Poliphenol Hepatoma 62 1091 1 PB
Poliphenol Hepatoma 62 1091 1 PB
Poliphenol Hepatoma 62 1091 1 PB
MINI REVIEW
Abstract
Plant polyphenols are secondary metabolites, primarily
synthesized to protect plants from biotic and abiotic
stresses. These compounds are found in fruits, vegetables
and beverages and are an important part of the human
diet. Plant derived polyphenols have been described as
antioxidant, antimicrobial and anticarcinogenic agents.
Human hepatocellular carcinoma is one of the most
common types of cancer worldwide and it is associated to
high mortality. The development of new treatments for
hepatocarcinoma is needed, and plant polyphenols
appear as a promising important source of compounds
for prevention and treatment of this disease. The aim of
this article is to review the current knowledge about the
use of plant polyphenolic extracts as potential agents for
the treatment of human hepatocellular carcinoma.
ISSN: 2348-1900
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These treatments are expected to improve patients
survival, but they are only applicable to a small proportion
of them with early tumors (Pang et al., 2006). Palliative
treatments, as chemoembolisation, are applied to patients
with advanced HCC (Llovet, Burroughs, & Bruix 2003).
Although actually sorafenib (a multikinase inhibitor) or
hepatic artery infusion chemotherapy are available
treatments, the life expectancy of the treated patients
remains low and persons with a late HCC diagnosis have
very poor possibilities (Song & Bae, 2014; Rasool et al.,
2014).
In this scenario, new antitumoral drugs are really
needed, appearing natural compounds as an important
source of new molecules to be used for the prevention and
treatment of HCC. In consequence, many researchers are
focused on the investigation of the antitumoral activity of
natural polyphenols. The main objective of this article is to
summarize the current knowledge about the in vitro and in
vivo antitumoral activity of natural polyphenolic extracts
(PE), as potential human antihepatocarcinoma agents.
Natural Polyphenolic Extracts: Biologic activity in
human hepatocarcinoma in vitro and in vivo models
Plant polyphenols activity has been largely studied
against several types of human cancers such as colon,
prostate and breast (Nzaramba, Reddivari, Bamberg, &
Miller Jr, 2009; Thakur, Gupta, & Gupta, 2012; Sahpazidou
et al., 2014). In the particular case of HCC, there are a great
number of publications about different effects of
polyphenols against this disease. This anti human
hepatocarcinoma activity has been described for several
PE from commonly consumed fruits, vegetables and
beverages (Sun, Chu, Wu, & Liu, 2002; Chu, Sun, Wu & Liu,
2002; Ramos et al., 2005; Wang et al., 2011); but also, for
many autochthonous herbs used in traditional medicine
(Naowaratwattana, De-Eknamkul, & De Mejia, 2010;
Sawadogo, Schumacher, Teiten, Dicato, & Diederich, 2012;
Sakulnarmrat, Fenech, Thomas, & Konczak, 2013). Tables
(supplementary material) summarize the biological
activity of a variety of PE in different in vitro (Table 1) or in
vivo (Table 2) models and the solvents used for extractions
of the phenolic compounds.
1. In vitro assay
In vitro assays using the human hepatocarcinoma cell
line HepG2, showed that PE from vegetables consumed
worldwide (broccoli, spinach, carrot, potato and lettuce)
exerted significant cytotoxic activity after a 96 hours
treatment (Chu et al., 2002; Wang et al., 2011). Treatments
with PE from different kinds of fruits, such as strawberries
and plums, were also tested as anti-HCC agents. These PE
produced an inhibition of HepG2 cells proliferation,
possibly through the activation of apoptosis (Ramos et al.,
2005). Naowaratwattana et al. (2010), investigated the
effect of four different mulberry extracts (aqueous, 100%
215
216
Asmah (2004) studied the effect of other commonly
consumed beverage extracts in rats with induced
hepatocarcinoma. The treatment with Cacao liqueur
extracts (CLE) of tumor induced in Sprague Dawley rats,
resulted in a reduction of tumor marker enzymes in
plasma and liver. This finding suggests that CLE may have
a
potential
effect
in
reducing
severity
of
hepatocarcinogenesis.
Conclusions
The evidences summarized in this article from in vivo
and in vitro studies demonstrate that plant polyphenols
are a promising good source to find new candidate
molecules to be used for the prevention and treatment of
HCC. Although, more in vivo experiments are needed to
completely understand the mechanisms of action of these
compounds in the inhibition of HCC. Also, it is extremely
important to study and consider the bioavailability and
stability of these compounds once they are absorbed in
vivo. This would help to estimate, for example the daily
consumption needed of certain food to exert their
preventive effect or the necessary doses of polyphenolic
compounds to act as antiHCC agents.
Another important aspect to consider is that
polyphenolic extracts are a mixture of different molecules.
Although, many studies are conducted to isolate and
characterize the active compound responsible for the
biological activity of the polyphenolic extract, it is
necessary to consider that whole extracts may act
synergically, being involved in the modulation of multiple
intracellular pathways. As hepatocellular carcinoma is a
complex disease, with multiple molecular mechanisms
involved in its development, polyphenolic extracts would
provide a wide spectrum of compounds capable of
targeting different molecular pathways for treatment.
References
Amin, I., Koh, B.K., Asmah, R. (2004). Effect of Cacao liquior
extract on tumor marker enzymes during chemical
hepatocarcinogenesis in rats. Journal of medicinal food, 7:
7-12. http://dx.doi.org/10.1089/109662004322984635,
PMID: 15117546.
Banjerdpongchai, R., Wudtiwai, B., Sringarm, K. (2013). Cytotoxic
and apoptotic inducing effects of purple rice extracts and
chemotherapeutic drugs on human cancer cell lines. Asian
Pacific Journal of Cancer Prevention, 14: 6541-6548. PMID:
24377565.
Byambaragchaa, M., de la Cruz, J.,Yang, S.H., Hwang, S.G. (2013).
Antimetastatic potential of etanol extract of Saussurea
involucrata against hepatic cncer in vitro. Asian Pac J
Cancer Prev., 14: 5397-402, PMID: 24175833.
Chu, Y.F., Sun, J., Wu, X., Liu, R.H. (2002). Antioxidant and
antiproliferative activities of common vegetables. Journal of
agricultural and food chemistry. 50: 6910-6916.
http://dx.doi.org/10.1021/jf020665f, PMID: 12405796.
Daglia, M. (2012). Polyphenols as antimicrobial agents. Current
Opinion
in
Biotechnology,
23:174-181.
Horizon e-Publishing Group
PMID:
D' Archivio, M., Filesi, C., Di Benedetto, R., Gargiulo, C.G., Masella,
R. (2007). Polyphenols, dietary sources and bioavailability.
Ann Ist super Sanit, 43: 348-361, PMID: 18209268.
Darvesh, A.S., Bishayee, A. (2013). Chemopreventive and
therapeutic potential of tea polyphenols in hepatocellular
cancer.
Nutrition
and
Cancer,
65:
329-344.
http://dx.doi.org/10.1080/01635581.2013.767367, PMID:
23530632.
Feitelson, M.A., Sun, B., Tufan, N.L.S., Liu, J., Pan, J., Lian, Z. (2002).
Genetic mechanisms of hepatocarcinogenesis. Oncogene, 21:
2593-2604. http://dx.doi.org/10.1038/sj/onc/1205434, PMID:
11971194.
Freise, C., Ruehl, M., Erben, U., Neumann, U., Seehofer, D., Kim,
K.Y., ... Somasundaram, R. (2011). A hepatoprotective
Lindera obtusiloba extract suppresses growth and
attenuates insulin like growth factor 1 receptor signaling
and NF-kappaB activity in human liver cancer cell line. BMC
Complement
Altern
Med.,11:
39.
http://dx.doi.org/10.1186/1472-6882-11-39,
PMID:
21569410.
Gonzalez de Mejia, E., Ramirez-Mares, M.V., Arce-Popoca, E.,
Walling, M., Villa-Trevio, S. (2004). Inhibition of liver
carcionogenesis in Wistar rats by consumption of an
aqueous extract from leaves of Ardisia compressa. Food
and
Chemical
Toxicology,
42:
509-516.
http://dx.doi.org/10.1016/j.fct.2003.10.016,
PMID:
14871594.
Gul, M.Z., Ahmad, F., Kondapi, A.K., Qureshi, I.A., Ghazi, I.A. (2013).
Antioxidant and antiproliferative activities of Abrus
precatorius leaf extracts an in vitro study. Complementary
and
alternative
medicine,
13.
http://dx.doi.org/10.1186/1472-6882-13-53,
PMID:
23452983.
Hong, S.W., Jung, K.H., Lee, H.S., Choi, M.J.,Zheng, H.M., Son, M.K., ...
Hong, S.S. (2012). Apoptotic and antiangiogenic effects of
Pulsatilla koreana extract on hepatocellular carcinoma. Int J
Oncol.
40:
452-60.
http://dx.doi.org/10.3892/ijo.2011.1204, PMID: 2193557.
Hsu, S.C., Kuo, C.L., Lin, J.P., Lee, J.H., Lin, C.C., Su, C.C., ... Chung, J.G.
(2007). Crude extracts of Euchresta formosanaradix induce
cytotoxicity and apoptosis in human hepatocellular
carcinoma cell line (Hep3B). Anticancer Res. 27: 2415-25,
PMID: 17695533.
Hyun, T.K., Kim, M.O., Lee, H., Kim, Y., Kim, E., Kim, J.S. (2013).
Evaluation of anti-oxidant and anti-cancer properties of
Dendropanax morbifera Lveille. Food Chem. 141: 1947-55.
http://dx.doi.org/10.1016/j.foodchem.2013.05.021,
PMID:
23870914.
Jin, X., Zheng, R., Li, Y. (2008). Green tea consumption and liver disease:
a systematic review. Liver international, 28: 990-996.
http://dx.doi.org/10.1111/j.1478-3231.2008.01776.x, PMID:
18482271.
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. Oncol Rep. 28: 1757-63.
http://dx.doi.org/10.3892/or.2012.1985, PMID:22923154.
Kim, H.S., Quon, M.J., Kim, J. (2014). New insights into the
mechanisms of polyphenols beyond antioxidant properties;
lessons
from
the
green
tea
polyphenols,
ISSN: 2348-1900
217
ISSN: 2348-1900
http://dx.doi.org/10.1089/jmf.2010.1021,
PMID:
20828312.
Newell, A.M.B., Yousef, G.G., Lila, M.A., Ramirez-Mares, M.V.
(2010). Comparative in vitro bioactivities of tes extracts
from six species of Ardisia and their effect on growth
inhibition of HepG2 cells. Journal of ethnopharmacology,
130: 536-544. doi:10.1016/j.jep.2010.05.051, PMID:
20561930.
Nzaramba, M.N., Reddivari, L., Bamberg, J.B., Miller Jr, J.C. (2009).
Antiproliferative activity and cytotoxicity of Solanum
jamessi tuber extracts on human colon and prostate cancer
cells in vitro. Journal of agricultural and food chemistry, 57:
8308- 8315. http://dx.doi.org/10.1021/jf901567k, PMID:
19711917.
Oboh, G., Agunloye, O.M., Akinyemi, A.J., Ademiluyi, A.O.,
Adefegha, S.A. (2012). Comparative study on the inhibitory
effect of caffeic and chlorogenic acids on key enzymes
linked to Alzheimer's disease and some pro-oxidant
induced oxidative stress in rats brain in vitro. Neurochem
Res 38, 2: 413-419. doi:10.1007/s11064-012-0935-6,
PMID:23184188.
Okuda, K. (2000). Hepatocellular carcinoma.
Hepatology, 32, 225-237. PMID: 10728807.
Journal
of
218
Sakulnarmrat, K., Fenech, M., Thomas, P., Konczak, I. (2013).
Cytoprotective and pro-apoptotic activities of native Australian
herbs polyphenolic-rich extracts. Food Chem.136: 9-17.
http://dx.doi.org/10.1016/j.foodchem.2012.07.089,
PMID:
23017386.
Sawadogo, W.R., Schumacher, M., Teiten, M.H., Dicato, M.,
Diederich, M. (2012). Traditional West African
pharmacopeia, plants and derived compounds for cancer
therapy. Biochemical Pharmacology, 84: 1225-1240. doi
:10.1016/j.bcp.2012.07.021, PMID: 22846603.
Shin, D.Y., Ryu, C.H., Lee, W.S., Kim, D.C., Kim, S.H., Hah, Y.S., Lee,
S.J., Shin, S.C., Kang, H.S., Choi, Y.H. (2009). Induction of
apoptosis and inhibition of invasion in human hepatoma
cells by anthocyanins from Meoru. Annals of the New York
Academy
of
Sciences,
1171:
137-148.
http://dx.doi.org/10.1111/j.1749-6632.2009.04689.x,
PMID: 19723048.
Singh, B.N., Singh, B.R., Sarma, B.K., Singh, H.B. (2009). Potential
chemoprevention
of
N-nitrosodiethylamine-induced
hepatocarcinogenesis by polyphenolics from Acacia nilotica
bark.
Chem
Biol
Interact.,
181:
20-8.
http://dx.doi.org/10.1016/j.cbi.2009.05.007,
PMID:
19446540.
Song, M.J., Bae, S.H. (2014). Newer treatments for advanced
hepatocellular carcinoma. Korean Journal of International
Medicine,
29:
149-155.
http://dx.doi.org/10.3904/kjim.2014.29.2.149,
PMID:
24648795.
Stagos, D., Amougias, G., Matakos, A., Spyrou, A., Tsatsakis, A.M., &
Kouretas, D. (2012). Chemoprevention of liver cancer by
plant polyphenols. Food and Chemical Toxicology, 50:
2155-2170. http://dx.doi.org/10.1016/j.fct.2012.04.002,
PMID: 22521445.
Sun, J., Chu, Y, Wu, X., Liu, R.H. (2002). Antioxidant and
antiproliferative activities of common fruits. Journal of
Agricultural and food Chemistry, 50: 7449-7454.
http://dx.doi.org/10.1021/jf0207530, PMID: 12452674.
Thakur, V.S., Gupta, K., Gupta, S. (2012). Green tea polyphenols
causes cell cycle arrest and apoptosis in prostate cancer
cells by suppressing class I histone deacetylases.
International Journal of Oncology, 41: 353-361.
http://dx.doi.org/10.3892/ijo.2012.1449,
PMID:
22552582.
Wang, H.C., Chung, P.J., Wu, C.H., Lan, K.P., Yang, M.Y., Wang, C.J. (2010).
Solanum nigrum L. polyphenolic extract inhibtis
hepatocarcinoma cell growth by inducing G2/M phase arrest
and apoptosis. Journal of Science of Food and Agriculture, 91:
178-185.
http://dx.doi.org/10.1002/jsfa.4170,
PMID:
20853273.
Wang, Q., Chen, Q., He, M., Mir, P., Su, J., Yang, Q. (2011). Inhibitory
effect of antioxidant extract from various potatoes on the
proliferation of human colon and liver cancer cells.
Nutrition
and
Cancer,
63:
1044-1052.
http://dx.doi.org/10.1080/01635581.2011.597538, PMID:
21888504.
Yang, C.S., Landau, J.M., Huang M.T., Newmark H.L. (2001).
Inhibition of carcinogenesis by dietary polyphenolic
compounds.
Annu.
Rev.
Nutr,
21:
381-406.
http://dx.doi.org/10.1146/annurev.nutr.21.1.381, PMID:
11375442.
Yang, M.Y., Hsu, L.S., Peng, C.H., Shi, Y.S., Wu, C.H., Wang, C.J.
(2010). Polyphenol-rich extracts from Solanum nigrum
ISSN: 2348-1900