Lycopene, a carotenoid pigment found abundantly in tomatoes and other red fruits, has garnered significant attention for its potential role in cancer prevention. Numerous studies have suggested that lycopene exhibits anticancer properties through various mechanisms, including interference with growth factors, regulation of cell proliferation, and induction of apoptosis.
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Introduction
Extensive research has been dedicated to unraveling the potential health benefits of carotenoids in human health and disease. While early investigations predominantly focused on pro-vitamin A carotenoids, recent attention has shifted towards exploring the roles of non-provitamin A carotenoids, such as lycopene, in preventing chronic diseases, including cancer. Although epidemiological and animal studies suggest a potential chemopreventive effect of lycopene, the biochemical mechanisms underlying these effects remain poorly defined. Several studies have highlighted various beneficial effects of lycopene, including its antioxidant function, enhancement of cellular communication, activation of phase II enzymes, suppression of cell proliferation, inhibition of angiogenesis, and induction of apoptosis. Furthermore, recent research has delved into the metabolic fate of lycopene and its metabolites, shedding light on their potential roles in cancer prevention.
Lycopene Metabolism
Carotenoids, a group of lipophilic compounds, boast a polyisoprenoid structure with conjugated double bonds sensitive to oxidative modification and cis-trans isomerization. Among these, β-carotene has been extensively studied, but lycopene has recently garnered attention for its potential health benefits, including reduced risk of chronic diseases like cancer. While both share similar molecular mass and formula, lycopene differs by lacking the β-ionone ring structure. Despite this, understanding lycopene's metabolism remains a challenge.
Chemical Oxidation of Lycopene
Several studies have explored the chemical oxidation of lycopene, unveiling various metabolites and oxidation products. Researchers conducted incubation experiments, identifying eight oxidative products, such as apo-14'-lycopenal, apo-12'-lycopenal, apo10'-lycopenal, apo-8'-lycopenal, and apo-6'-lycopenal. Subsequent studies revealed additional metabolites like 3-keto-apo-13lycopenone and identified novel oxidative metabolites such as lycopene-5,6,5',6'diepoxide. Different oxidizing systems produced distinct metabolites, indicating lycopene's susceptibility to various oxidation pathways. While many products are identified in vitro, their significance in vivo remains unclear, although they may be implicated in oxidative stress-related conditions like smoking and drinking.
Fig 1. Schematic illustration of lycopene metabolic pathway by CMO2 (Mein J.R., et al. 2008).
Enzymatic Cleavage of Lycopene
CMO2, responsible for excentric cleavage of carotenoids, has gained attention for its role in lycopene metabolism. Studies demonstrate CMO2's ability to cleave all-trans β-carotene and cis-lycopene isomers effectively. However, the preference for cis-lycopene over all-trans lycopene remains enigmatic. The structural resemblance of cis-lycopene isomers to β-carotene suggests a possible mechanism for CMO2 substrate specificity. Further investigation into the kinetics and mechanisms of lycopene cleavage by CMO2 is essential for understanding lycopene's metabolic fate and biological functions.
Biological Activities of Lycopene Metabolites
Antioxidant Properties
Lycopene is renowned for its potent antioxidant capabilities, a trait commonly associated with carotenoids. Its ability to scavenge free radicals and quench singlet oxygen surpasses that of other naturally occurring carotenoids like β-carotene and α-tocopherol. Epidemiological studies, primarily conducted with tomato-based products rich in lycopene, have suggested a correlation between lycopene consumption and reduced DNA damage, protection against oxidative stress, and inhibition of LDL oxidation or lipid peroxidation. However, caution is warranted when attributing these benefits solely to lycopene, as tomatoes contain a plethora of micronutrients and phytochemicals. Despite lycopene's established role as an antioxidant, there's limited evidence supporting the antioxidant activity of its metabolites. Recent research indicates that lycopene metabolites, such as apo-10'-lycopenoic acid, may indeed exhibit antioxidant properties. Studies have demonstrated a dose-dependent reduction in reactive oxygen species (ROS) production and protection against oxidative damage in cells treated with apo-10'-lycopenoic acid, akin to the effects observed with established antioxidants like tert-butylhydroquinone (TBHQ).
Gap-Junction Communication (GJC)
Gap junctions facilitate cellular communication, allowing the exchange of various substances between adjacent cells. Connexin proteins form these channels, with Connexin 43 (Cx43) being widely expressed. Retinoids and carotenoids have been implicated in modulating GJC, a process crucial for regulating cell growth and differentiation. Studies have shown that carotenoid oxidative products/metabolites, including those derived from lycopene, can enhance GJC. For instance, the oxidation of lycopene produces metabolites like 2,7,11-trimethyl-tetradecahexaene-1,14-dial, which effectively increase GJC levels comparable to retinoic acid. Similarly, lycopene-5,6-epoxide and acyclo-retinoic acid have been shown to upregulate Cx43 expression, albeit with varying potencies. These findings suggest a potential role for lycopene metabolites in modulating GJC, offering insights into their physiological effects beyond mere antioxidant properties.
Induction of Phase II Enzymes
Phase II detoxification enzymes play a crucial role in metabolizing various compounds, including carcinogens and dietary constituents. Evidence suggests that lycopene, either intact or in the form of its metabolites, can induce the expression of these enzymes. Apo-10'-lycopenoic acid, for instance, has been shown to upregulate the expression of several phase II enzymes in vitro, possibly through the activation of the Nrf2 transcription factor pathway. This induction of phase II enzymes highlights another potential mechanism by which lycopene metabolites exert their biological effects beyond traditional antioxidant activities.
Interference with Growth Factors
One of the key mechanisms underlying the anticancer activity of lycopene involves interference with the insulin-like growth factor (IGF) signaling pathway. IGFs, particularly IGF-1 and IGF-2, play pivotal roles in regulating cellular proliferation, differentiation, and apoptosis. Lycopene has been shown to disrupt IGF signaling by inhibiting IGF-1-stimulated cell growth and reducing the DNA binding activity of transcription factors involved in cell cycle regulation. By modulating the availability of IGFs and their binding proteins, lycopene may attenuate hyperproliferation and survival signal expression, thereby inhibiting the development of various cancer types, including prostate, breast, colorectal, and lung cancer.
Regulation of Cell Proliferation and Apoptosis
In addition to interfering with growth factors, lycopene exhibits direct effects on cell proliferation and apoptosis. Studies have demonstrated that lycopene inhibits the growth of various cancer cell lines, including breast, prostate, lung, colon, and oral cavity cancer cells. This growth inhibitory effect is mediated through the regulation of cell cycle regulators, such as cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors, leading to decreased cell cycle progression and induction of apoptosis. Furthermore, lycopene metabolites, particularly apo-10'-lycopenoic acid, have shown similar inhibitory effects on cell proliferation and apoptosis, suggesting their potential role in mediating the anticancer activity of lycopene.
Conclusion
In conclusion, lycopene holds immense potential as a natural compound for cancer prevention. Its ability to interfere with growth factors, regulate cell proliferation, and induce apoptosis underscores its multifaceted mechanism of action against cancer development. However, a better understanding of lycopene metabolism, identification of its metabolites, and clarification of their biological activities are essential for harnessing its full therapeutic potential. Further research is needed to elucidate the intricate interplay between lycopene, environmental factors, and cancer risk, paving the way for the development of effective strategies for cancer prevention and treatment.
Reference
- Mein J.R., et al. Biological activity of lycopene metabolites: implications for cancer prevention. Nutrition Reviews. 2008, 66(12): 667-83.
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