ReviewChallenges in liver cancer and possible treatment approaches
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].
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These authors contribute equally to this work.