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Cover page of the Journal of Health Sciences


 
 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 11  |  Issue : 1  |  Page : 3-11

Review of selected herbal phytoconstituents for potential melanoma treatment


1 Dr. Prabhakar Kore Basic Science Research Center, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India
2 Dr. Prabhakar Kore Basic Science Research Center, KLE Academy of Higher Education and Research; Department of Pharmacognosy and Phytochemistry, KLE University's College of Pharmacy, KLE Academy of Higher Education and Research, Belagavi, Karnataka, India

Date of Web Publication17-Jan-2018

Correspondence Address:
Sunil Satyappa Jalalpure
KLE University's College of Pharmacy, KLE Academy of Higher Education and Research, Nehru Nagar, Belagavi - 590 010, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kleuhsj.kleuhsj_319_17

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  Abstract 


Malignant melanoma is the most aggressive form of skin cancer, with a high mortality rate. The current chemotherapies have a relatively low success rate due to the development of multidrug resistance and side effects. Hence, there is need of discovering new compounds that are safe and more effective against melanoma to improve the efficiency and to lower the treatment cost for cancer care. Melanoma chemoprevention with natural herbal phytoconstituents is an emerging strategy to prevent, cure, or treat melanoma. This review summarizes the latest research in melanoma chemoprevention and treatment using the herbal phytoconstituents. Relevant mechanisms involved in the pharmacological effects of these phytochemical are discussed. Phytoconstituents that are discussed in this review are carotenoids, flavonoids, some polyphenols, piperine alkaloid, and sulforaphane having high anticancer potential mostly to be used for the treatment of melanoma.

Keywords: Anticancer, chemoprevention, melanoma, phytoconstituents


How to cite this article:
Kurangi BK, Jalalpure SS. Review of selected herbal phytoconstituents for potential melanoma treatment. Indian J Health Sci Biomed Res 2018;11:3-11

How to cite this URL:
Kurangi BK, Jalalpure SS. Review of selected herbal phytoconstituents for potential melanoma treatment. Indian J Health Sci Biomed Res [serial online] 2018 [cited 2018 Jul 22];11:3-11. Available from: http://www.ijournalhs.org/text.asp?2018/11/1/3/223431




  Introduction Top


Melanoma

Melanoma is the most fatal kind of skin cancer which is a malignant tumor that originates from melanocytes and especially involves the skin [Figure 1]. Apart from the skin, melanomas can also found in the eyes and meninges and on various mucosal surfaces. Usually, melanomas are pigmented and amelanotic. Even the small tumors can have a tendency to metastasize and thus lead to an unfavorable prognosis. The death rate associated with melanoma is 90% which can be related with cutaneous tumors.[1],[2] Melanoma incidence is going to be increased worldwide in the White populations with excessive sun exposure. In the USA, about 76,380 new cases of melanoma were diagnosed in 2016.[3] Approximately 132,000 cases of melanoma and over 2 million cases of nonmelanoma are diagnosed worldwide every year. The diagnosis for skin cancer throughout the world is one in every three cancers.[4] Worldwide, about 55,000 deaths were estimated in 2012.[5]Ultraviolet irradiation is the most important exogenous factor for melanoma, particularly intermittent sun exposure.[6] Malignant melanoma is most common among the White-skinned peoples than Black, Asian, or Hispanic population. The White-skinned people have approximately 10 times greater risk of developing melanoma.[7] However, in the plantar malignant melanoma, it was found that melanoma incidence is equal in both the White and Black population.[8] In India, malignant melanoma is not common and its incidence rate is <0.5%.[9]
Figure 1: Melanoma tumor development in the skin

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The current clinical approach and therapy selected for cutaneous melanoma are surgery, chemotherapy or immunotherapy, and/or the combination of the two. Unfortunately, attempts made for improving the survival by surgically removing lymph nodes can result in no overall survival benefits.[10] Other than surgery, there are two major alternatives for the management of melanoma such as chemotherapy and immunotherapy. Although the current chemotherapies have their advantages, they are either not effective enough or cause serious side effects and toxicity. In the randomized experiments to date for melanoma, it has been reported that no single drug or combination of therapies is superior to existing drugs.[11] Therefore, there is need for herbal drugs which can offer improved efficacy over existing chemotherapy, in melanoma therapy.

Need of natural herbal products

Development of multidrug resistance and severe adverse effects is the main problem that exists with chemotherapeutic agents. Some of the methods by which melanoma cells can develop resistant to chemotherapeutic agents are drug efflux systems, amplification of drug targets, or changes in drug kinetics.[12],[13],[14] To overcome drug resistance, different strategies have been attempted, such as use of nanoparticles, liposomes, and micellar drug delivery vehicles, with some reported successes.[14] The adverse effects, side effects, and multidrug resistance of cancer chemotherapy can be treated symptomatically, but in some instances, some secondary treatments may be very toxic, which is unacceptable to some cancer patients.[15],[16],[17]

Because of the drawbacks associated with conventional cancer chemotherapies, interest has been grown for natural therapies. Different phytochemical compounds obtained from the extracts of plant roots, bulbs, barks, leaves, stems, and others have shown promising potential as anticancer drugs or for serving as lead compounds in the synthesis of new drugs. The main limiting factor for natural products and traditional medicines is the different preparation method. Apart from that chemical composition, dosage determination, dose adjustment, and suitable route of administration are also important factors for the herbal medicines. Although much research on the compounds of natural origin is required to produce new drug products for which research, specifically aimed at naturally derived medicines to optimize dosages for the intended route of administration and to design the most effective dosage forms, has become essential.[18]


  Phytoconstituents Showing Activity for Melanoma Top


Phytoconstituents exerts different types of immunomodulatory, anti-inflammatory, and antioxidant properties, but generally, they have the highest potential of exerting chemopreventive action in melanoma.[19] Number of research has been done to find out the correlation between antioxidant properties and anticancer activity of these phytoconstituents. No strong evidence has been found related with such a correlation still, but the antioxidant potential of a phytoconstituent is being regarded as an indication for potential anticancer activity.[20],[21] Phytoconstituents such as carotenoids, flavonoids, and terpenoids having high anticancer potential can be used for the treatment of melanoma [Figure 2].[22],[23],[24]
Figure 2: Classification of phytoconstituents

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Flavonoids

Flavonoids are pigmentary compounds which exist in plants. Structurally, flavonoids contain two benzene rings which are connected through a linear carbon chain and an aromatic chromophore.[25] Flavonoids include flavones, flavanones, isoflavones, anthocyanins, and flavan-3-ols (catechins). [Figure 3] describes the chemical structures of some flavonoids which exhibit anticancer activities.
Figure 3: Chemical structures of selected flavonoids having anticancer potential

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Epigallocatechin-3-gallate

The catechin epigallocatechin-3-gallate (EGCG) is one of the main flavonoid compounds found in green tea which has been received enormous pharmacological attention because of its potential benefits to health. EGCG possess anti-inflammatory, antioxidant, antimutagenic, and anticarcinogenic properties.[26],[27],[28]

It has been reported that EGCG has the capacity to induce apoptosis and cell cycle arrest in melanoma cells, either alone or in combination with vorinostat in vitro.[29],[30] For the melanoma treatment, a combination strategy with interferon has shown synergistic antiproliferative effects in both in vitro and in vivo studies.[31] Different mechanisms by which EGCG has shown effects include upregulation of Bcl-2-associated X protein, downregulation of apoptosis-inhibiting proteins, cell survival-promoting proteins, a pro-apoptosis protein, activation of caspases-3, -7, and -9, and through the induction of tumor suppressor proteins.[32],[33] EGCG showed pro-apoptotic activity, selective toward melanoma cells and not toward the normal melanocytes.[33] Development of EGCG into a practical therapeutic agent may require an interdisciplinary approach to modify EGCG structure and increase its potency and pharmacokinetic properties.

Quercetin

Quercetin is the most abundant flavonol present in the human diet and in plants in different glycosidic forms, such as galactosides, rhamnosides, arabinosides, or glucosides.[34],[35] The derivatives of quercetin accounts for 60% of the total flavonoids ingested daily and are the most abundant and important dietary flavonoids present in the human diet.[36] The quercetin derivatives are commonly found in many fruits and vegetables, such as red onions, apples, berries, parsley, olive oil, cocoa, citrus fruits, tea, and red wine.[37],[38]

The mechanism by which quercetin had shown activity against melanoma at low concentrations by affecting cell viability and at higher concentrations by inducing apoptosis.[39] It was reported that in murine melanoma cells, quercetin induced apoptosis by diminishing the expression of B-cell lymphoma 2 and increasing the effectiveness of caspase-3 activity.[40] The recent study has reported that the quercetin activity for melanoma may be due to inhibitory effects on signal transducer and activator of transcription 3, which is an oncogenic protein.[41] Overall quercetin could be used to take advantage of tyrosinase activity in melanoma treatment with minimum additional side effects related with it. However, dietary intake would be suitable in the development of preventative approaches, while systems including nanoparticles or any other nanoformulation will be required to achieve the best effective quercetin concentrations for therapeutic approaches.

Kaempferol

Kaempferol, a natural flavonol compound belonging to flavonoids category, occurs mostly in a variety of plants and plant-derived food products. Kaempferol is abundantly available in tea, broccoli, beans, strawberries, and apples.[42]

Kaempferol acts in the different mechanisms for regulation of cancer cells. It has been reported that kaempferol is a potent promoter of apoptosis and also it modifies a host of cellular signaling pathways such as inhibiting cell proliferation.[43] Compared to standard chemotherapeutic drugs, kaempferol is much less toxic to normal cells.[44] A study has shown that kaempferol blocks choroidal melanoma cell cycle progression in the G2/M phase.[45] For transdermal delivery, the kaempferol submicron emulsion systems has been developed, and it was found that because of emulsion systems, there was significant influence on the flux, the amount of drug deposition in skin and lag time.[46] The synergistic activity along with quercetin has been shown in melanogenesis inhibition. Moreover, they were considered as good blockers of enzyme activity, especially in hyperpigmentation.[47]

Daidzein

Daidzein is an isoflavone, which is a hormone-like substance found exclusively in soybeans and other legumes. It is highly soluble in alkaline environments and is part of a group of compounds, called phytoestrogens.[48]

Daidzein has shown some effective photo-protection potential in the skin by topical application.[49] Daidzein and genistein have been investigated to produce synergistic inhibitive effect on the metastatic melanoma cells (murine K1735M2).[50]

Apigenin

Apigenin is a naturally occurring product belonging to the flavonoids category which is anaglycone of several naturally occurring glycosides. Apigenin is mostly found in celery, oranges, tea, parsley, thyme, and onions.[51]

The anticancer activities of apigenin have been observed in vitro in the melanoma cell lines (MELs-28). The different mechanisms by which apigenin exerts action include inducing cell cycle arrest in the G2/M phase, upregulating tumor necrosis factor receptor (TNF-receptor), and the TNF-related apoptosis-inducing ligand receptor apoptotic pathway.[33] The combinations of all these actions result into chemoprotective effects of apigenin. Subsequent studies on apigenin has shown antimelanoma effects, which includes inhibition metastasis of melanoma.[52],[53] Along with quercetin, there is inhibition of melanoma growth and invasive and metastatic melanoma.[52]

Rutin

Rutin is the glycoside which is the combination of quercetin flavonol and the rutinose disaccharide. It occurs in a wide variety of plants such as passion flower, buckwheat, tea, and apple. It is one of the vital nutritional components of food stuff.[54]

It has demonstrated a number of pharmacological activities, including antioxidant, cytoprotective, vasoprotective, anticarcinogenic, neuroprotective, and cardioprotective activities.[55],[56] One study has reported that rutin inhibited the growth and tumor weight of B16 melanoma as well as melanin content in C57BL/6 mice.[57]

Carotenoids

Carotenoids are a class of >750 naturally occurring fat-soluble pigments commonly found in plants, algae, and photosynthetic bacteria.[58] The carotenoids containing the structure such as distinctive conjugated double bond which acts as a light-absorbing chromophore and that imparts yellow, orange, or red color to vegetables, oranges, and other food products.[59] Carotenoids are divided into two classes, such as xanthophylls and carotenes. [Figure 4] describes the chemical structures of some carotenoids which exhibit anticancer activities, especially against melanoma.
Figure 4: Chemical structures of selected carotenoids having anticancer potential

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Lycopene

The red color to fruits and vegetables is imparted by a natural pigment which is lycopene. Lycopene is found in watermelons, pink grapefruits, apricots, and pink guavas. It is found in particularly high amounts in tomatoes and tomato products.[59]

Lycopene is one of the most effective carotenes for oxidative stress reduction. It should be considered as an excellent additive to the diets of patients which are at high risk for melanoma.[60] Studies have shown that lycopene inhibits platelet-derived growth factor-BB, which in turn reduces melanoma cell-induced fibroblast migration and signaling transduction. Hence, this explains that lucopene bears the antitumor properties.[61]

Fucoxanthin

Fucoxanthin is an orange-colored pigment, together with chlorophylls a, c and β-carotene which are to be found in chromophyta, brown seaweeds, and diatoms.[62]

Fucoxanthin exerts anticancer effects such as reduced tumor incidences, cell cycle arrest, induction of apoptosis, inhibition of proliferation, and inhibition of metastasis.[63] The in vitro and in vivo study has shown that fucoxanthin inhibits the growth of B16F10 melanoma cells.[64] In SK-MEL-28 malignant MEL-28 study, the anticancer effect of fucoxanthin has also been reported.[65] Fucoxanthin also shown the activity against metastatic melanoma by suppressing murine melanoma cells, by downregulation of proteins involved in cell migration, cell interaction, and cell adhesion.[66]

β-Carotene

β-Carotene is an organic, abundantly found in plants and fruits. β-Carotene is a pigment which has strong red-orange color. In nature, β-carotene is a precursor to vitamin A. β-Carotene was described as an antioxidant that protected against cancer, heart disease, macular degeneration, and aging.[67],[68],[69]

The in vitro study in melanoma cells reported that β-carotene is able to induce apoptosis by activating caspases-3, -8, and -9 through caspase cascade.[70] It was reported that the diet high in β-carotene may be related to a decreased melanoma risk.[71],[72]

Alkaloid

Alkaloids are a group of naturally occurring nitrogenous chemical compounds found in plants, typically insoluble in water. The different organisms such as bacteria, fungi, plants, and animals are the main source of the alkaloids. Alkaloids are exerting different pharmacological actions such as antimalarial, antiasthma, anticancer, vasodilatory, antiarrhythmic, analgesic, antibacterial, and antihyperglycemic activities.[73] Berberine, cryptolepine, and vinca alkaloids have been shown activity for melanoma. In this present review, the alkaloid discussed for antimelanoma activity is piperine.[74],[75],[76]

Piperine

Piperine is an alkaloid found in Piper nigrum and Piper longum. It exhibits wide variety of biological actions such as anti-inflammatory, antioxidant, antiarthritic and antidepressant effects [Figure 5] shows chemical structure of piperine.[77],[78]
Figure 5: Chemical structure of piperine

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Piperine inhibits CYP3A4 and P-glycoprotein by which bioavailability of other drugs can be enhanced.[79] Curcumin has different stability problems.[80] Along with curcumin, administration of piperine increases bioavailability of curcumin.[76] Clinical trials are also being conducted to evaluate the effect of piperine in enhancing the bioavailability of other phytoconstituents. The antiproliferative effects of piperine in murine as well as in human melanoma cells were studied. The studies have reported that growth inhibitory effects of piperine were mediated by apoptosis and cell cycle arrest of both the cell lines, i.e., SK-MEL-28 and B16 F0 cells in G1 phase.[81]

Polyphenol

Polyphenols are mainly natural but also synthetic or semisynthetic, organic chemicals characterized by the presence of large multiples of phenol structural rings. There are over 8000 identified polyphenols compounds found most abundantly in whole foods such as dried spices, fruits, vegetables, red wine, and cocoa, tea, wine, and chocolates.[82] Polyphenol plays an important role in the prevention and in reduction of progression of diseases such as diabetes, cardiovascular and neurodegenerative diseases, and cancer. [Figure 6] shows the chemical structure of selected polyphenols having anticancer potential.[83]
Figure 6: Chemical structures of selected polyphenols having anticancer potential

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Ellagic acid

Ellagic acid is a fused four-ring polyphenol. Ellagic acid is present in many red fruits and berries, including raspberries, strawberries, blackberries, cranberries, pomegranate, and some nuts including pecans and walnuts.

It possesses antifibrotic and antioxidant properties and also exhibits in vitro antitumor properties against various cancer cells.[84],[85] Ellagic acid had shown apoptosis induction property in human melanoma cells.[86] Ellagic acid is thought to suppress melanogenesis by reacting with activated melanocytes and without injuring cells.[87]

Resveratrol

Resveratrol is a nutraceutical which has exciting pharmacological potential and because of this recently attracted a lot of research attention. It is a phytoalexin compound found in many plants such as grapes, peanuts, and berries. Resveratrol is a model stilbene having cardioprotection, chemoprevention, and antitumor activities.[88]

Resveratrol has been investigated as an anticancer agent. In doxorubicin-resistant murine melanoma cells, the potency of resveratrol has been demonstrated by inducing apoptosis and inhibiting the growth of melanoma tumors in mice.[89] The in vitro study had shown that combination with temozolomide act as an effective cytotoxic agent against melanoma cells.[90] Due to its low bioavailability, the in vivo anticancer effects of resveratrol are strongly limited.[91] Hence, approaches are to be done to increase its bioavailability either by bioenhancer or by nanotechnology approaches. The study had shown that resveratrol sensitizes melanoma cells to interleukin-2 immunotherapy which had caused induced cell death.[92]

Indoles and glucosinolates

Glucosinolates are a group of secondary products found in plants of the family Cruciferae. On enzymatic hydrolysis, they give rise to volatile, pungent, and physiologically active compounds which have antifungal, antibacterial, bioherbicidal, biopesticidal, antioxidant, antimutagenic, and anticarcinogenic activity. Recently, indole glucosinolates are attracting attention because of its properties. On hydrolysis either by chemical or enzymatic, the indole glucosinolates give the different involatile indole compounds which have anticarcinogenic activity.[93]

Sulforaphane

Sulforaphane is an isothiocyanate found especially in broccoli sprouts, Chinese kale, cabbage, and watercress. It prevents or delays preneoplastic lesions [Figure 7] shows chemical structure of sulforaphane. Sulforaphane has therapeutic activity in tumor cell cultures, carcinogen-induced cancer models, and genetic animal cancer models.[94],[95] The mechanisms by which sulforaphane exerts anticancer activity by suppressing various critical hallmarks of cancer, such as cell growth and proliferation, apoptosis, invasion, and migration.[ 96] In combination with quercetin, sulforaphane inhibits the proliferation and migration of melanoma (B16F10) cells more effectively than either compound used alone. This combined effect was predominantly due to a decrease in matrix metalloproteinases expression in the mouse tumors.[97]
Figure 7: Chemical structure sulforaphane

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The sulforaphane has shown antimetastatic activity in murine melanoma model with in vivo study by which it will be helpful in cancer immunotherapy.[98]


  Pharmaceutical Developmental Challenges and Opportunities Top


Traditional use of natural herbal phytoconstituents in melanoma treatment is relatively cheap due to the availability of plants and the simple methods used in formulation development. However, commercialization of natural compounds for cancer treatment, i.e., for melanoma, may result in declining of natural resources and problems with producing a consistent quality of adulteration. Hence, most naturally derived medicinal compounds are eventually manufactured by either semisynthetically or fermentation. For commercial use, then, these are formulated into an appropriate dosage form by which cost of the products get increased. As cancer chemoprevention and treatment using natural phytoconstituents have been such an attractive approach, further efforts are fully justifiable to thoroughly understand their potencies, pharmacokinetic performances, pharmacodynamic responses, metabolisms, toxicities, drug–drug interactions, polymorphisms, and then formulations, stabilities and degradations, and dosage regimens. Lots of scientific research are to be needed to evaluate and optimize the herbal phytochemical products for safe and more effective human use. Phytochemical products should be formulated by a novel method of nanotechnology. The drawbacks related to phytoconstituents such as poor pharmacokinetic properties, targetability, and poor bioavailability of herbal phytoconstituents, for which nanotechnology should be introduced.


  Conclusion Top


From this review, it has become clear that herbal phytoconstituents can play a major role in future melanoma treatments. This article has summarized some selected herbal phytoconstituents such as carotenoids, flavonoids, some polyphenols, piperine alkaloid, and sulforaphane which have been studied for their possible antimelanoma activity. Antimelanoma activities of phytoconstituents can be ascribed to a distinct phytochemical or to a combination of the effects of different phytochemicals. Most of the phytoconstituents have shown both in vitro and in vivo activity for melanoma. Hence, natural phytoconstituents have been and will continue to be a promising and active source for the drug discovery in the treatment of melanoma.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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