Understanding Liver Cancer

compiled by John G. Connor, M.Ac., L.Ac. edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
 
Introduction
Research on Natural Compounds which may have Specific Application to Liver Cancer      
References

Introduction
Hepatocellular carcinoma (HCC) is one of the most frequent tumor types worldwide. It is the fifth most common cancer and the third leading cause of cancer death. (El-Serag & Rudolph 2007)

The incidence of HCC is predicted to increase over the next several decades as survival in patients with predisposing diseases, such as cirrhosis, is expected to increase over time. (El-Serag, 2002; Marrero, 2006).

Primary hepatocellular carcinoma can be found most frequently (80-90 %) in patients with liver cirrhosis. The most frequent causes of liver cirrhosis are chronic hepatitis B and C virus infections and chronic alcohol consumption. The occurrence of hepatocellular carcinoma is about 3-15 % in patients with alcoholic liver disease. Other predisposing causes can be: non-alcoholic steatohepatitis (NASH), obesity, diabetes mellitus, autoimmune hepatitis, intrahepatic biliary inflammations (primary biliary cirrhosis, primary sclerosing cholangitis), copper and iron metabolic diseases (Wilson-disease, haemochromatosis), congenital alpha-1-antitripsin deficiency. Other pathogenic factors are smoking, and different chemical agents. (Feher and Lengyet 2010)

Surgical resection, in the form of partial hepatectomy or total hepatectomy followed by liver transplantation, is the only curative option, but only 10–30% of patients are candidates for surgery at the time of presentation, due to either poor hepatic reserve or the presence of unresectable or metastatic disease. Attesting to the aggressive nature of this disease, the five-year survival is only 15–40% after curative resection. Conventional chemotherapy is largely ineffective for this disease, with response rates of only 20% and no improvement in survival. Therefore, there is a pressing need for the development of new therapeutic approaches for advanced HCC. (Ning et al 2009)

In advanced HCC, cancer cells do not respond to the cytotoxic effects of most of the available chemotherapeutic agents. Therefore, there is a pressing need to identify alternative chemotherapeutic strategies that circumvent these limitations. Phytochemicals show promise in this area because of both their potential as chemopreventive agents and their chemotherapeutic activities against HCC in experimental studies. (Huo et al 2008)

We need to be thinking about targeting a biological network, not just a single molecule.  Any time you put pressure on cells and their dynamic signaling networks, you are inevitably challenging them to get around the problem they are experiencing.  We need to be smart up front and know how these cells will respond to a drug challenge, and the dominant resistance mechanisms. (Weiner et al 2010)

Research on Natural Compounds which may have Specific Application to 
Liver Cancer Cell Lines 
·  Anthocyanidins
· Artemisinin
·  Asparagus racemosus
·  Bacopa
·  Baicalein & Silymarin
·  Boswellic acids
· Curcumin
· Epicatechin
· Ganoderma lucidum
· Ginger
· Ginkgo
· Pterostilbene
· Quercetin
·   Resveratrol
·   Rosemary
·
  Salvia miltiorrhiza
·   Scutellaria barbate
·    Silymarin
·    Sulforaphane
·    Ursolic acid
·    Viscum album

Anthocyanidins such as delphinidin – are reddish pigments widely distributed in fruit and vegetables. Induction of apoptosis by anthocyanidins is a pivotal mechanism of their cancer chemopreventive functions. (Yeh & Yen 2005)

Artemisinin – ART (artemisinin) and DHA (dihydroartemesinin) have significant anticancer effects against human hepatoma cells, regardless of p53 status, with minimal effects on normal cells, indicating that they are promising therapeutics for human hepatoma used alone or in combination with other therapies. ART and DHA exerted the greatest cytotoxicity to hepatoma cells but significantly lower cytotoxicity to normal liver cells. The compounds inhibited cell proliferation, induced G(1)-phase arrest, decreased the levels of cyclin D1, cyclin E, cyclin-dependent kinase 2, cyclin-dependent kinase 4, and E2F1, and increased the levels of Cip1/p21 and Kip1/p27. They induced apoptosis, activated caspase-3, increased the Bax/Bcl-2 ratio and poly(ADP-ribose) polymerase, and down-regulated MDM2.  (Hou et al 2008)

Asparagus racemosus (Shatavari) – These results prove that the aqueous extract of the roots of Asparagus racemosus has the potential to act as an effective formulation to prevent hepatocarcinogenesis induced by treatment with DEN. (Agarwal et al 2008)

Bacopa monniera – Bacoside A (the active constituent of Bacopa monniera) is effective to prevent DEN-induced hepatocellular carcinoma. (Janani et al 2010)

Baicalein & Silymarin – The combination of baicalein and silymarin eradicates tumor cells efficiently, has minimal deleterious effects to the surrounding normal cells, and offers mechanistic insight for further exploitation of HCC treatment. (Chen et al 2009)

Boswellic acids – have anti-proliferation and anti-cancer effects on Hep G2 cells. The apoptotic effect is mediated by a pathway dependent on caspase-8 activation. The acids may be a promising drug for the chemoprevention of liver cancer. (Liu et al 2002)

Curcumin – Treatment with curcumin resulted in a 40% decrease in tumor growth in vivo. These results suggest for the first time that down-regulation of Notch1 signaling with curcumin is an attractive new therapeutic strategy for the treatment of patients with HCC.  (Ning et al 2009) To study the anticancer activities of curcumin on human hepatocarcinoma cell line Sk-hep-1 we showed that curcumin inhibited proliferation of Sk-hep-1 cells in a dose-dependent manner. (Wang et al 2010)

Epicatechin – induces NF-kappaB, activator protein-1 (AP-1) and nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2) via phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and extracellular regulated kinase (ERK) signalling in HepG2 cells. (Granada-Serrano et al 2010)

Ganoderma lucidum – The treatment of mitogen-activated protein kinase (MEK) inhibitors (PD98059 and U0126) and Lucidenic acid (an isolate of G. lucidum) to HepG(2) cells could result in a synergistic reduction on the MMP-9 expression along with an inhibition on cell invasion. Moreover, Lucidenic acid also strongly inhibited PMA-stimulated nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA-binding activities of HepG(2) cells. (Weng et al 2008)

Ginger – The aims of this study were to evaluate the anti-invasion activity of 6-shogaol and 6-gingerol, two compounds found in ginger, on hepatoma cells.  These results suggest that 6-shogaol and 6-gingerol might both exert anti-invasive activity against hepatoma cells through regulation of MMP-9 and TIMP-1 and that 6-shogaol could further regulate urokinase-type plasminogen activity. (Weng et al 2010)

Ginkgo biloba – presented inhibitory actions during initiation but not promotion of rat liver carcinogenesis induced by DEN. (Dias 2008)

Pterostilbene – Pterostilbene inhibits tumor invasion via suppressing multiple signal transduction pathways – NF-kappaB, AP-1, p38MAPK and MMP-9 – in human hepatocellular carcinoma cells. (Pan et al 2009)

Quercetin –
These data suggest that NF-kappa B and AP-1 play a main role in the tight regulation of survival/proliferation pathways exerted by quercetin and that the sustained JNK/AP-1 activation and inhibition of NF-kappa B provoked by the flavonoid quercetin induced HepG2 death. (Granado-Serrano et al 2010)

Resveratrol – significantly suppressed TNF-alpha-mediated NF-kappa B expression and invasion of HepG2 cells. Our results showed that resveratrol inhibited TNF-alpha-mediated MMP-9 expression and invasion of human hepatocellular carcinoma cells. The inhibitory effects are partly associated with the downregulation of the NF-kappa B signaling pathway. (Yu et al 2008)

Rosemary –
Essential oils from Rosmarinus officinalis can affect the pattern of Bcl-2 and bax genes expressions, and this may increase the apoptosis of liver cancer cell line HepG2 (Wei et al 2008)


Salvia miltiorrhiza –
Nontoxic herbal compound extract “Songyou Yin” (which contains Salvia miltiorrhiza and 4 other herbs) inhibited tumor growth and prolonged survival, via inducing apoptosis and down-regulation of MMP2 and VEGF, which indicated its potential use in patients with advanced HCC. (Huang et al 2009)


Scutellaria barbate –
MTT assay showed that extracts from S. barbata (ESB) could inhibit the proliferation of hepatoma H22 cells in a time-dependent manner. (Dai et al 2008)


Silymarin –
One study demonstrated that silymarin treatment inhibited proliferation and induced apoptosis in the human hepatocellular carcinoma cell line HepG2. (Ramakrishnan 2009) In another study, silibinin was found to inhibit hypoxia-induced HIF-1alpha accumulation and HIF-1 transcriptional activity in human cervical (HeLa) and hepatoma (Hep3B) cells. (Garcia-Maceira & Mateo 2009)  

Sulforaphane – At a higher concentration, sulforaphane is an effective apoptosis inducer in HepG(2) cells through regulation of Bcl-2. (Yeh & Yen 2005)


Ursolic acid –
has been found to be a potent antioxidant and it can be suggested as an excellent chemopreventive agent in overcoming a disease like hepatocarcinogenesis in vivo which is mediated by free radicals. (Gayathri et al 2009)


Viscum album L (extract of Mistletoe) –
induced apoptosis in both SK-Hep-1 (p53-positive) and Hep 3B (p53-negative) cells through p53- and p21-independent pathways. Viscum album l. (VCA) induced apoptosis by down-regulation of Bcl-2 and by up-regulation of Bax functioning upstream of caspase-3 in both cell lines. In addition, we observed down-regulation of telomerase activity in both VCA-treated cells. Our results provide direct evidence of the anti-tumor potential of this biological response which comes from inhibition of telomerase and consequent inducing apoptosis. (Lyu et al 2002)

Viscum album (Mistletoe lectin) – induces apoptosis and telomerase inhibition in human A253 hepatoma cancer cells through dephosphorylation of Akt. (Choi et al 2004)

References

Bagchi, Debasis & Harry G. Preuss, Phytopharmaceuticals in Cancer Chemoprevention, CRC Press, Boca Raton, 2005

Beckett, Geoffrey, Simon Walker, Peter Rae & Peter Ashby, Lecture Notes – Clinical Biochemistry, 8th edition, Wiley-Blackwell, Oxford,  2010
 
Boik, John, Natural Compounds in Cancer Therapy, Oregon Medical Press, Princeton, MN, 2001
 
Boik, John, Cancer & Natural Medicine, A Textbook of Basic Science and Clinical Research, Oregon Medical Press, Princeton, MN, 1996

Chernecky, Cynthia C, and Barbara J. Berger, Laboratory Tests and Diagnostic Procedures, Saunders, St. Louis, 2008

Heber, David, Editor-in –Chief, Nutritional Oncology, Second Edition, Academic Press, London, 2006

McKenna, Dennis J., PhD,  Kenneth Hones & Kerry Hughes, Botanical Medicines, The Desk Reference for Major Herbal Supplements, Second Edition, The Haworth Herbal Press, New York, 2002

Neal, Michael J., Medical Pharmacology at a Glance, Sixth edition, Wiley-Blackwell, Oxford, 2009

Stargrove, Mitchell, Jonathan Treasure & Dwight L. McKee, Herb, Nutrient, and Drug Interactions, Mosby Elsevier, St. Louis,  2008

Weiss, Rudolf, MD & Volker Fintelmann, MF, Herbal Medicine, Thieme, New York, 2000

Yance, Donald, “Donald Yance’s Eclectic Triphasic Medical System (ETMS): An Integrative Wholistic Approach to Treating and Preventing Cancer”, (Monograph) 2010

Yance, Donald, Herbal Medicine, Healing & Cancer, Keats Publishing, Lincolnwood (Chicago) IL, 1999


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