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Skin is a complex structure of the body and acts as an intermediary between the internal organ and external environment. It is a multi-lamellar organ occupied with the three distinctive layers namely epidermis, dermis and subcutaneous tissue. The skin accounts for 16% of the body weight and its thickness and surface area are approximately 1.5 – 4 mm and 2 m2 respectively (Tortora & Derrickson 2014). Figure 1 indicates the structure of skin in terms of its three main tissue layers.
The epidermis is made up of keratinized stratified squamous epithelium along with a basal lamina. The outermost layer of epidermis is stratum corneum and approximately it accounts 10-20 µm thickness. Figure 2 illustrates the structure of epidermis, “brick and mortar” model of the stratum corneum and intercellular space in the stratum corneum.
The stratum corneum consists the few layers of flattened skin cells known as corneocytes which are mostly made up of the high molecular-weight keratin. They are surrounded by a protein-lipid envelope (Elias 1988). Michaels et al. (1975) depicted the structure of the stratum corneum by using “brick and mortar” model. As demonstrated in this model, the corneocytes act as the hydrophilic brick wall while intercellular matric lipids and desmosomes serve as the hydrophobic motor (Figure 2: B). The corneocytes are embedded in the intercellular space, filled with neutral lipids organized in multiple bilayers (Figure 2:C) and they are linked to each other by desmosomes.
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Corneocytes contain the natural moisturizing factor (NMF) which is a mixture of water soluble and low molecular weight molecules to maintain the adequate hydration of the skin. Stratum corneum contains the low water content and approximately 14% of its composition comprises lipid. The principle lipid components of lamellar sheets present in the intercellular matrix are ceramides, cholesterol, and free fatty acids. There are also some minor components such as glucosylceramides, cholesterol esters and cholesterol sulfate (Wertz & Bergh 1998).
Structurally heterogeneous ceramides represent approximately 50% of the stratum corneum lipid mass. They are complex group of sphingolipids containing derivatives of sphingosine bases. Ceramides are important for the maintenance of water permeability barrier (Coderch et al 2003). Free fatty acids account approximately 15% of stratum corneum lipid mass and it increases the lattice density of the structure.
Cholesterol represents 25% of the stratum corneum lipid mass and it is one of the abundant lipid class presents in the stratum corneum. The function of cholesterol in the epidermal barrier seems to be providing a degree of fluidity and flexibility to the membrane which could otherwise be a rigid and fragile (Bouwstra et al 2000). This unique mixture of lipids in the lamellar bodies is important to maintain the barrier function, to prevent the immoderate water loss from the skin and to enhance its water holding properties (Wertz & Bergh 1998).
The epidermis is further subdivided into four distinct layers namely stratum lucidum, stratum granulosum, stratum spinosum and stratum basale (Figure 2: A). The keratinocytes found in the dermal-epidermal junction are referred to as the basal cells. These columnar shape basal cells contain nuclei and collagen fibres which anchor basal cells to the dermis (Wertz & Bergh 1998). In addition to keratinocytes, other important cell types such as melanocytes, Langerhans cells and Merkel cells can also be found in this layer (Benson & Watkinson 2012).
The dermis is thicker than epidermis and its thickness varies between 3-5 mm. It is made of elastic connective tissues and collagen which are responsible for flexibility and strength of the skin respectively.
Dermis layer contains a variety of cell types including fibroblast, macrophages, lymphocytes as well as blood vessels, hair follicles, sweat and sebaceous glands (Benson & Watkinson 2012). The subcutaneous tissue layer is known as hypodermis or superficial fascia which made of specialized layer of fat cells. These fat cells are linked to each other by elastin and collagen fibres. The hypodermis plays a significant role as a heat insulator in addition to shock absorption and reserves large quantities of calories (Tortora & Derrickson 2014)
Skin cancer is one of the most common malignancy of white population (Naves et al 2017) and in US, one in five people will develop the skin cancer during their lifetime (Stem 2010). Skin cancers are classified into three major types namely basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous malignant melanoma (CM) based on their originated cell type and clinical behaviours. The BCC and SCC skin cancers are grouped together as non-melanocytic skin cancers (Naves et al 2017).
Cutaneous Malignant Melanoma
Melanoma is the most common form of skin cancer and yearly it accounts more than 65 000 people deaths worldwide (World Health Organization 2018). According to American cancer society (2018) and American academy of dermatology association (2018), the incident and mortality rate of cutaneous malignant melanoma has been rising in the United States, on average one person in US dies from malignant melanoma in every one hour. At present, melanoma is regarded as fifth and sixth most common cancer in men and women respectively in US (American Academy of Dermatology Association (2018). In 2018, there will be 91,270 new cases of cutaneous melanoma and 9,320 deaths from melanoma in US (American cancer society (2018).
Cutaneous malignant melanoma originates from genetically altered melanocytes which are located in the basal layer of epidermis. They have ability to synthesize and transfer melanin pigments to neighboring keratinocytes (Eskandarpour 2007). As discussed in Clark’s model, the development and progression of the melanoma can be divided into five main distinct steps. Figure 3 indicates the metastasis melanoma tumor progression based on the Clark’s model.
During step one, benign nevus is formed in basal layer of epidermis as the result of mutations in normal melanocytes. In step two further alteration and uncontrolled growth of pre-existing benign lesions give rise to dysplastic nevus. During step three melanocytes in radial growth phase begin to proliferate and spread horizontally within epidermis as the result of “cadherin switching”. Malignant cells begin to invade basement and proliferate in the dermis through vertically in step four. The last step is metastasis which is considered as the most critical aspect of melanoma. Malignant melanocytes enter the blood vessels and/or lymphatic system to reach distant sites to form tumors. The most common site of metastasis is lymph nodes followed by skin, lung, liver, bone and the brain (Oraz & Sanz-Moreno 2012).
There are two main factors namely host characteristics and environmental factors appear to be the significant risk for developing malignant melanoma. Ultraviolet(UV) radiation is considered as most important environmental risk for melanoma due to its genotoxic effects (Rastelli et al 2014). The sun emits three main UV radiations including UV-A (λ = 320-400 nm), UV-B (λ = 280 -320 nm) and UV-C (200-280 nm) (Volkovova et al 2012). UVA is the predominant component of sunlight reaching the earth’s surface accounts 98.7%. It penetrates fivefold deeper into the dermis compared to the UVB since UVA wavelength is shorter than UVB (He et al. 2004).
UVB can cause direct DNA damage which may contribute to induce the mutations in keratinocytes, upregulate gene expression and suppress immune reactions which leads to develop the skin cancer in human whereas UVA is proven to cause structural damage to the DNA indirectly through the formation of reactive oxygen species (ROS) such as hydrogen peroxide, superoxide, etc. It has been experimentally demonstrated that 92% of all melanoma cases are mediated by UVB radiation even it accounts minor component of the sunlight (Davies et al 2002) The most host risk factors that cause malignant melanoma are genetic susceptibility, family history, skin type, number and type of nevus cells and pigmentation (Eskandarpour 2007).
Therapeutic Approaches for Melanoma
Malignant melanoma is the most aggressive type of skin cancer. It exhibits poor prognosis which largely result from the high metastatic potential and extraordinary resistance against conventional chemotherapy. In addition, melanocytes exhibit enhanced survival properties since they are originated from the highly motile cells (Soengas & Lowe 2003). The potential mechanisms for drug resistance in melanoma has not been fully understood yet. However, as discussed by many studies, dysregulation of apoptosis is the main cause for drug resistance in melanoma compared to other mechanisms such as detoxification by glutathione conjugation, RAS mutation, DNA transport and topoisomerases (Grossman & Altieri 2001).
Most chemotherapeutic drugs suppress the tumor growth of melanoma through the induction of apoptosis. However, it is found that low level of spontaneous apoptosis is associated with the melanoma cells compared to the other tumor cells. This notorious resistance towards to all the current cancer therapies including chemotherapy, immunotherapy and radiotherapy will undermine the success of treatment of melanoma (Gray-Schopfer et al. 2007).
Even though local therapy including radiation and surgery do play the role in melanoma treatment, the majority of melanoma patients are treated with systemic therapy Systemic therapy plays an important role in the treatment of melanoma and can be categorized into three main strategies which are immune therapy, cytotoxic chemotherapy and combination approaches. Metastasis melanoma has been treated with chemotherapy for over the past few decades and it is associated with the different types chemotherapeutics agents including alkylating agents (dacarbazine, temozolomide), antimicrotubular agents, platinum analogs etc. (Bhatia et al 2009).
Until 2011, intravenously administrated prodrug dacarbazine(DTIC) was the only standard treatment approved by the FDA for the patients diagnose with melanoma. DTIC is a cytostatic agent and converted into its active alkylating metabolite MTIC in the liver to inhibit cell proliferation via inducing the growth arrest and suppressing DNA synthesis (Lui et al 2007). In 2011, two novel drugs namely ipilimumab and vemurafenib were approved by FDA and after 20 years these are the first two drugs that demonstrated the overall survival improvement and nearly 50% response rate in clinical trials. As the result of improving knowledge of biology and complex mechanisms behind the melanoma development and progression, few more target therapies were developed over the past years. The main limitation of these developed drugs is, they are associated with severe side effects and fatal.
Several studies have proved that the response rate and the number of survivals can be improved via using combinational chemotherapy for the patients with melanoma. For an instance CDBT combination therapy that includes cisplatin, dacarbazine, BCNU and tamoxifen has been tested with the patients with metastasis melanoma to compare the response rate and number of survivals between single agent and combination chemotherapy ( Propper et al 2000 ).
In addition to this, many different combination therapies have been tested in clinical trials including but not limited to the combination of cisplatin, vinblastine and dacarbazine (CVD regimen) (Legha et al 1989), PC combination that includes paclitaxel and carboplatin ( Rao et al 2006) , but none of these combinations has able to obtain regulatory approval. Overall, combination of chemotherapeutic agents has been reported to have greater response rate than dacarbazine single agent therapy but unfortunately, these combination therapies have had minimal impact on the patient survival.
Resveratrol is a polyphenol compound which plays a key role as an antioxidant and a phytoalexin. This compound is found naturally in grapes, blueberries, peanuts, cranberries, red wine and many other plants and was shown to have multiple biological effects including ant carcinogenesis, anticancer and anti-inflammatory activities (Wang et al 2014). It has been demonstrated that resveratrol is associated with multifaceted anticancer properties including tumour initiation, promotion and progression.
Furthermore, it inhibits kinase enzyme activities and induces cancer cell apoptosis and senescence (Osmond et al 2012; Niles et al. 2003, Gatouillant et al 2010). However, the potency of resveratrol is undermined by its poor pharmacokinetic properties. This compound naturally occurs as cis(Z) and trans(E) isomers and cis – resveratrol is biologically inactive. It is found that cis form of the resveratrol can exhibit more potent anticancer activity via methylating key positions of cis-resveratrol.
Resveratrol has received significant attention due to its radiation effects. Fang et al. (2013) study evaluated the radiation sensitivity of the resveratrol on radioresistant melanoma skin cells and the results found that resveratrol plays a significant role as a radiation sensitizer on melanoma cell lines via inhibiting cell proliferation and inducing apoptosis. Resveratrol has been extensively studied for melanoma skin cancer in past few decades. As discussed by Bhattacharya, Darjatmoko & Polans (2012) study, Akt/PKB was inactivated and downregulated by resveratrol to reduce cell migratory and invasive properties of highly invasive melanoma cells (B16F10 and B16BL6). Therefore, resveratrol is considered as one of the attractive treatment for melanoma skin cancer.
It is found that resveratrol analogues which hydroxyl groups of stilbene moiety are substituted with methoxy groups increase the inhibition of cell proliferation of melanoma cancer cells and metabolic stability and bioavailability in comparison with resveratrol (Androutsopoulos, Fragiadaki & Tosca (2015). 3,4,5,4’ -trans – tetramethoxystilbene (3,4,5,4’ TMS) is a methoxylated analogue of resveratrol which has been synthesized to enhance pharmacological and pharmacokinetic properties of the resveratrol. As discussed by Androutsopoulos et al (2016) study 3,4,5,4’ TMS indicated anti-proliferative effects in A375 human melanoma cell lines (in vitro) and in Xenograft model (in vivo). The study results further demonstrated that methylated analogue of resveratrol effectively inhibited the cell proliferation via induction of apoptosis and cell cycle arrest. This growth inhibiting action was accompanied by induction of the expression of MAPK, JNK and p38 and Aurora A.
Curcumin is a yellow colored polyphenol extracted from plant curcuma longa (Sahebkar 2014). It has been widely studied in human diseases due to its pharmacological properties such as anti-inflammatory, antioxidant, anti-ischemic, anti-angiogenic, anti-depressant properties (Anand et al. 2007). It is found that curcumin has ability to regulate different type of targets including but not limited to protein kinase, adhesion molecules, cytokines (Sahebkar 2014). Curcumin is known for its both in-vivo and in-vitro anti-tumor effects.
In vivo animal studies have shown that curcumin inhibits cell growth and induce apoptosis in various types of cancers such as breast, pancreas, lung, bladder, brain, melanoma etc. (Sanidad et al. 2016). Similar findings were observed in human studies. A phase II clinical trial evaluated the anticancer efficacy of curcumin in pancreatic cancer patients and the results showed that curcumin is well tolerated, safe and pharmacologically effective in patients with advanced pancreatic cancer (Dhillon et al. 2008).
The incidence and mortality of melanoma have increased in white population at an alarming rate and curcumin is introduced as a novel drug molecule to treat melanoma due to its pharmacokinetic profile. Curcumin has demonstrated the broad range of the anticarcinogenic activity in vivo models of breast, skin oral and colon cancers (Huang et al. 1994) The limited systemic bioavailability and low aqueous solubility are considered as major problems in developing curcumin as a potential therapeutic agent.
In addition, low or unpredictable level of curcumin is observed in plasma or tissues due to its poor adsorption, rapid metabolism and elimination (Anand et al. 2007). Curcumin is less stable at the physiological pH thus leading to generate various metabolites and degradation products such as curcumin glucuronide, curcumin sulfate and tetrahydrocurcumin. The pharmacological properties of those generated degradation products are almost similar or stronger to curcumin.
