Review
Challenges in liver cancer and possible treatment approaches

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Abstract

Globally, liver cancer is the most frequent fatal malignancy; in the United States, it ranks fifth. Patients are often diagnosed with liver cancer in advanced stages, contributing to its poor prognosis. Of all liver cancer cases, >90% are hepatocellular carcinomas (HCCs) for which chemotherapy and immunotherapy are the best options for therapy. For liver cancer patients, new treatment options are necessary. Use of natural compounds and/or nanotechnology may provide patients with better outcomes with lower systemic toxicity and fewer side effects. Improved treatments can lead to better prognoses. Finally, in this review, we present some of the problems and current treatment options contributing to the poor outcomes for patients with liver cancer.

Introduction

As the most frequent cause of cancer deaths across the globe and fifth most common in the United States, liver cancer is the only one of the top five deadliest cancers to have an annual percentage increase in occurrence [1]. Developing countries have more incidence of liver diseases [2]. Risk factors include hepatitis B virus, hepatitis C virus, fatty liver disease, alcohol-related cirrhosis, smoking, obesity, diabetes, iron overload, and various dietary exposures [3]. The prognosis for liver cancer is poor. Only 5% to 15% of patients are eligible for surgical removal, which is suitable only for early-stage patients and due to diminished hepatic regenerative capacity, typically without cirrhosis; right hepatectomy carry a higher risk for post-operative complications compared to left hepatectomy. Treatment options for more advanced stages include the following: (a) Trans-arterial chemoembolization (TACE), which leads to a 23% improvement in the 2-year survival in comparison to conservative therapy for intermediate stage HCC patients. (b) Oral dosing with sorafenib, a kinase inhibitor and the most accepted option for late-stage cases. However, fewer than one-third of patients benefit from the treatment, and drug resistance is evident within six months of initiating the regimen [4]. With long-term use, chemotherapeutic drugs, such as sorafenib, have additional issues such as toxicity and/or drug inefficacy. As a result, neither current ablation therapies nor chemotherapy is appreciably effective in improving outcomes of this devastating disease. Further research to find better methods for treating liver cancer are necessary.

Prevention, development, progression, and treatment of cancers is associated with the diet of patients. A European study showed that a higher dietary intake of fruits and vegetables is associated with a lower risk of cancer development [5]. Diverse natural compounds in fruits, vegetables, and spices function in suppressing mechanisms that are involved in development of cancers, and they stimulate mechanisms that are associated with prevention of the disease. These compounds activate anti-tumor, anti-proliferative, anti-inflammatory, and anti-oxidant systems that may provide therapeutic options for new cancer treatment regimens [[6], [7], [8]]. Some compounds demonstrate selectivity in causing cytotoxicity to cancer cells, leaving non-cancerous cells unaffected [9]. For instance, compounds such as piperine, inhibit enzymes necessary for drug metabolism, which may indicate a future use of co-administration with current or potential chemotherapeutic drugs to increase plasma concentrations [10]. Other natural compounds may enhance the efficacy of current drug regimens without increasing host toxicity. As an example, for H22 cells, polysaccharides from Lentinus edodes and Tricholoma matsutake enhance the inhibitory effect of 5-fluorouracil (5-FU) [11].

The immune system is commonly involved in killing cancer cells. In this process, antigen-presenting cells present the peptides of tumor fragments to class I and II major histocompatibility complex (MHC) molecules. However, this mechanism may be ineffective due to the capacity of malignancies to evade these functions [12,13]. Moreover, biomarkers of tumor growth and desmoplasia can be targeted to prevent tumor progression [14]. With chemotherapeutic agents, multidrug resistance is an issue. Cancer stem-like cells/cancer-initiating cells are responsible for resistance, providing a pathway for tumor recurrence and metastasis. Immunotherapy helps fight resistance to common chemotherapies by targeting stem cells [15]. Other useful approaches, through immune checkpoint inhibitors, such as PD-1 and PD-L1 targeting, and cancer vaccines hinder cancer progression and kill cancer cells. Sorafenib prevents immunosuppression, giving reason to consider combination therapy with this drug [16,17].

Nanotechnology, which may be utilized to create or enhance treatments that lead to better results for neoplasms, can improve the activity of minimally effective drugs in targeting and killing cancer cells. This is accomplished by optimizing the size and surface properties of drugs and/or utilizing tissue-specific homing devices to target sites that lower the likelihood of systemic toxicity and side-effects [18]. Nanotechnology may alter current combination therapy approaches and improve permeability, retention, and pharmacokinetic profiles, and thereby reduce side effects [19,20]. Nanoparticle techniques provide a promising future through treatment programs that combine separate agents to improve the effects of drugs [21,22].

The poor prognosis for liver cancer leads scientists and physicians to search for novel treatment options to improve patient survival. Combining medications and altering drug administration/delivery methods give new horizons to improving the outcomes for malignancies. In this study, we describe some of the most common agents used for treatment of advanced HCCs, including natural compounds, chemotherapies, immunotherapies, and nanoparticles, and the rationale behind some current clinical trials.

Section snippets

Natural compounds and their outcomes in liver cancer

Piperine, an alkaloid extracted from black and long peppers, has anti-tumor, anti-mutagenic, anti-oxidant, and anti-proliferative activities [23]. It lowers lipid peroxidation and inhibits enzymes involved in drug metabolism, such as aryl hydrocarbon hydroxylase and UDP-glucuronyl transferase, which increase the bioavailability of drugs and phytochemicals [24]. It also improves intestinal absorption upon interaction with the lipid environment of the gut [25].

Drug resistance is an issue for a

Chemotherapy for treating liver cancer

Oral administration of the multi-kinase inhibitor, sorafenib, is recommended worldwide as the first-line therapy for advanced stages of HCC supported by the results of several trials [48,49]. This clinically approved drug suppresses tumor angiogenesis, cell division, and proliferation through inhibition of the MAP kinase cascade, and it induces apoptosis of cancer cells. Proteins inhibited by sorafenib include serine-threonine kinase Raf-1, platelet-derived growth factor receptor-β, c-KIT,

Immunotherapy for liver cancer

Cancers can be treated by modifying the immune systems of patients so that they recognize specific antigens on cancer cells, by enhancing immune activity through blocking immune checkpoints responsible for immunosuppressive signaling, by cancer vaccines to prevent infection or inflammatory responses, and by non-specific cancer immunotherapies that provide a general boost to the immune system. In 2013, this field of research was selected as the Advance of the Year by the American Society of

Nanotechnology based approaches for treating liver cancer

Nanotechnology has allowed scientists to improve the effectiveness of drugs in treating liver cancers. This is accomplished by utilizing various nanocarrier-based drug delivery systems that, in turn, allow for decreases in the amounts of drug necessary to elevate the therapeutic index, lower occurrences of systematic toxicity, extended release of the medication for days after a single administration, and enhanced selective targeting of liver cancer cells. An in vitro study utilized luminescent,

Conclusion

In some countries, there has been an improvement in the survival rates for patients with liver cancer [86]. Improvements in HCC patient outcomes are attributed to clinical trials optimizing individual treatment strategies and to the development of more complex therapeutic modalities. Constant development of new techniques and new drugs is providing hope of further advances. Given the various treatment options now available, including natural compounds, chemotherapeutics, immunotherapies, and

Declaration of Competing Interest

All authors have no conflict of interest to disclose.

Acknowledgments

This work was supported by the National Institute of Health [Award Numbers SC1CA193758; U54CA118638]; and from the Department of defense [Award Number W81XWH1810429].

References (86)

  • V. Gunasekaran et al.

    Targeting hepatocellular carcinoma with piperine by radical-mediated mitochondrial pathway of apoptosis: an in vitro and in vivo study

    Food Chem. Toxicol.

    (2017)
  • J. Singh et al.

    Piperine, a major ingredient of black and long peppers, protects against AFB1-induced cytotoxicity and micronuclei formation in H4IIEC3 rat hepatoma cells

    Cancer Lett.

    (1994)
  • V. Patial et al.

    Synergistic effect of curcumin and piperine in suppression of DENA-induced hepatocellular carcinoma in rats

    Environ. Toxicol. Pharmacol.

    (2015)
  • B. Polini et al.

    Oleocanthal and oleacein contribute to the in vitro therapeutic potential of extra virgin oil-derived extracts in non-melanoma skin cancer

    Toxicol. in Vitro

    (2018)
  • J.B. Jeong et al.

    Protective effect of the extracts from Cnidium officinale against oxidative damage induced by hydrogen peroxide via antioxidant effect

    Food Chem. Toxicol.

    (2009)
  • Z.Y. Cheng et al.

    Phenylpropanoids from Juglans mandshurica exhibit cytotoxicities on liver cancer cell lines through apoptosis induction

    Bioorg. Med. Chem. Lett.

    (2017)
  • S. Jelic et al.

    Hepatocellular carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up

    Ann. Oncol.

    (2010)
  • J. Bruix et al.

    Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial

    J. Hepatol.

    (2012)
  • A.L. Cheng et al.

    Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial

    Lancet Oncol.

    (2009)
  • H. Richly et al.

    Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial

    Eur. J. Cancer

    (2009)
  • T.F. Greten et al.

    Targets for immunotherapy of liver cancer

    J. Hepatol.

    (2018)
  • F.S. Hodi et al.

    Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial

    Lancet Oncol.

    (2018)
  • F. Ballout et al.

    Thymoquinone-based nanotechnology for cancer therapy: promises and challenges

    Drug Discov. Today

    (2018)
  • M. Saraswathy et al.

    Different strategies to overcome multidrug resistance in cancer

    Biotechnol. Adv.

    (2013)
  • R.L. Siegel et al.

    Cancer statistics, 2019

    CA Cancer J. Clin.

    (2019)
  • B.Q. Starley et al.

    Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection

    Hepatology (Baltimore, Md.)

    (2010)
  • M.M. Center et al.

    International trends in liver cancer incidence rates

    Cancer Epidemiol. Biomark. Prev.

    (2011)
  • S. Banerjee et al.

    Combinatorial effect of curcumin with docetaxel modulates apoptotic and cell survival molecules in prostate cancer

    Front. Biosci (Elite Ed)

    (2017)
  • S.K. Singh et al.

    Resveratrol induces cell cycle arrest and apoptosis with docetaxel in prostate cancer cells via a p53/p21WAF1/CIP1 and p27KIP1 pathway

    Oncotarget

    (2017)
  • R.K. Bhardwaj et al.

    Piperine, a major constituent of black pepper, inhibits human P-glycoprotein and CYP3A4

    J. Pharmacol. Exp. Ther.

    (2002)
  • T. Boon et al.

    Human T cell responses against melanoma

    Annu. Rev. Immunol.

    (2006)
  • Y. Chen et al.

    Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice

    Hepatology (Baltimore, Md.)

    (2014)
  • Q.Z. Pan et al.

    Annexin A3 as a potential target for immunotherapy of liver cancer stem-like cells

    Stem Cells

    (2015)
  • M. Kudo

    Immune checkpoint blockade in hepatocellular carcinoma: 2017 update

    Liver Cancer

    (2016)
  • X. Zhao et al.

    Codelivery of doxorubicin and curcumin with lipid nanoparticles results in improved efficacy of chemotherapy in liver cancer

    Int. J. Nanomedicine

    (2015)
  • S.K. Singh et al.

    Drug delivery approaches for breast cancer

    Int. J. Nanomedicine

    (2017)
  • M.E. Davis et al.

    Nanoparticle therapeutics: an emerging treatment modality for cancer

    Nat. Rev. Drug Discov.

    (2008)
  • A. Tawani et al.

    Evidences for Piperine inhibiting cancer by targeting human G-quadruplex DNA sequences

    Sci. Rep.

    (2016)
  • K. Srinivasan

    Black pepper and its pungent principle-piperine: a review of diverse physiological effects

    Crit. Rev. Food Sci. Nutr.

    (2007)
  • S.C. Gupta et al.

    Therapeutic roles of curcumin: lessons learned from clinical trials

    AAPS J.

    (2013)
  • K.L. Pang et al.

    The biological activities of Oleocanthal from a molecular perspective

    Nutrients

    (2018)
  • A. Bishayee

    The role of inflammation and liver cancer

    Adv. Exp. Med. Biol.

    (2014)
  • H. Koga et al.

    Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation

    Hepatology (Baltimore, Md.)

    (1999)
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