Lycopene Enriched Tomato Extract Inhibits Hypoxia, Angiogenesis, and Metastatic Markers in early Stage N-Nitrosodiethylamine Induced Hepatocellular Carcinoma

Abstract

Targeting altered pathways during initial stage of hepatocellular carcinoma (HCC) development is viewed as an effective and promising strategy to control this disease. Present study investigated the potential effect of lycopene-enriched tomato extract (LycT) on hypoxia-induced factor (HIF)-1α, HOX, VEGF, CD31, matrix metalloproteinase (MMP)-2, MMP-9, and alpha fetoprotein (AFP)expression during initial stages of N-nitrosodiethylamine (NDEA) induced HCC. Female Balb/c mice (8-10 wk) were assigned to 4 groups: control, NDEA (200 mg NDEA i.p./kg body weight, cumulative), LycT (5 mg lycopene orally/kg body weight; 3 times a week), and LycT + NDEA. LycT treatment began 2 wk before NDEA administration and continued until the end of the 10 wk study. The onset of HCC by NDEA was associated with significant alteration in serum biochemical markers [alanine transaminases (ALT), aspartate transaminases (AST), and alkaline phosphatases (ALP), lactate dehydrogenase (LDH), urea, A/G ratio, and bilirubin] and in liver histopathology. LycT treatment significantly reduced the levels of these markers. LycT treatment to NDEA mice also led to significant reduction in protein levels of AFP, HIF-1α, VEGF, CD31, MMP-2, and MMP-9 in comparison with NDEA group alone. These parameters are important biomarkers of hypoxia, angiogenesis, and metastasis, which reflect the advanced disease stage. The study provides evidence that prophylactic dietary supplementation with LycT may counteract HCC progression and/or protect against disease onset.

β‐Cryptoxanthin Inhibits Angiogenesis in Human Umbilical Vein Endothelial Cells Through Retinoic Acid Receptor

“…Interestingly, inhibition of angiopoietin–TEK pathway by all‐ trans retinoic acid has been described in EC1 human cellular line of esophagus cancer, which is in agreement with our results, taking into account that β‐cryptoxanthin is a provitamin A carotenoid. Such antiangiogenic capacity against development of several diseases has been previously proposed for several carotenoids, including β‐cryptoxanthin, based on chemoprotection studies . Yet, to the best of our knowledge, the present work represents the first report on β‐cryptoxanthin antiangiogenic effect on endothelial‐cells.…”

“…Interestingly most carotenoids have the ability to influence angiogenesis, mainly inhibiting it. This effect could explain some of their healthy actions . Indeed, carotenoid intake prevents macular‐degeneration risk associated to aging .…”

Lycopene treatment stalls the onset of experimentally induced hepatocellular carcinoma: a radioisotopic, physiological and biochemical analysis

“…Similar observations were also noticed by Farooq et al [41] and Gangar et al [42] , who also observed the alterations in various hematological parameters in patients suffering from gastric and forestomach carcinoma respectively. LycT treatment to NDEA insulted mice tends to restore the levels of these markers which might be attributed to decreased hypoxia and reduction in tumor growth by an enhancement of apoptosis [18,23] . Several other researchers have also supported the restoration of blood parameters upon lycopene treatment thus showing its anti-inflammatory potential [43,44] .…”

“…The role of LycT in delaying the process of hepatocarcinogenesis has already been studied in terms of diminished histopathological alterations, reduced mortality and induction of apoptosis [3,18] . Moreover, the anti-angiogenic and anti-metastatic potential of lycopene was also investigated recently in our laboratory [23] . Periodical assessment of serological markers at early stages could serve as an important parameter to evaluate the onset of hepatic pathology.…”

“…Recently, in our laboratory, the role of LycT in inhibiting multiple dysregulated pathways including hypoxia, angiogenesis and metastasis has also been delineated. The study suggested that it does so by attenuating the expression of hypoxia inducible factor-alpha, vascular endothelial growth factor, cluster of differentiation 31, matrix metalloproteinases (MMP)-2 and MMP-9 [23] . Moreover, the modulation of hepatic tumor marker [alpha fetoprotein (AFP)] and hepatic functional markers by LycT was also demonstrated [23] .…”