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Cancers 2012, 4(2), 323-339; doi:10.3390/cancers4020323
Article

Micronutrient Synergy in the Fight against Hepatocellular Carcinoma

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Received: 6 December 2011; in revised form: 14 February 2012 / Accepted: 21 March 2012 / Published: 23 March 2012
(This article belongs to the Special Issue Advances and Research Progress in Hepatocellular Carcinoma)
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Abstract: The incidence of hepatocellular carcinoma (HCC), once thought to be a rare tumor in North America, has rapidly increased in recent years in the United States. Current treatment modalities to halt the progression of this disease are only marginally effective. The mainstay treatment is liver transplantation, which is often confronted with donor shortage. Invasion, metastasis and recurrence contribute to the high mortality rate of this disease. Matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) have been associated with the progression, invasion and metastasis of the disease. We have developed strategies to strengthen the ECM collagen and inhibit MMPs through micronutrients such as lysine, proline and ascorbic acid. Addition of epigallocatechin gallate or green tea extract to these micronutrients synergistically enhanced anti-carcinogenic activity in HepG2 cells. Addition of certain other micronutrients, such as N-acetylcysteine, selenium, copper and zinc (NM) synergistically enhanced the anticancer activity of the mixture in a model of hepatocellular carcinoma using HepG2 cells. In vitro studies using HepG2 demonstrated that NM was very effective in inhibiting cell proliferation (by MTT assay), MMPs secretion (by gelatinase zymography), cell invasion (through Matrigel) and induction of apoptosis (by live green caspase). In addition, NM was shown to down-regulate urokinase plasminogen activator (by fibrin zymography) and up-regulate tissue inhibitors of metalloproteinases (by reverse zymography) in another HCC cell line, SK-Hep-1. MMP-2 and MMP-9 activities were further modulated by phorbol 12-myristate 13-acetate (PMA) induction and inhibited by NM. In previous studies, NM inhibited Sk-Hep-1 xenografts in nude mice and also inhibited hepatic metastasis of B16FO melanoma cells. Our results suggest that NM is an excellent candidate for therapeutic use in the treatment HCC by inhibiting critical parameters in cancer development and progression, such as proliferation, invasion and metastasis, and by inducing apoptosis.
Keywords: hepatocellular carcinoma; HepG2; SK Hep-1; nutrient synergy; cell proliferation; MMPs; u-PA; TIMPs; matrigel invasion; apoptosis hepatocellular carcinoma; HepG2; SK Hep-1; nutrient synergy; cell proliferation; MMPs; u-PA; TIMPs; matrigel invasion; apoptosis
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Roomi, M.W.; Roomi, N.W.; Kalinovsky, T.; Niedzwiecki, A.; Rath, M. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma. Cancers 2012, 4, 323-339.

AMA Style

Roomi MW, Roomi NW, Kalinovsky T, Niedzwiecki A, Rath M. Micronutrient Synergy in the Fight against Hepatocellular Carcinoma. Cancers. 2012; 4(2):323-339.

Chicago/Turabian Style

Roomi, M. Waheed; Roomi, Nusrath W.; Kalinovsky, Tatiana; Niedzwiecki, Aleksandra; Rath, Matthias. 2012. "Micronutrient Synergy in the Fight against Hepatocellular Carcinoma." Cancers 4, no. 2: 323-339.



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