Melanoma is one of the most dangerous forms of skin cancer that develops in melanin-producing cells (brown pigment of the skin) called melanocytes. Melanoma can develop as a result of skin exposure to harmful UV rays from the sunlight, leading to the mutation (abnormal changes) of certain DNA called BRAF mutations. Irreparable DNA damage in the skin cells typically leads to formation of malignant tumor(s) in the melanocytes, present in the basal layer of the epidermis (skin). Melanoma is a complex disease, often resembling moles with characteristic black or brown color, but also in pink, skin-colored and purple colors.

Commonly, melanoma is classified into four types:

Superficial spreading melanoma – a most common form of melanoma, which spreads on the skin top layer over years before spreading to other body parts. Usually a benign mole can turn into this type of melanoma. This form is most common in young adults.

Lentigo maligna – often classified as a precancerous lesion characterized by flat or moderately elevated, mottled tan or dark brown coloration. Most commonly seen in the elderly.

Acral lentiginous melanoma – usually appears as brown or black discoloration and present in the soles of the extremities or beneath the nails. Common in African Americans and Asians. As it is often diagnosed in the later stages, it could be invasive at the time of diagnosis.

Nodular melanoma – characterized by black, gray, red or brown tan discoloration with bump(s). Usually invasive at the time of diagnosis.

Ocular melanoma – develops in the melanocytes of the eye. Not commonly diagnosed.

Amelanotic and desmoplastic melanomas – often aggressive and difficult to diagnose due to lack of pigmentation.

Early diagnosis and treatment can cure melanoma. If left undiagnosed or untreated, the malignancy is likely to spread to distant organs and can be fatal. Once melanoma spreads to other parts of the body, it is known as metastatic melanoma, and it becomes more difficult to treat. During the later stages, melanoma can spread to the lungs, liver, brain, and bones. Melanoma is the fifth common malignancy in the United States, claiming over 10,150 lives every year.

Some of the reported risk factors for developing melanoma are dysplastic nevi (abnormal moles), having more than 50 ordinary moles, fair skin that is more prone to sunburns, weakened immune system, more exposure to UV radiation, severe blistering sunburns and clinical or familial history of melanoma.

Melanoma is generally treated by the stage and location of the malignancy. The standard treatment is surgical excision with or without radiation therapy, immunotherapy, and chemotherapy and imiquimod cream. Even these treatments cannot cure melanoma, and recurrence is not uncommon in most patients.

The incidence of cutaneous melanoma is increasing, and treatment outcomes are generally poor. Development of targeted therapies for driver mutations such as BRAF/MEK appears to be novel, but the emergence of drug resistance is inevitable. Most of the patients are unresponsive to immunotherapies, which questions the rationale of breakthrough therapies, prompting the scientific community to look into alternative approaches for the treatment of metastatic melanoma.

Δ9-Tetrahydrocannabinol Promotes Apoptosis and Autophagy in Melanoma Cells

Autophagy is a lysosomal-mediated cell scavenging mechanism for the removal of damaged or aged organelles and proteins. Under normal health conditions, autophagy turnover is normal and based on metabolic stress; whereas in a diseased state, activation of autophagy is against pathogens and abnormal cells. In early stages of cancer, autophagy inhibits tumorigenesis, whereas in advanced stages autophagy acts as an energy supplier, and contributes to drug resistance to cytotoxic therapies. By exacerbation, cytotoxic autophagy can be induced to promote cell death and treat cancer. Targeting ER stress response and cytotoxic autophagy could represent significant therapeutic value for the treatment of cancers – including metastatic melanoma.

Among the cannabinoids, THC is being investigated as a promising cannabinoid for the treatment of various cancers. In vitro studies have shown that THC activates cytotoxic autophagy, resulting in apoptosis in the melanoma cell lines. Administration of THC induces apoptosis in dendritic cells via caspase cascade-dependent mitochondrial pathways (mediated by cannabinoid receptors). THC exerts anticancer properties via up-regulation of transcriptional coactivator p8, induction of autophagy and endoplasmic reticulum (ER) stress and execution of apoptosis. This cytotoxic pathway is mediated by p8/TRIB3 and autophagy-induced upstream of apoptosis.

THC exerts anti-tumor effects via the activation of non-canonical autophagy, and resultant apoptosis in melanoma cells. Although the complete mechanisms underlying these benefits have been not understood, it is believed to be due to the effect of THC (via de novo synthesis of ceramide) in the activation of ER stress, inhibition of TRIB3-induced Akt/mTORC1 signaling and autophagy-induced apoptosis. Briefly, THC administration induces melanoma cell death by formation of sphingolipid ceramide, which increases the stress on endoplasmic reticulum (ER), and contributes to apoptosis. Additionally, via activation of TRIB3, THC inhibits Akt/mTORC1 signaling pathway (involved in inhibition of apoptosis of cells). During this stress response, TRIB3 switches from cell survival mode to apoptosis. Administration of THC induces TRIB3 to mediate cell apoptosis and ER stress-induced autophagy in melanoma cells. Collectively, by increasing the stress response and preventing the cell survival pathway, THC promotes rapid death of melanoma cells, in a dose-dependent manner. However, the normal cells remain untouched, which is noteworthy.

THC-induced autophagy of melanoma is also independent of Ambra1 and Beclin-1 interacting proteins, which are also involved in the complex regulation of autophagy. THC promotes autophagy and apoptosis in both BRAF-mutated and BRAF wild type in melanoma cells, despite the melanoma cells elicit treatment-resistance measures such as autophagy deregulation. Considering this evidence, we can begin to understand that THC might be really effective against melanoma, regardless of BRAF mutational status.

According to a recent study, both THC and CBD were found to decrease the viability of melanoma cells. Combined administration of low dose THC with CBD resulted in significant anti-tumor effects, which was found to be equally effective to that of higher dose THC-alone treatment. In melanoma patients, a higher dose of THC monotherapy may cause undesirable side effects, which can be fended-off by considering low dose THC plus CBD, which is equally effective. CBD promotes cell apoptosis via caspase activation and generation of free radicals (oxidative stress) in the malignant cells. These findings suggest that CBD and THC act in different molecular pathways to synergistically promote tumor cell death.

Similar results were also observed by other independent studies. According to these studies, plant-derived THC inhibited melanoma cells and treated skin tumors; however, these benefits were observed only in exogenous cannabinoids but not with endogenous cannabinoids. THC-induced anti-cancer benefits were also observed in non-melanoma skin tumors; however in such cases, the therapeutic potential was found to be due to abrogation of EGF-receptor functions and pro-angiogenic factors. So, medical marijuana might be useful to treat most of types of skin cancer, including melanoma and non-melanoma skin tumors.

Based on the available scientific evidence, cancer has been included as a qualifying medical condition for medical marijuana programs across several states in the United States. Despite the availability of experimental research evidence, no standardized clinical trials have been conducted for the treatment of melanoma and other dreadful diseases. Amending legislation and changing the social stigma towards medical cannabis might change the situation, and hopefully more controlled clinical trials will be conducted in the future. These steps might be helpful for clinicians and patients to understand the medicinal benefits of cannabis, and to make an informed decision to treat skin cancers – including melanoma.

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