagnosis of hepatocellular carcinoma. World Journal of Gastroenterology, 15(11), 1301–1314.

    Google Scholar 

  8. Lim, S. O., Gu, J. M., Kim, M. S., et al. (2008). Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: Methylation of the E-cadherin promoter. Gastroenterology, 135(6), 2128–2140, 2140.e2121-2128.

    CAS  Google Scholar 

  9. Itoh, T., Shiro, T., Seki, T., et al. (2000). Relationship between p53 overexpression and the proliferative activity in hepatocellular carcinoma. International Journal of Molecular Medicine, 6(2), 137–142.

    CAS  Google Scholar 

  10. Zhou, L., Liu, J., & Luo, F. (2006). Serum tumor markers for detection of hepatocellular carcinoma. World Journal of Gastroenterology, 12(8), 1175–1181.

    CAS  Google Scholar 

  11. Baek, H. J., Lim, S. C., Kitisin, K., et al. (2008). Hepatocellular cancer arises from loss of transforming growth factor beta signaling adaptor protein embryonic liver fodrin through abnormal angiogenesis. Hepatology, 48(4), 1128–1137.

    CAS  Google Scholar 

  12. Masaki, T., Shiratori, Y., Rengifo, W., et al. (2000). Hepatocellular carcinoma cell cycle: Study of Long-Evans cinnamon rats. Hepatology, 32(4 Pt 1), 711–720.

    CAS  Google Scholar 

  13. Lévy, L., Renard, C. A., Wei, Y., & Buendia, M. A. (2002). Genetic alterations and oncogenic pathways in hepatocellular carcinoma. Annals of the New York Academy of Sciences, 963, 21–36.

    Google Scholar 

  14. Zhu, A. X., & Raymond, E. (2009). Early development of sunitinib in hepatocellular carcinoma. Expert Review of Anticancer Therapy, 9(1), 143–150.

    CAS  Google Scholar 

  15. Dimri, M., & Satyanarayana, A. (2020). Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel), 12(2), 491. https://doi.org/10.3390/cancers12020491.

    Article  CAS  Google Scholar 

  16. Fabregat, I., & Caballero-Díaz, D. (2018). Transforming growth factor-β-induced cell plasticity in liver fibrosis and hepatocarcinogenesis. Frontiers in Oncology, 8, 357.

    Google Scholar 

  17. Elsonbaty, S. M., Zahran, W. E., & Moawed, F. S. (2017). Gamma-irradiated β-glucan modulates signaling molecular targets of hepatocellular carcinoma in rats. Tumour Biology, 39(8), 1010428317708703.

    Google Scholar 

  18. Goyal, L., Muzumdar, M. D., & Zhu, A. X. (2013). Targeting the HGF/c-MET pathway in hepatocellular carcinoma. Clinical Cancer Research, 19(9), 2310–2318.

    CAS  Google Scholar 

  19. Rawat, D., Shrivastava, S., Naik, R. A., Chhonker, S. K., Mehrotra, A., & Koiri, R. K. (2018). An overview of natural plant products in the treatment of hepatocellular carcinoma. Anti-Cancer Agents in Medicinal Chemistry, 18(13), 1838–1859.

    CAS  Google Scholar 

  20. Fahmi, A., Hassanen, N., Abdur-Rahman, M., & Shams-Eldin, E. (2019). Phytochemicals, antioxidant activity and hepatoprotective effect of ginger. Biomarkers, 24(5), 436–447.

    CAS  Google Scholar 

  21. Akhtar, T., & Sheikh, N. (2016). Chemopreventive prospective of dietary spices against hepatocellular carcinoma. Current Science, 110(4), 579–583.

    CAS  Google Scholar 

  22. Wang, Y., Wang, S., Song, R., et al. (2019). Ginger polysaccharides induced cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. International Journal of Biological Macromolecules, 123, 81–90.

    CAS  Google Scholar 

  23. Wani, N. A., Zhang, B., Teng, K. Y., et al. (2018). Reprograming of glucose metabolism by zerumbone suppresses hepatocarcinogenesis. Molecular Cancer Research, 16(2), 256–268.

    CAS  Google Scholar 

  24. Kim, Y. J., Jeon, Y., Kim, T., et al. (2017). Combined treatment with zingerone and its novel derivative synergistically inhibits TGF-β1 induced epithelial-mesenchymal transition, migration and invasion of human hepatocellular carcinoma cells. Bioorganic & Medicinal Chemistry Letters, 27(4), 1081–1088.

    CAS  Google Scholar 

  25. Chen, S. Y., Lee, Y. R., Hsieh, M. C., et al. (2018). Enhancing the anticancer activity of Antrodia cinnamomea in hepatocellular carcinoma cells via cocultivation with ginger: The impact on cancer cell survival pathways. Frontiers in Pharmacology, 9, 780.

    CAS  Google Scholar 

  26. Tian, N., Shangguan, W., Zhou, Z., Yao, Y., Fan, C., & Cai, L. (2019). Lin28b is involved in curcumin-reversed paclitaxel chemoresistance and associated with poor prognosis in hepatocellular carcinoma. Journal of Cancer, 10(24), 6074–6087.

    CAS  Google Scholar 

  27. Elmansi, A. M., El-Karef, A. A., Shishtawy, M. M. E., & Eissa, L. A. (2017). Hepatoprotective effect of curcumin on hepatocellular carcinoma through autophagic and apoptotic pathways. Annals of Hepatology, 16(4), 607–618.

    CAS  Google Scholar 

  28. Wang, F., Ye, X., Zhai, D., et al. (2020). Curcumin-loaded nanostructured lipid carrier induced apoptosis in human HepG2 cells through activation of the DR5/caspase-mediated extrinsic apoptosis pathway. Acta Pharmaceutica, 70(2), 227–237.

    CAS  Google Scholar 

  29. Marquardt, J. U., Gomez-Quiroz, L., Arreguin Camacho, L. O., et al. (2015). Curcumin effectively inhibits oncogenic NF-κB signaling and restrains stemness features in liver cancer. Journal of Hepatology, 63(3), 661–669.

    CAS  Google Scholar 

  30. Goel, A., & Aggarwal, B. B. (2010). Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs. Nutrition and Cancer, 62(7), 919–930.

    CAS  Google Scholar 

  31. Aly, S. M., Fetaih, H. A., Hassanin, A. A. I., Abomughaid, M. M., & Ismail, A. A. (2019). Protective effects of garlic and cinnamon oils on hepatocellular carcinoma in albino rats. Analytical Cellular Pathology (Amsterdam), 2019, 9895485.

    Google Scholar 

  32. Ng, K. T., Guo, D. Y., Cheng, Q., et al. (2012). A garlic derivative, S-allyl cysteine (SAC), suppresses proliferation and metastasis of hepatocellular carcinoma. PLoS One, 7(2), e31655.

    CAS  Google Scholar 

  33. Tong, D., Qu, H., Meng, X., et al. (2014). S-allylmercaptocysteine promotes MAPK inhibitor-induced apoptosis by activating the TGF-β signaling pathway in cancer cells. Oncology Reports, 32(3), 1124–1132.

    CAS  Google Scholar 

  34. Xiao, J., Xing, F., Liu, Y., et al. (2018). Garlic-derived compound. Acta Pharmaceutica Sinica B, 8(4), 575–586.

    Google Scholar 

  35. Chu, Y. L., Ho, C. T., Chung, J. G., Raghu, R., Lo, Y. C., & Sheen, L. Y. (2013). Allicin induces anti-human liver cancer cells through the p53 gene modulating apoptosis and autophagy. Journal of Agricultural and Food Chemistry, 61(41), 9839–9848.

    CAS  Google Scholar 

  36. Kim, H. J., Han, M. H., Kim, G. Y., Choi, Y. W., & Choi, Y. H. (2012). Hexane extracts of garlic cloves induce apoptosis through the generation of reactive oxygen species in Hep3B human hepatocarcinoma cells. Oncology Reports, 28(5), 1757–1763.

    Google Scholar 

  37. Belloir, C., Singh, V., Daurat, C., Siess, M. H., & Le Bon, A. M. (2006). Protective effects of garlic sulfur compounds against DNA damage induced by direct- and indirect-acting genotoxic agents in HepG2 cells. Food and Chemical Toxicology, 44(6), 827–834.

    CAS  Google Scholar 

  38. Perng, D. S., Tsai, Y. H., Cherng, J., et al. (2016). Discovery of a novel anticancer agent with both anti-topoisomerase I and II activities in hepatocellular carcinoma SK-Hep-1 cells in vitro and in vivo: Cinnamomum verum Component 2-methoxycinnamaldehyde. Drug Design, Development and Therapy, 10, 141–153.

    CAS  Google Scholar 

  39. Bolhassani, A., Khavari, A., & Bathaie, S. Z. (2014). Saffron and natural carotenoids: Biochemical activities and anti-tumor effects. Biochimica et Biophysica Acta, 1845(1), 20–30.

    CAS  Google Scholar 

  40. Liu, T., Tian, L., Fu, X., Wei, L., Li, J., & Wang, T. (2019). Saffron inhibits the proliferation of hepatocellular carcinoma via inducing cell apoptosis. Panminerva Medica. https://doi.org/10.23736/S0031-0808.18.03561-9.

  41. Kim, B., & Park, B. (2018). Saffron carotenoids inhibit STAT3 activation and promote apoptotic progression in IL-6-stimulated liver cancer cells. Oncology Reports, 39(4), 1883–1891.

    CAS  Google Scholar 

  42. Amin, A., Hamza, A. A., Daoud, S., et al. (2016). Saffron-based crocin prevents early lesions of liver cancer: In vivo, in vitro and network analyses. Recent Patents on Anti-Cancer Drug Discovery, 11(1), 121–133.

    CAS  Google Scholar 

  43. Noureini, S. K., & Wink, M. (2012). Anti-proliferative effects of crocin in HepG2 cells by telomerase inhibition and hTERT down-regulation. Asian Pacific Journal of Cancer Prevention, 13(5), 2305–2309.

    Google Scholar 

  44. Humans IWGotEoCRt. Drinking coffee, mate, and very hot beverages. 2018.

    Google Scholar 

  45. Kennedy, O. J., Roderick, P., Buchanan, R., Fallowfield, J. A., Hayes, P. C., & Parkes, J. (2017). Coffee, including caffeinated and decaffeinated coffee, and the risk of hepatocellular carcinoma: A systematic review and dose-response meta-analysis. BMJ Open, 7(5), e013739.

    Google Scholar 

  46. Bravi, F., Tavani, A., Bosetti, C., Boffetta, P., & La Vecchia, C. (2017). Coffee and the risk of hepatocellular carcinoma and chronic liver disease: A systematic review and meta-analysis of prospective studies. European Journal of Cancer Prevention, 26(5), 368–377.

    CAS  Google Scholar 

  47. Bøhn, S. K., Blomhoff, R., & Paur, I. (2014). Coffee and cancer risk, epidemiological evidence, and molecular mechanisms. Molecular Nutrition & Food Research, 58(5), 915–930.

    Google Scholar 

  48. Tamura, T., Hishida, A., & Wakai, K. (2019). Coffee consumption and liver cancer risk in Japan: A meta-analysis of six prospective cohort studies. Nagoya Journal of Medical Science, 81(1), 143–150.

    Google Scholar 

  49. Tran, K. T., Coleman, H. G., McMenamin, Ú., & Cardwell, C. R. (2019). Coffee consumption by type and risk of digestive cancer: A large prospective cohort study. British Journal of Cancer, 120(11), 1059–1066.

    Google Scholar 

  50. Tamura, T., Wada, K., Konishi, K., et al. (2018). Coffee, green tea, and caffeine intake and liver cancer risk: A prospective cohort study. Nutrition and Cancer, 70(8), 1210–1216.

    CAS  Google Scholar 

  51. Wiltberger, G., Wu, Y., Lange, U., et al. (2019). Protective effects of coffee consumption following liver transplantation for hepatocellular carcinoma in cirrhosis. Alimentary Pharmacology & Therapeutics, 49(6), 779–788.

    CAS  Google Scholar 

  52. Bimonte, S., Albino, V., Piccirillo, M., et al. (2019). Epigallocatechin-3-gallate in the prevention and treatment of hepatocellular carcinoma: Experimental findings and translational perspectives. Drug Design, Development and Therapy, 13, 611–621.

    CAS  Google Scholar 

  53. Soundararajan, P., & Kim, J. S. (2018). Anti-carcinogenic glucosinolates in cruciferous vegetables and their antagonistic effects on prevention of cancers. Molecules, 23(11), E2983. https://doi.org/10.3390/molecules23112983.

    Article  CAS  Google Scholar 

  54. Pocasap, P., Weerapreeyakul, N., & Thumanu, K. (2019). Alyssin and iberin in cruciferous vegetables exert anticancer activity in HepG2 by increasing intracellular reactive oxygen species and tubulin depolymerization. Biomolecules & Therapeutics (Seoul)., 27(6), 540–552.

    Google Scholar 

Download references

Acknowledgements

Author Contributions: Dr. Hammad Zafar conceived the idea and subsequently all the authors have diligently contributed to the development and preparation of this research manuscript (book chapter), including the literature search, concept organization, data interpretation, and writings. All the authors have read and approved the final draft for publication.

Conflict of Interest: The authors declare that they have no conflicts of interest associated with this book chapter.

Financial Disclosures: None to disclose.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, AdventHealth, Orlando, FL, USA

    Hammad Zafar, Mamoon Ur Rashid, Deepika Sarvepalli, Bayarmaa Mandzhieva, Akriti Gupta Jain, Rima Shobar & Anum Jalil

  2. Khyber Teaching Hospital, Peshawar, Khyber Pakhtunkhwa, Pakistan

    Muzammil Muhammad Khan

  3. AdventHealth Cancer Institute and FSU and UCF Colleges of Medicine, Orlando, FL, USA

    Sarfraz Ahmad

Authors
  1. Hammad Zafar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mamoon Ur Rashid
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Deepika Sarvepalli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Muzammil Muhammad Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bayarmaa Mandzhieva
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akriti Gupta Jain
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Rima Shobar
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Anum Jalil
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sarfraz Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hammad Zafar .

Editor information

Editors and Affiliations

  1. Winship Cancer Institute, Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA

    Ganji Purnachandra Nagaraju

Rights and permissions

Reprints and permissions

Copyright information

© 2020 The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Zafar, H. et al. (2020). Emerging Roles of Phytochemicals in Hepatocellular Carcinoma. In: Nagaraju, G.P. (eds) Phytochemicals Targeting Tumor Microenvironment in Gastrointestinal Cancers. Springer, Cham. https://doi.org/10.1007/978-3-030-48405-7_13

Download citation

Publish with us

Policies and ethics

Search

Navigation