INTRODUCTION:

Worldwide, oral cancer is becoming an increasingly important public health issue due to its rising incidence and high mortality rate. It is a significant impediment to the diagnostic and therapeutic parts of healthcare services. Oral and pharyngeal cancers combined account for the sixth most prevalent type of cancer worldwide¹. Oral cancer is expected to have an annual incidence of around 275,000 cases and pharyngeal cancer is estimated to have an annual incidence of approximately 130,300 cases in developing nations, excluding nasopharyngeal cancers². Oral cancer is one of the most common diseases in India, accounting for between 11 percent and 52 percent of all cancers identified in the country. According to the National Cancer Registry, the country's illness spectrum is concentrated in states such as Uttar Pradesh, Madhya Pradesh, Bihar, Maharashtra, Gujarat, Andhra Pradesh, Karnataka, and Tamil Nadu.

The occurrence varies according to geographic area and unfavourable habits. Oral cancer has a usually bad prognosis, with a five-year life expectancy of fewer than 50%. Many patients have local recurrences and lymph node metastases, although distant metastasis is typically absent³. There have been numerous studies that have shown a link between oral lesions, such as leukoplakia and erythroplakia, and an increased risk of cancer progression. Such lesions are collectively referred to as 'oral possibly infectious tumors'. The World Health Organization (WHO) defined oral possibly malignant sickness in 2005 as "the risk of cancer arising in a precancerous lesion or condition, whether at the point of first identification or in the future⁴. The term does not imply that all lesions classified under it will progress to cancer; rather, it refers to a family of morphologic abnormalities that potentially predispose some lesions to malignant transformation. Early detection of these potentially malignant conditions enables patients to avoid the high rates of morbidity and mortality connected with some of these lesions. Throughout history, oxidative stress was implicated in the development of a number of illnesses. This is a condition that results from the body's antioxidative defense defences' inability to radical scavenging activity. Free radicals have a short half-life and are highly reactive chemical entities. Atoms, or clusters of them, combine to create molecules, each with a single unoccupied electron⁵.Plant pigments called carotenoids, which collectively make up the majority of the pigments found in nature's colours, are a large family of fat-soluble compounds. Vitamin A and antioxidant (AO) capabilities make them essential nutrients for the human body⁶.

Lycopene is a carotenoid that is fat soluble. Humans get lycopene mostly through tomatoes and tomato-based products as well as apricots, cranberries, grapefruit and pink grapefruit; guavas; papayas; watermelons; and pomegranates. Lycopene has a high capacity for quenching singlet oxygen. Due to its vibrant colour and nontoxicity, it is an effective food colouring additive. Additionally, lycopene is involved in the treatment of a variety of oral disorders, like leukoplakia, oral submucous fibrosis, lichen planus, and OSCC⁷.

BENEFITS ON HUMAN HEALTH:

Oral cancer and precancerous lesions are among the conditions for which lycopene has been found to be beneficial in clinical trials^8. A number of its therapeutic properties could be contributed to its anti-oxidant action, including the suppression of cancer cell proliferation and growth factor enhancement as well as the stimulation of phase II enzymes, transcription regulation and gap junction restoration, even though lycopene lacks pro-vitamin A activity. Most potent singlet oxygen quenching carotenoid, lycopene imposes its action by quenching free radicals through both physical and chemical means. In the absence of conversion to vitamin A, the lycopene could be completely accessible for other usage (e.g., antioxidation). There may be an increase in Lycopene's AO activity due to the lack of a b-ionone structure in the ring structure. Lycopene's stereochemical properties are unique from many other frequently eaten carotenoids, allowing this to thrive with just a few subcellular environments. As far as quenching singlet oxygen and free radicals is concerned, lycopene appears to be the most effective of the carotenoids in vitro. Plasma and various tissues of specific groups contain the highest concentrations of the carotenoid lycopene. Lycopene's unique biochemical features may enable it to shield specific cellular components from damage caused by highly reactive oxygen species (ROS⁾⁹. Lycopene's inhibitory effect on cancer cells has been associated with a reduction in cell cycle progression from the Go/G1 to the S phase^10,11.

Lycopene's Preventative Role in Cancer:

Bioactive mechanism of Lycopene:

Even though there is substantial research indicating for lycopene's role in cancer prevention, the mechanism of action is unknown. Unlike certain other carotenoids, lycopene does not have a b-ionone ring structure or a provitamin A activity. ^12,13. As a result, the biological effects of this compound were ascribed to processes other than vitamin A. Antioxidant and anti-inflammatory qualities are the two main hypotheses put up to explain lycopene's bioactivity (Figure. 1).

Figure 1: Anticancer Mechanism of Lycopene

Lycopene protects against oxidative stress by acting as a quencher of single oxygen and a scavenger of free radicals¹⁴. The quantity of conjugated double bonds in a carotenoid impacts its capacity to quench singlet oxygen, making lycopene one of the most powerful antioxidants, capable of quenching singlet oxygen ten times better than vitamin E. Antioxidant effects of lycopene include the inactivation of free radicals and the reduction of oxidative processes generated by free radicals, such as lipid peroxidation, hence minimising tissue injury. Lycopene's anticarcinogenic mechanisms of action include the enhancement of gap-junction communication (GJC), gene function regulation, antiproliferation and prodifferentiation activities, induction of apoptosis, modulation of carcinogen metabolising enzymes, and modulation of immune function¹⁵. GJC between cells is believed to be one of the anti-cancer strategies. GJC deficiency has been linked to a variety of human malignancies, whereas restoration or overexpression of GJC has been linked to decreased tumour cell proliferation. An increase in the expression of the connexin 43 gene has been found to directly create intercellular GJC in several human and animal cells^16,17. Lycopene has been shown to inhibit the C0 C1 phase of the cell cycle and induce S phase block in a range of cancer cells, including those from the prostate, breast, lung, endometrial, and hepar. The proliferation of numerous types of cancer cells was then inhibited as a result of these impacts. Additionally, it has been demonstrated that lycopene on its own stimulates cell differentiation, as determined by the phorbol ester-dependent decrease of nitroblue tetrazolium and the expression of the cell surface antigen CD14¹⁸. Apoptosis contributes to health maintenance by removing diseased, excessive, or abnormal cells. In the absence of apoptosis, a damaged cell has the potential to become malignant. The fact that lycopene can cause cell death in cell lines derived from various human cancer tissues has been studied in vitro recently suggests that it may have chemotherapeutic potential. Brienholt et al. (2004)¹⁹ also discovered that lycopene strongly increases cytochrome P450-dependent enzymes, phase I enzymes, in a dose-dependent manner and a phase II enzyme, hepatic quinone reductase, by twice. This class of enzymes is critical for the body's elimination of foreign chemicals and carcinogens. Additionally, the immunomodulatory impact of lycopene may be a result of its regulation of intrathymic T-cell differentiation, which was hypothesised to be a reason for lycopene treatment-induced tumour development inhibition in SHN retired mice²⁰.

Lycopene's Role in Oral Disease Prevention:

Oral cancer:

There are several stages to Neoplasm, and even a single cancerous cell can spread to healthy tissue and finally destroy the entire organ. A number of free radicals, both endogenous and exogenous, have long been recognised as mutagenic and can play a role in cancer development. A recent study found that free radicals are also responsible for the phenotypic and genetic changes that accompany the progression from genetic change to malignanciess. As a result, these have been postulated that free radicals could play a key role in human cancer formation²¹The 12th most prevalent cancer in the world is mouth cancer. Carcinogen exposure causes genetic, epigenetic, and metabolic alterations that contribute to oral squamous cell carcinoma (OSCC). In terms of oral cancer prevention, there is a lot of emphasis on diet and nutrition²²

Despite the fact that neoplasia can be treated surgically or with radiotherapy in its initial phases, many people have been diagnosed with the disease at a later stage. In recent years, treatment outcomes have not improved considerably in the late stages of disease. Preventive strategies may be effective in lowering the incidence of this condition. Methods for preventing the onset of OSCC by blocking the initiation, promotion, and advancement stages in the multi-step process of premalignant lesions are referred to as preventive measures (prevention)²³. Lycopene may protect critical biological macromolecules such as lipids, lipoproteins, proteins, and DNA from carcinogenesis and atherogenesis²⁴. There is evidence that Lycopene can inhibit cancer growth in both in vitro and in vivo studies. There are several ways in which lycopene's anti-carcinogenic properties can be explained, including ROS scavenging and upregulation of detoxification systems, interference with cell proliferation and stimulation of gap junction communication, and suppression of cell cycle progression. It has already been shown that lycopene can enhance cancer cells' p53 protein levels^25,26

Figure 2: Pharmacological action of Lycopene in preventing oral and other cancers

Oral leukoplakia:

Leukoplakia (OL) of the mouth is a precancerous lesion that can't be categorised as any other known lesion because it is primarily white in colour^28,29. The link between cigarette smoking and OL has been established for a long time and is undeniable. By generating reactive free radicals and active oxygen species, tobacco use plays a substantial role in etiopathogenesis of oral cancers and contributes to carcinogenesis through mutations²¹. Before beginning treatment for OL, it is possible to establish the extent of epithelial dysplasia. Surgical surgery is advised in mild to severe cases of epithelial dysplasia^.30. However, OLs with low to moderate risk of malignancy may or may not be completely removed, depending on other factors such as location, size, and, in the case of smokers, their dedication to smoking cessation, as well as other factors such as the size of the OL³¹. OL Conventional surgery³²,electro cauterization, laser ablation³³, or cryosurgery are all options for surgical treatment³⁴

It appears that lycopene is a very promising AO for use in OL treatment since it can protect cells from injury and function as a preventative factor against dysplasia advancement by decreasing tumour cell growth. According to a recently released study, lycopene's potent anti-cancer effects on human oral cancer cells were first discovered³⁵. Nagao et al. attempted to determine the relationship amoung serum micronutrient concentrations and OL. Lycopene serum levels were substantially lower in males with OL than in controls^.36.Gupta et al. attempted to establish a link between nutritional intake and OL prevalence. They discovered that tomato consumption—the principal source of lycopene—has the strongest preventive role against OL of all the dietary variables studied³⁷

Lycopene was found to be effective in the treatment of OL in a trial conducted in Belgaum, Karnataka. They also discovered that an 8mg lycopene daily dose was more beneficial than a 4mg lycopene daily dose. Lycopene's efficacy has been attributed to its AO characteristics³⁸. Zakrzewska concluded that lycopene causes significant histological changes in patients with OL in their research of 58 cases^39.

Oral submucous fibrosis:

Oral submucous fibrosis (OSMF) is a persistent scarring disorder that typically affects people of South-East Asian descent⁴⁰. High chilli intake, genetic predisposition, autoimmunity, iron and vitamin deficiency have all been related to OSMF⁴¹. Nonetheless, it is firmly connected with the eating of areca nuts and the preparation of pan masala⁴².In human skin fibroblasts, ethanolic extracts of areca nut have been shown to stimulate collagen synthesis and stabilise and prevent collagen fibrils against breakdown by collagenase, resulting in fibrosis, according to laboratory experiments⁴³. Besides copper, areca nut has been found to promote collagen creation via increasing the activity of an enzyme that is essential for collagen production and cross-linking^.44

Similar to other precancerous lesions of the mouth, oral submucous fibrosis behaves and progresses in a similar manner. As a result, it has been hypothesised that AOs could likewise be used to reverse and inhibit the disease process in OSMF, as has been shown in other premalignant lesion therapies of the oral cavity. Numerous authors believe that conservative treatments are better than conventional ones^.45,46

Oral lichen planus:

LP is a chronic inflammatory mucocutaneous illness affecting around 0.2–4% of the overall population and involves the skin and/or mucosa.⁴⁷ However, it is hypothesised that free radicals and oxidative stress play a role in the evolution of the illness.⁴⁸An affirmative therapy is also difficult to come by because there are so many scientific treatments in the research⁴⁹. Additionally, because to its AO and anticancer effects^50, it may be beneficial in preventing malignant transformation of the OLP.

Periodontal diseases:

Gingival crevicular fluid can be collected non-invasively from periodontal tissues, making it a useful tool for research on ROS-mediated tissue injury and AO defence in response to bacterial invasion^51,52. Carotenoids are potent antioxidants that contribute to an individual's overall health and protect against cancer, heart disease, and oral malignancies and illnesses. Lycopene is the most powerful carotenoids. Additionally, it promotes the activity of other carotenoids. Additionally, it is antibacterial and antifungal⁵³. It is an useful adjuvant for gingivitis treatment when combined with oral prevention. Lycopene inhibits Candida albicans growth by inflicting substantial damage to the cell membrane⁵⁴ Chandra et al. (2007⁾⁵⁵conducted a randomised, placebo-controlled, split-mouth trial of gingivitis in 20 healthy adults with clinical indications of gingivitis. For two weeks, the treatment group (n = 10) got 8mg/day lycopene (LycoRed®), whereas the control group (n = 10) received a placebo. Gingivitis and bleeding index were significantly reduced in participants treated with lycopene in this study. Chandra et al. Lycopene has been demonstrated to be more potent when coupled with other antioxidants such as vitamin C.

CONCLUSION:

According to preliminary human clinical research, the antioxidant lycopene has the ability to treat premalignant lesions including OSF and oral leukoplakia. Furthermore, proof from epidemiological data, as well as in vitro and in vivo studies, suggests that lycopene could be a potential anti - carcinogenic agent for oral cancer. Although there are several areas that need further investigation,. More mechanistic research and rigorously structured clinical trials are needed to assess the potential utility of lycopene as an adjuvant to the treatment of oral premalignant lesions and its impact in lowering the risk of oral carcinogenesis.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this review.

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Received on 01.08.2022 Modified on 17.06.2023

Research J. Pharm. and Tech. 2024; 17(3):1393-1397.

DOI: 10.52711/0974-360X.2024.00220