Understanding Melanoma

compiled by John G. Connor, M.Ac., L.Ac., edited by Barbara Connor, M.Ac., L.Ac.

Table of Contents
Research on Natural Compounds That May be Suppressive Against Melanoma
Understanding Conventional Therapies Used In Melanoma
Understanding Biomarkers, Growth Factors and Mutations in Melanoma

Melanoma is a malignant tumor of melanocytes. (Lovly et al 2012) Ultraviolet (UV) radiation is a well established etiologic risk factor for the incidence of melanoma and non-melanoma skin cancers, and these skin cancers are a major burden on the health care system. The incidence of skin cancers is equivalent to the incidence of malignancies in all other organs combined. One of the hallmark events of exposure to UVB radiation (290–320 nm) is the induction of apoptotic cell death of keratinocytes, the results of which are evident within the epidermis as sunburn cells. The formation of sunburn cells in UV-exposed skin indicates the severity of DNA damage. The repair of DNA damage in UVB-exposed skin cells can prevent the accumulation of damaged cells. If cells are not repaired, they may continue to replicate and may lead to cutaneous malignancies. This means that DNA repair process is a protective mechanism. Alternatively, induction of apoptosis of keratinocytes to UVB radiation is also a protective mechanism relevant in limiting the survival of cells with irreparable DNA damage. (Katiyar et al 2011)

The treatment of early-stage melanoma consists primarily of surgical removal of the tumour. The overall 5-years survival rate for malignant melanoma is 81%. (Perrotta et al 2010)

According to the Surveillance Epidemiology and End Results data, melanoma is the sixth most common fatal malignancy in the United States, responsible for 4% of all cancer deaths and 6 of every 7 skin cancer-related deaths. (Riker et al 2010)

Malignant melanoma is noted for its aggressive clinical behavior, a propensity for lethal metastasis and striking therapeutic resistance. (Dankort et al 2009) Melanoma has a poor prognosis due to its strong metastatic ability. (Baljinnyam et al 2010)

Melanoma skin cancer is among one of the leading cancers targeting adolescents and young adults in the North America. Melanoma is notoriously chemo-resistant and the modes of treatment for melanoma are very limited, relying mainly on surgical excision of the primary site during early detection, and whatever limited chemotherapy and immunotherapy for metastasized melanoma that is available. However, these therapies have limited success and incur side effects. (Chatterjee et al 2011)

Melanoma originates from melanocytes, and the biology of these cells may give clues to the pathophysiology of melanoma. Cutaneous melanocytes originate from neural crest progenitors that migrate to the basal layer of the epidermis during embryonic development. Epidermal keratinocytes regulate melanocyte homeostasis via secretion of factors that regulate survival, differentiation, and proliferation. Ultraviolet radiation stimulates the release of these factors from keratinocytes, thus ultimately causing the release of melanin from melanocytes. During the evolution from benign melanocyte to malignant melanoma, this tight-knit regulation from keratinocytes is lost. The lost communication can lead to a benign nevus; however, with continued lack of regulation a malignant melanoma can develop. The 4 main clinical types of melanoma (superficial spreading, lentigo maligna, nodular, and acral lentiginous) may all have a unique and different pathophysiologic and molecular basis. (Kudhcadkar 2010)

Over the past several decades, volumes of work and data have accumulated to identify the characteristics of primary melanoma, which are used to stratify patients based on risk of recurrence and overall survival. Currently, Breslow thickness is the single most widely used clinicopathologic factor to individualize surgical management, with a difference of 0.01 mm in the thickness of 2 otherwise identical melanomas being enough to signal a difference in treatment. Clinical stage I melanomas (those with a primary melanoma ≤1 mm) are associated with a very low rate of distant metastasis and death from melanoma and with a low rate of local or regional recurrence. Melanomas <0.76 mm in thickness are at particularly low risk for any type of recurrence or metastasis. There is considerable interest in further refining which “thin” melanomas are at sufficient risk of nodal metastasis to justify surgical staging of the regional nodes by sentinel lymph node biopsy. Thin melanomas with ulceration (T1b) are very infrequent, but the available data suggest their risk of nodal metastasis is high enough to justify sentinel node biopsy. The 2010 version of the American Joint Committee on Cancer Melanoma Staging System replaces Clark level with mitotic rate, such that nonulcerated T1 melanomas with a mitotic rate of ≥1 mm2 are considered T1b regardless of Clark level and T1a melanomas are those with a mitotic rate of zero. (Gonzalez et al 2010)

Few agents are available for treating advanced disease to enable long-term patient survival, which is driving the search for new compounds inhibiting deregulated pathways causing melanoma. Akt3 is an important target in melanomas since its activity is increased in ~70% of tumors, decreasing apoptosis in order to promote tumorigenesis. (Sharma et al 2009)

At least 6 genes have been shown to be recurrently mutated in melanoma, including the serine-threonine kinase encoded by BRAF; the receptor tyrosine kinase encoded by KIT; the GTP-binding proteins encoded by NRAS,GNA11, and GNAQ; and the WNT signaling pathway component encoded by CTNNB1. (Lovly et al 2012)

Individual studies estimate that as many as 69% of US cancer patients employ some type of complementary and alternative medicine, 76% of patients in a study of Midwestern cancer patients and 95% of radiation oncology patients in another study.  (Wargovich et al 2010)

There is an ever growing interest in treatment with natural compounds as an adjuvant cancer therapy along with conventional cancer therapy. (Virk-Baker et al 2010) For example the combination of a natural VEGF inhibitor along with lower doses of a pharmacological agent may prove helpful in reducing the unwanted side effects of chemotherapy. (Wargovich et al 2010)

Recent evidence shows that pharmaconutrients may act against proliferation, angiogenesis and metastasis in different types of human cancer. (Granci et al 2010)

Because sunscreen use does not completely prevent skin cancer induced by ultraviolet radiation, additional chemopreventive methods for protecting against and reversing the effects of ultraviolet photodamage need evaluation. Recent years have brought increased interest in dietary factors, such as natural botanicals and vitamins, for the prevention of melanoma. Although randomized controlled trials of humans are lacking, basic science and epidemiologic studies show promising benefits of many natural products in chemoprevention for melanoma. (Jensen et al 2010)
Research on Natural Compounds which may be Suppressive Against Melanoma
Betulinic acid – Our results showed that hydroxylation at the C3 position of betulinic acid is likely to enhance the apoptotic activity of betulinic acid derivatives (23-hydroxybetulinic acid and 3-oxo-23-hydroxybetulinic acid) on murine melanoma B16 cells. (Liu et al 2004) 

Bitter melon (Momordica charantia) – The present Super Mario study demonstrate chemopreventive potential of Momordica fruit and leaf extracts on DMBA (dimethyl benz(a)nthracene) induced skin tumorigenesis, melanoma tumour and cytogenicity. (Agrawal & Beohar 2010)

Bromelain – We describe its anti-proliferative, anti-inflammatory and subsequent anti-cancer effects in vitro, against human epidermoid carcinoma-A431 and melanoma-A375 cells. Bromelain exhibited reduction in proliferation of both these cell-lines and suppressed their potential for anchorage-independent growth. Further, suppression of inflammatory signaling by bromelain was evident by inhibition of Akt regulated-nuclear factor-kappaB activation via suppression of inhibitory-kappaBα phosphorylation and concomitant reduction in cyclooxygenase-2. (Bhui et al 2011)

Cordycepin (a component of Cordyceps sinensis) – These results suggest that ADP accelerated hematogenic metastasis and cordycepin has an inhibitory effect on hematogenic metastasis of B16-F1 melanoma cells via blocking of ADP-induced platelet aggregation in vivo. (Yoshikawa et al 2009) 

Curcumin has potent antiproliferative and proapoptotic effects in melanoma cells. These effects were associated with the suppression of NF-kappaB and IKK activities but were independent of the B-Raf/MEK/ERK and Akt pathways. (Siwak et al 2005) 

Dry olive leaf extract (DOLE) – Taken together, the results of this study indicate that DOLE possesses strongantimelanoma potential. When DOLE was applied in combination with different chemotherapeutics, various outcomes, including synergy and antagonism, were observed. This requires caution in the use of the extract as a supplementary antitumor therapeutic. (Mijatovic et al 2011)

Ginsenoside Rk1 isolated from red ginseng might be a promising compound to induce apoptosis through both extrinsic and intrinsic pathways in SK-MEL-2 human melanoma cells. (Ginsenosides are active compounds isolated from Panax ginseng Meyer.)  (Kim et al 2012) 

Grape Seed Proanthocyanidins (GSPs) – These results indicate that GSPs have the ability to inhibit melanoma cell invasion/migration by targeting the endogenous expression of COX-2 and reversing the process of epithelial-to-mesenchymal transition. (Vaid et al 2011)

ISC-4 (Isoselenocyanate-4) topical treatment – can delay or slow down melanocytic lesion or melanomadevelopment in preclinical models and could impact melanoma incidence rates if similar results are observed in humans. (Nguyen et al 2011)

Isothiocyanates – were identified as candidates but low potency requiring high concentrations for therapeutic efficacy made them unsuitable. Therefore, more potent analogs called isoselenocyanates were created using the isothiocyanate backbone but increasing the alkyl chain length and replacing sulfur with selenium. Synthetic isoselenocyanates are therapeutically effective for inhibiting melanoma tumor development by targeting Akt3 signaling to increase apoptosis in melanoma cells with negligible associated systemic toxicity. (Sharma et al 2009) 

5Lipoxygenase inhibitors can inhibit the expression of ICAM-1 in human melanoma cells and may be valuable for treatment of melanoma metastasis. (Wang et al 2004) 

Pterostilbene (PTER) and quercetin (QUER) – Our findings demonstrate that the association of PTER and QUER inhibits metastatic melanoma growth and extends host survival. (Ferrer et al 2005) 

Resveratrol – All these data support a potential use of resveratrol alone or in combination with other chemotherapeutic agents in the management of chemoresistant B16 melanoma tumors. (Gatouillat et al 2010)

Selenium might be a potent inhibitor of theاقوي اكشن من  metastatic capacity of melanoma cells, via down-modulation of IL-18 expression. (Song et al 2011)

Theaflavin (black tea polyphenol) – we report that theaflavin causes an inhibition of the expression and activity of pro-MMP-2 by a process involving multiple regulatory molecules in human melanoma cells, A375. (Sil et al 2010)

Ursolic acid – All these results demonstrate that ursolic acid induce apoptosis in B16F-10 metastatic melanomacells via inhibition of NF-kappaB induced bcl-2 mediated anti-apoptotic pathway and subsequent activation of p53 mediated and TNF-alpha induced caspase-3 mediated pro-apoptotic pathways. (Manu et al 2008) 

Whey protein isolate – Caspase-3 expression on melanoma cells (B16F10) increased significantly in all media containing F and R fractions, and also in the presence of BCH or WPI. Apoptosis was extremely high at low concentration (400 microg/mL) of the F1-F3 fractions. It is suggested that a mechanism for tumorigenesis inhibition may involve the caspases cascade and apoptosis. (Castro et al 2009) 

Understanding Conventional Therapies Used In Melanoma
Melanoma is among the top six cancers responsible for cancer-related mortality worldwide. Once melanoma metastasizes treatment outcome is poor. Only a few chemotherapeutic agents have been shown to be active in the treatment of melanomas. The most often used drug is dacarbazine (DTIC), which needs metabolic activation to generate the active DNA-methylating carbenium ions inside the cell. Temozolomide (TMZ), which is a triazene derivative that needs no metabolic activation, also has activity in melanoma cells. It hydrolyses spontaneously in aqueous solution, giving rise to the active metabolite 5-(3,3-methyltriazen-1-yl)imidazole-4-carboxamide that further decomposes to yield DNA-methylating species. The response rate after treatment with these methylating drugs is ~20%. (Naumann et al 2009)

Dovitinib (TKI258) is an orally available inhibitor of fibroblast growth factor (FGF), VEGF, and platelet-derived growth factor receptors. This phase I/II dose-escalation study was conducted to evaluate the safety, pharmacodynamics, and preliminary efficacy of dovitinib in the treatment of advanced melanoma. At a dose of 400 mg/d, dovitinib showed an acceptable safety profile and limited clinical benefit and inhibited FGFR and VEGFR. (Kim et al 2011)

Ipilimumab with dacarbazine – In 2011, a significant survival benefit of the combination of ipilimumab with dacarbazine compared with dacarbazine alone for first-line treatment was reported. (Eggermont & Robert 2011)
Sunitinib may have activity in patients with melanoma and KIT mutations; more study is needed. KIT mutations may represent an adverse prognostic factor in metastatic melanoma. (Minor et al 2012) 

Vemurafenib (Zelboraf) – While the majority of melanoma patients with BRAF-mutated disease show favorable treatment responses shortly after initiation of vemurafenib therapy, the median progression-free survival is 6 months, making the search for resistance mechanisms a high priority. While vemurafenib represents an excellent model for successful targeted anticancer therapy, long-term safety data are needed and rational combination with other agents will be critical to prevent or circumvent the development of resistance.(Amaria et al 2012)

Vemurafenib – A significant impact on both progression-free and overall survival was demonstrated for vemurafenib compared with dacarbazine in a phase-III trial. (Eggermont & Robert 2011)

The Dermatolgic Cooperative Oncology Group study contributes to the recognition of in vitro chemosensitivity testing as a reasonable tool for the selection of individualized chemotherapy regimens. The present study was not designed to compare two different therapy regimens, but rather to help identify the individually most effective drugs among multiple nonstandard options. Our results show that the assay used in this study is predictive of therapy outcome, and indicate that nonstandard chemotherapeutics are effective in melanoma if they are applied selectively based on individual chemosensitivity profiles. However, these encouraging results need further evaluation by prospectively randomized trials. (Ugurel et al 2006)

Understanding Biomarkers, Growth Factors and Mutations in Melanoma
Bcl-2 – All these results demonstrate that ursolic acid induce apoptosis in B16F-10 melanoma cells via inhibition of NF-kappaB induced bcl-2 mediated anti-apoptotic pathway and subsequent activation of p53 mediated and TNF-alpha induced caspase-3 mediated pro-apoptotic pathways. (Manu & Kuttan 2008)

BRAF – Activating mutations of BRAF are seen in 50% to 60% of melanomas and are also frequently present in benign nevi. However, most nevi do not transform into malignant melanoma. This implies that BRAF mutation may be necessary but not sufficient to induce malignant transformation. The most common mutation seen is the V600E mutation in which a glutamine is substituted for a valine. This leads to constituently stimulated MAPK pathway, thus leading to increased survival and growth. (Kudhcadkar 2010)

BRAF & MAPK – Oncogenic mutations in the serine/threonine kinase B-RAF (also known as BRAF) are found in 50-70% of malignant melanomas. These results provide new insights into resistance mechanisms involving the MAPK pathway and articulate an integrative approach through which high-throughput functional screens may inform the development of novel therapeutic strategies. (Johannessen et al 2010)

COX-2 – Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers. (Elmets et al 2010)

E-cadherin  – A central event in the development of malignant melanoma is the loss of the tumor-suppressor protein E-cadherin. Here, we report that this loss is linked to the activation of the proto-oncogene c-Jun, a key player in tumorigenesis. (Spangler et al 2011)

EGFR – appears to be involved in progression and metastasis of a subset of melanomas. Targeting EGFR could therefore represent a therapeutic option for these melanomas. (Boone et al 2011)

HDAC 1 and 2 – Our data identify critical requirements for HDAC1/2 in epidermal development and indicate thatHDAC1/2 directly mediate repressive functions of p63 and suppress p53 activity. (LeBoeuf et al 2010)

KI-67 rates the mitotic rate (Histopathology 20002, 41, 519-525, British Journal of Cancer (2007) 96, 445–449. Melanoma Res. 2005 Oct;15(5):375-81, Journal of the American Academy of Dermatology, Feb 23, 2001)

LOX-5 (Acta Pharmacol Sin. 2004 May;25(5):672-7)

MGMT (methylguanine-DNA- methyltransferase) Loss of MGMT expression, as
measured by MGMT promoter methylation, has been correlated with improved response rate and progression-free survival to temozolomide (Clinical Cancer Research January 2009 15; 502)

MMP-2  – We translated the in vitro data in mice model and observed enhanced tumor growth with higher MT1-MMP expression and MMP-2 activation in the tumors upon injection of HABP1 treated melanoma cells. The treatment of curcumin, the anticancer drug along with HABP1, inhibited the migration, expression of MT1-MMP and activation of MMP-2 and finally tumor growth supports the involvement of HABP1 in tumor formation. (Prakash et al 2011)

MMP-9 & 1 – High serum levels of matrix metalloproteinase-9 and matrix metalloproteinase-1 are associated with rapid progression in patients with metastatic melanoma. (Nikkola et al 2005) There is evidence, however, indicating that their MMP-9 results in serum do not reliably reflect the circulating levels of MMP-9. Measurement of MMP-9 levels in serum has been reported as artificially high compared with the results obtained from plasma samples.Therefore, there is strong evidence indicating that serum samples should not be used to measure circulating MMP-9 levels as a diagnostic or as a prognostic marker of disease. (Gerlach 2005) 

mTOR (JAAD, Volume 60, Issue 5, Pages 863-868, May 2009, Br J Dermatol. 2009 May;160(5):955-64. Epub 2008 Dec 16, Journal of the American Academy of Dermatology, Volume 60, Issue 5, May 2009, Pages 863-868)

NF-kappaB – All these results demonstrate that ursolic acid induce apoptosis in B16F-10 melanoma cells via inhibition of NF-kappaB induced bcl-2 mediated anti-apoptotic pathway and subsequent activation of p53 mediated and TNF-alpha induced caspase-3 mediated pro-apoptotic pathways. (Manu & Kuttan 2008)

p53 – All these results demonstrate that ursolic acid induce apoptosis in B16F-10 melanoma cells via inhibition of NF-kappaB induced bcl-2 mediated anti-apoptotic pathway and subsequent activation of p53 mediated and TNF-alpha induced caspase-3 mediated pro-apoptotic pathways. (Manu & Kuttan 2008)
PDGF and c-Kit (Clin Cancer Res. 2008 Dec 1;14(23):7726-32)

PI3K and mTOR – Phosphoinositide 3-kinase (PI3K)/protein kinase B/Akt and Ras/mitogen-activated protein kinase pathways are often constitutively activated in melanoma and have thus been considered as promising drug targets. Compounds targeting PI3K and mTOR simultaneously were advantageous to attenuate melanoma growth and they develop their potential by targeting tumor growth directly, and indirectly via their interference with angiogenesis. (Marone et al 2009)

PTEN – Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor. However, the critical genetic targets of UVB radiation are undefined. Here we show that attenuating PTEN in epidermal keratinocytes is a predisposing factor for UVB-induced skin carcinogenesis in mice. In skin papilloma and squamous cell carcinoma (SCC), levels of PTEN were reduced compared with skin lacking these lesions. (Ming et al 2011)

PTEN  – Correspondingly, gain- and loss-of-function studies established that PTEN loss increases invasion and migration of melanoma cells and non-transformed melanocytes, and such biological activity correlates with a shift to phosphorylation of AKT2 isoform and E-cadherin down-regulation. Thus, PTEN inactivation can drive the genesis and promote the metastatic progression of RAS activated Ink4a/Arf deficient melanomas. (Nogueira et al 2010)

STAT3 – The activation of signal transducer and activator of transcription 3 (STAT3) has been identified as a key mediator that drives the fundamental components of melanoma malignancy, including immune suppression in melanoma patients.(Cancer Immunol Immunother. 2009 Jul;58(7):1023-32. Epub 2008 Nov 11) (Kong et al 2009)

Survivin – Together, our results showed that survivin enhanced the migration and invasion of melanocytic cells and suggested that survivin may promote melanoma metastasis by supporting Akt-dependent upregulation of α5 integrin. (McKenzie et all 2010)

TGF-beta – Melanoma often metastasizes to bone where it is exposed to high concentrations of TGF-β. Our results demonstrate that therapeutic targeting of TGF-β may prevent the development of melanoma bone metastases and decrease the progression of established osteolytic lesions. (Mohammad et al 2011)

TNF-alpha – All these results demonstrate that ursolic acid induce apoptosis in B16F-10 melanoma cells via inhibition of NF-kappaB induced bcl-2 mediated anti-apoptotic pathway and subsequent activation of p53 mediated and TNF-alpha induced caspase-3 mediated pro-apoptotic pathways. (Manu & Kuttan 2008)

VEGFR-1 – Melanoma growth is driven by malignant melanoma-initiating cells (MMIC). Our results show that VEGFR-1 function in MMIC regulates VM and associated laminin production and show that this function represents one mechanism through which MMICs promote tumor growth. (Frank et al 2011)

VEGF, bFGF, and IL-8 – Our data suggest that the angiogenic serum factors VEGF, bFGF, and IL-8 are useful predictive markers for overall and progression-free survival in melanoma patients. (Ugurel et al 2001)

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