ERK inhibitor - (BVD-523) Ulixertnib. A new approach to targeted therapy for melanoma? Here's hoping!!!

Remember this crazy diagram????

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (ulixertinib). Germann, Furey, Markland, et al. Mol Cancer Ther. 2017 Sep 22.

Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF- and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic anti-proliferative effects in a BRAFV600E mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to single-agent and combination BRAF/MEK targeted therapy. Based on these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway  (NCT01781429, NCT02296242 and NCT02608229).  


I like ERK!!!  I mean, I like it as I've always liked onomatopoeia!!!  (Don't you just love to say THAT word???  Onomatopoeia!!!)  I like "ERK!!!" like I like "BAM!!" in comics.  Or "tic tock" in Mother Goose and scary stories!  When I was a kid, my sisters and I played dramatic pretend games, with one of us telling the other, "Pretend like....." .  Then, the other...would indeed pretend like - whatever  - as had been prescribed for the story line.  Words like "POW!!!" and "ERK!!!" figured largely in abrupt crashes and conclusions.  So....yeah.  I like ERK!!!  Let's put the brakes on melanoma!  ERK!!!! (Thanks to the mice.  Here we go, ratties!) - love, c

ASCO 2017: ERK inhibitor - Ulixertinib (BVD-523) working in NRAS as well as BRAF V600 and non-V600 melanoma

Many "innovative" combinations that would make targeted therapy better have long been discussed, including: Hsp90,   HDAC,   PI3 kinase/AKT,   ERK, and   ERBb3 inhibitors and then some.  Data is more readily available on some than others.  Keeping the diagram posted yesterday in mind...as well as this one:

 Here is a report on Ulixertinib, an ERK inhibitor:

First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study.

ASCO 2017. J Clin Oncol 35, 2017. Li, Janku, Patel, ...Flaherty, ...Sznol, Sosman..., Ribas, ….Infante.

Backkground: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head and neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head and neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429

Despite a lot of back and forth about cohorts and expansion cohorts....as best as I can tell, 108 patients with various sold tumors, took ulixertinib, 600 mg orally, twice daily.  Most common side effects were rash, diarrhea, fatigue and nausea...no drug related deaths, though 32% required a drug reduction.  Of 83 evaluable patients, 9 had a partial response.  Three of these were NRAS mutant melanoma and 4 had tumors that were BRAF V600E mutant, but only one of those had melanoma and they had been refractory to prior BRAFi/MEKi treatment.  

So...incredibly small numbers period...especially in regard to melanoma...but...you gotta start somewhere!!!  Hang in there ratties. - c

Everything Cures Melanoma....# 7

Yep, the list of melanoma cures (in a petri dish - for the most part) is long and varied!!!  The short list includes ~ coffee (multiple reports), tea, doxycycline, curcumin and curry (many reports), cimetadine, NSAID's, shiitake mushrooms, exercise, red wine, strawberry juice, snake venom, sephora root, glycoalkaloids (found in eggplants, potatoes, and tomatoes), dill and parsley extracts, wild olive leaves, emu oil, oyster extract, Brazilian lima beans, lichen, sandalwood, beta blockers, and vitamin D (there may actually be something to this one!!) ~ to name a few!!!  Here are links to the data:  Everything Cures Melanoma: Installment #6

But, there is still more!

Melanoma and brown seaweed: an integrative hypothesis.  Teas, Irhimeh.  J Apppl Phycol. 2017.  

Although relatively rare, melanoma accounts for 2 % of cancer diagnoses globally and accounts for about 1 % of all cancer deaths. Worldwide, the annual incidence of melanoma is 272,000 cases which vary hugely, ranging from Japan where it is incredibly infrequent, to Queensland, Australia, where it is nearly 100 times higher. Based on epidemiology and laboratory studies, there is compelling evidence suggesting that seaweed might be protective against different types of cancers such as breast cancer in seaweed consuming populations. By comparing countries where melanoma is more common with countries where it is infrequent, it is possible to construct a hypothesis for how consuming brown seaweeds which may hold clues to the differences in melanoma susceptibility between Japanese and Western nations. Unlike in these other countries, where melanoma incidence has increased dramatically over the last two decades, in Japan, rates have remained remarkably low and stable. There is limited evidence from clinical studies and animal models that have used whole seaweed or isolated fractions from seaweed and measured changes in biomarkers. They have demonstrated the effectiveness of seaweed at inhibiting melanoma development and progression. In this review, the various results will be described. Although there are several effective fractions, it is proposed that consuming whole seaweeds may hold additional benefits that could be lost by consuming only a single extract.

Mitochondria-Associated Apoptosis in Human Melanoma Cells Induced by Cardanol Monoene from Cashew Nut Shell Liquid. Su, Lin, Yu, et al. J Agric Food Chem. 2017 Jun 19.  

Cardanol monoene (CM) is the major phenolic component extracted from cashew nut shell liquid (CNSL), which has been relevant to wide range of biological effects. In this study, we found that CM could inhibit the M14 human melanoma cells proliferation in a dose dependent and time dependent manner, and the IC50 values were determined to be 23.15 ± 2.42 μM and 12.30 ± 1.67 μM after 24 h and 48 h treatment, respectively. The flow cytometric analysis demonstrated that CM induced M14 cell cycle arrest at S phase, along with the collapse of mitochondrial membrane potential (ΔΨm) and the accumulation of reactive oxygen species (ROS) level in cells but the apoptotic cells reduced when treated with Z-VAD-FMK (pan-caspase inhibitor). Western blotting showed that the expressions of p53, cytochrome C, caspase-3 and PARP were up-regulated, the expression level of Bax/Bcl-2 ratio increased significantly. The 2527 significant differentially expressed genes were obtained by RNA-seq, which were assigned to 270 KEGG pathways. These results indicated that CM induced M14 cells apoptosis via the ROS triggered mitochondrial-associated pathways, which supports the potential application of CM for the therapy of melanoma cancer.

Young leaves of reed (Phragmites communis) suppress melanogenesis and oxidative stress in B16F10 melanoma cells. Sim, Ham, Lee. Biomed Pharmacother. 2017 Jun 16. 

This study investigated the effects young leaves of reed (Phragmites communis) water extract (YLR) on melanogenesis and oxidative stress using B16F10 cells. YLR decreased the intracellular melanin content, protein expression and enzyme activity of tyrosinase in a dose-dependent manner. YLR significantly decreased the gene and protein expression of melanogeneis-related proteins, such as microphthalmia-associated transcription factor (MITF), and tyrosinase-related protein-1 and -2. In addition, YLR up-regulated the melanogenesis inhibitory proteins, extracellular signal-regulated kinase (ERK) and protein kinase B (AKT), while it dose-dependently down-regulated p38 and cAMP response element-binding protein (CREB). Moreover, YLR significantly reduced H₂O₂-induced reactive oxygen species levels in B16F10 cells and showed antioxidant activity based on DPPH and ABTS free radical scavenging activity and SOD-like activity. These results suggest that YLR have anti-melanogensis properties that function through regulation of the CREB/MITF/tyrosinase pathway in B16F10 cells and antioxidant activity. Overall, these findings indicate that YLR has the potential for use in treatment of skin disorders and skin-whitening.

A polymethoxyflavone mixture extracted from orange peels, mainly containing nobiletin, 3,3',4',5,6,7,8-heptamethoxyflavone and tangeretin, suppresses melanogenesis through the acidification of cell organelles, including melanosomes. Yoshizaki, Hashizume, Masaki.  J Dermatol Sci. 2017 Jun 10.

Skin color is determined by melanin contents and its distribution. Melanin is synthesized in melanosomes of melanocytes, catalyzed by tyrosinase, melanogenic enzymes. Regarding the process of melanin synthesis, melanosomal pH is considered to play an important role, because it has been reported to differ between Caucasian and Black melanocytes.
Although polymethoxyflavone (PMF) has many beneficial effects, it has not been reported which PMF suppresses melanogenesis. In this study, we identified the mechanism underlying the effect of PMF on melanogenesis METHODS: We determined the effects of a PMF mixture extracted from orange peels on melanogenesis, on tyrosinase expression, on the localization of tyrosinase and on the acidification of organelles, including melanosomes, in HM3KO human melanoma cells. RESULTS TREATMENT: with the PMF mixture elicited the suppression of melanogenesis, the degradation of tyrosinase in lysosomes and the mislocalization of tyrosinase associated with the acidification of intracellular organelles, including melanosomes. The neutralization of cell organelle pH by ammonium chloride restored melanogenesis and the correct localization of tyrosinase to melanosomes, which had been suppressed by the PMF mixture.  These results suggest that the PMF mixture suppresses the localization of tyrosinase to melanosomes and consequently inhibits melanogenesis due to the acidification of cell organelles, including melanosomes.

Bioactivities of ethanol extract from the Antarctic freshwater microalga, Chloromonas sp. Suh, Yang, Lee, et al. Int J Med Sci. 2017 Apr 28.  

Cancer is the principal cause of human death and occurs through highly complex processes that involve the multiple coordinated mechanisms of tumorigenesis. A number of studies have indicated that the microalgae extracts showed anticancer activity in a variety of human cancer cells and can provide a new insight in the development of novel anti-cancer therapy. Here, in order to investigate molecular mechanisms of anticancer activity in the Antarctic freshwater microalga, Chloromonas sp., we prepared ethanol extract of Chloromonas sp. (ETCH) and performed several in vitro assays using human normal keratinocyte (HaCaT) and different types of cancer cells including cervical, melanoma, and breast cancer cells (HeLa, A375 and Hs578T, respectively). We revealed that ETCH had the antioxidant capacity, and caused significant cell growth inhibition and apoptosis of cancer cells in a dose-dependent manner, whereas it showed no anti-proliferation to normal cells. In addition, ETCH had a significant inhibitory effect on cell invasion without the cytotoxic effect. Furthermore, ETCH-induced apoptosis was mediated by increase in pro-apoptotic proteins including cleaved caspase-3 and p53, and by decrease in anti-apoptotic protein, Bcl-2 in ETCH-treated cancer cells. Taken together, this work firstly explored the antioxidant and anticancer activities of an Antarctic freshwater microalga, and ETCH could be a potential therapeutic candidate in the treatment of human cancer.

Anti-Metastatic Effect of Semi-Purified Nuphar Lutea Leaf Extracts. Ozer, Fishman, Eilam, et al.  J Cancer. 2017 May 12.  

Nuphar lutea L. SM., leaf and rhizome extracts (NUP), contain nupharidines as active components. Nupharidines belong to the sesquiterpene lactones class of a naturally occurring plant terpenoids. This family of compounds has gained considerable interest for treating infection, inflammation and cancer. NF-κB is a central, downstream regulator of inflammation, cell proliferation and apoptosis. In our previous work we demonstrated strong inhibition of NF-κB activity and induction of apoptosis by NUP. In addition, NUP exhibited anti-inflammatory properties and partial protection from LPS-induced septic shock by modulating ERK pathway and cytokine secretion in macrophages. In the present study, we examined the effect of NUP in a B16 melanoma experimental murine lung metastasis model and its ability to affect the ERK and NF-κB pathways in variety of cell lines. We showed that NUP and cisplatin combined treatment was synergistic and reduced the lung metastatic load. In addition NUP treatment inhibited TNFα-induced IκBα degradation and NF- κB nuclear translocation. We also observed that NUP induced ERK activation. Furthermore, ERK inhibition prevented NF-κB inactivation by NUP. Overall, our work implies that co-administration of NF-κB inhibitors such as NUP, with standard anti-cancer drugs, may act as "sensitizers" for more effective chemotherapy.

Antiproliferative and proapoptotic activities of anthocyanin and anthocyanidin extracts from blueberry fruits on B16-F10 melanoma cells. Wang, Liu, XU, Liu.Food Nutr Res. 2017 Jun 19.  

Background: Anthocyanins have been proven to affect multiple cancer-associated processes in different cancer cell lines. However, relatively few studies have investigated the effects of blueberry anthocyanins on metastatic melanoma. Thus, this study focuses on evaluating the chemopreventive potential of blueberry anthocyanins and their aglycones (anthocyanidins) in B16-F10 melanoma cells. Methods: Blueberry anthocyanin and anthocyanidin extracts were prepared mainly by combined chromatography techniques. Their antiproliferative and proapoptotic effects on B16-F10 cells were evaluated by MTT assay, calcein acetoxymethyl ester/propidium iodide (calcein-AM/PI) staining, and flow cytometry of the cell cycle and apoptosis. Results: The MTT and calcein-AM/PI staining results showed that both anthocyanin (purity of 62.5%) and anthocyanidin (75.1%) extracts could significantly inhibit the viability and proliferation of B16-F10 cells in a dose-dependent manner, while anthocyanidin extracts exhibited significantly higher (p < 0.05) cytotoxicity than anthocyanin extracts. Furthermore, anthocyanin and anthocyanidin extracts blocked cell cycle procession at the G0/G1 phase below 400 and 200 μg/mL, and induced early apoptosis below 400 and 300 μg/mL, respectively. Conclusions: These data suggest that both anthocyanin and anthocyanidin extracts inhibit the proliferation and trigger the apoptosis of B16-F10 cells, and anthocyanidin extracts may be a more promising candidate in preventing metastatic melanoma than anthocyanin extracts.

Hmmm, brown seaweed, cashew nut SHELL liquid, leaves of young (NOT old!!!) reeds, orange peels, microalga (Is there macro-algae????) from fresh water in the Antartic, lutea leaves, and blueberries!!!  Sounds like yuppie compost!  Hey, whatever works!

For what it's worth! - c

Cure your flu and melanoma too???

Interesting.... 

The clinically approved MEK inhibitor Trametinib efficiently blocks influenza A virus propagation and cytokine expression.  Schrader, Dudek, Schreiber, et al.  Antiviral Res. 2018 Jul 7.

Influenza A virus (IAV) infections are still a major global threat for humans, especially for the risk groups of young children and the elderly. Annual epidemics and sporadically occurring pandemics highlight the necessity of effective antivirals that can limit viral replication. The currently licensed antiviral drugs target viral factors and are prone to provoke viral resistance. In infected host cells IAV induces various cellular signaling cascades. The Raf/MEK/ERK signaling cascade is indispensable for IAV replication because it triggers the nuclear export of newly assembled viral ribonucleoproteins (vRNPs). Inhibition of this cascade limits viral replication. Thus, next to their potential in anti-tumor therapy, inhibitors targeting the Raf/MEK/ERK signaling cascade came into focus as potential antiviral drugs. The first licensed MEK inhibitor Trametinib (GSK-1120212) is used for treatment of malignant melanoma, being highly selective and having a promising side effect profile. Since Trametinib may be qualified for a repurposing approach that would significantly shorten development time for an anti-flu use, we evaluated its antiviral potency and mode of action. In this study, we describe that Trametinib efficiently blocks replication of different IAV subtypes in vitro and in vivo. The broad antiviral activity against various IAV strains was due to its ability to interfere with export of progeny vRNPs from the nucleus. The compound also limited hyper-expression of several cytokines. Thus, we show for the first time that a clinically approved MEK inhibitor acts as a potent anti-influenza agent.

I have ranted to kids and families for years about the importance of avoiding flu through good health care techniques and the flu vaccine!  Looking at data from the CDC from the late 70's through 2007 ~ 3,000 to 49,000 folks died from flu ANNUALLY, depending on the season, just in the United States!!  This study notes that in order for the flu A virus to replicate in our bodies, it requires the RAF/MEK/ERK signaling cascade.

Remember this diagram???  Anyhow, in this report researchers found that in little mice and the petri dish, Trametinib, the first FDA approved MEK inhibitor that we use in melanoma, blocked the replication of some types of flu A!   MEK inhibitors do come with some pretty gnarly side effects, at least for some, so I'm not sure it would be recommended for everyone, but maybe it would be a possibility for high risk folks.  We also have to remember that illness due to flu B makes up a huge part of flu cases as well.  The more important intel from this study may be noting once again how creepily similar cancer and viruses can be!  Thereby, holding out hope that one day, an effective vaccine may be developed for melanoma!!! 

For what it's worth! - c

Imiquimod and Mebendazole...drugs repurposed for mousie melanoma

Folks in melanoma world tend to go nuts when reports like these hit the news stand.  Partly out of desperation for an effective treatment, but also because sometimes such reports fail to make it clear that these great strides were attained in mousies rather than ratties.  Despite the skepticism my first sentence may convey, mice ARE the first step toward ratties and if they can find a treatment that works for more of my melanoma peeps, I'll take it!!!

First up is imiquimod, a cream that is usually used topically to treat venereal warts, basal cell carcinoma, and actinic keratosis.  These little mice seem to have had it applied topically (??? I think) as well as having it injected in their tail veins (not sure which vein that would be in ratties!!!) followed by radiation and it seemed to make melanoma lesions more responsive to that treatment.

Next there's mebendazole, an old, cheap, oral drug most often used to treat pin worms in kids...but also infestations of many other wormy critters as well as giardia.  Generally, it is safe to use, though in large doses can cause bone marrow suppression.  As an aside, I had a good many doses of this as a child because my mother seemed to have been of the persuasion that an ounce of prevention was worth a pound of cure....not that this med works like that for worms nor melanoma, as I sit here today as a Stage IV melanoma rattie!!!

At any rate, here you go.....

The TLR7 agonist imiquimod induces anti-cancer effects via autophagic cell death and enhances anti-tumoral and systemic immunity during radiotherapy for melanoma. Cho, Lee, Ko, et al. Oncotarget. 2017 Feb 15.

Toll-like receptor (TLR) ligands are strongly considered immune-adjuvants for cancer immunotherapy and have been shown to exert direct anti-cancer effects. This study was performed to evaluate the synergistic anti-cancer and anti-metastatic effects of the TLR7 agonist imiquimod (IMQ) during radiotherapy for melanoma. The pretreatment of B16F10 or B16F1 cells with IMQ combined with γ-ionizing radiation (IR) led to enhanced cell death via autophagy, as demonstrated by increased expression levels of autophagy-related genes, and an increased number of autophagosomes in both cell lines. The results also confirmed that the autophagy process was accelerated via the reactive oxygen species (ROS)-mediated MAPK and NF-κB signaling pathway in the cells pretreated with IMQ combined with IR. Mice subcutaneously injected with melanoma cells showed a reduced tumor growth rate after treatment with IMQ and IR. Treatment with 3-methyladenine (3-MA), ameliorated the anti-cancer effect of IMQ combined with IR. Additionally, the combination therapy enhanced anti-cancer immunity, as demonstrated by an increased number of CD8+ T cells and decreased numbers of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) in the tumor lesions. Moreover, the combination therapy decreased the number of metastatic nodules in the lungs of mice that were injected with B16F10 cells via the tail vein. In addition, the combination therapy enhanced systemic anti-cancer immunity by increasing the abundances of T cell populations expressing IFN-γ and TNF-α. Therefore, these findings suggest that IMQ could serve as a radiosensitizer and immune booster during radiotherapy for melanoma patients.

The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma.  Simulam-Rosenthal, Dakshanamurthy, Gaur, et al. Oncotarget. 2017 Feb 2.

Structure-based drug repositioning in addition to random chemical screening is now a viable route to rapid drug development. Proteochemometric computational methods coupled with kinase assays showed that mebendazole (MBZ) binds and inhibits kinases important in cancer, especially both BRAFWT and BRAFV600E. We find that MBZ synergizes with the MEK inhibitor trametinib to inhibit growth of BRAFWT-NRASQ61K melanoma cells in culture and in xenografts, and markedly decreased MEK and ERK phosphorylation. Reverse Phase Protein Array (RPPA) and immunoblot analyses show that both trametinib and MBZ inhibit the MAPK pathway, and cluster analysis revealed a protein cluster showing strong MBZ+trametinib - inhibited phosphorylation of MEK and ERK within 10 minutes, and its direct and indirect downstream targets related to stress response and translation, including ElK1 and RSKs within 30 minutes. Downstream ERK targets for cell cycle, including cMYC, were down-regulated, consistent with S- phase suppression by MBZ+trametinib, while apoptosis markers, including cleaved caspase-3, cleaved PARP and a sub-G1 population, were all increased with time. These data suggest that MBZ, a well-tolerated off-patent approved drug, should be considered as a therapeutic option in combination with trametinib, for patients with NRASQ61mut or other non-V600E BRAF mutant melanomas.  

Thanks to all the dear mousies!! love, rattie

EVERYTHING cures melanoma....so why do we have it??????

B saw the latest "coffee" data yesterday and it got me thinking about all the things that CURE melanoma!!!!  Now, mind you, I'm not claiming they do or they don't. The data is either too vague, too limited, or has so little to do with people that you can't tell.  AND....because there are no big bucks to be made as all of these things are pretty cheap, food, or over the counters...I don't see anybody forking over the money for study.  Oh well....for what it's worth....

COFFEE:  More than once daily...if you have the right genes, shows a "protective effect" for cutaneous melanoma.  Not sure exactly what that means, and not really clear if these genes might be the protection in and of themselves, without the addition of coffee.  Presumably they looked at that, but????

DOXYCYCLINE:  An older antibiotic, causes some nausea, but pretty good in treating acne, but...apparently...it kills and inhibits growth of melanoma cells.

CURCUMIN:  The yellow part of curry and mustard also stops melanoma in its tracks, at least in a petri dish.

CIMETADINE:  aka: tagamet, taken for heart burn, ulcers, etc, as it decreases stomach acid, helped get rid of melanoma in at least three horses.  There's a smattering of human "data" out there, too.

NSAID's:  Non steroidal anti-iflammatory drugs like Advil seem to decrease the risk of melanoma and squamous cell skin cancers.

SHIITAKES:  Good old Lentinula edodes mycelia!  If you're a mouse with melanoma and you have access to mushroom juice...you are in luck, my friend.

THE DATA:  Read at your own risk (the stuff on NAID's and Shiitakes I've posted before)!!

The protective effect of coffee consumption on cutaneous melanoma risk and the role of GSTM1 and GSTT1 polymorphisms.

Fortes C, Mastroeni S, Boffetta P, Antonelli G, Pilla MA, Bottà G, Anzidei P, Venanzetti F.

Source  Clinical Epidemiology Unit, Istituto Dermopatico dell'Immacolata, IDI-IRCSS, Via dei Monti di Creta, 104, 00167, Rome, Italy, c.fortes@idi.it.  2013 Jul 17. [Epub ahead of print]

Abstract

PURPOSES: The authors examined the association between coffee consumption and cutaneous melanoma and the implication of GSTM1 and GSTT1 polymorphisms.

METHODS: A hospital-based case-control study was conducted in the inpatient wards of IDI-San Carlo Rome, Italy, including 304 incident cases of cutaneous melanoma and 305 controls. Information on socio-demographic characteristics, medical history, smoking, sun exposure, pigmentary characteristics and diet was collected for all subjects. Within the study, individual patterns at two polymorphic genes (GSTM1 and GSTT1) belonging to glutathione S-transferases family were investigated in 188 cases of cutaneous melanoma and 152 controls. Logistic regression was the method used to estimate odds ratio and 95 % confidence intervals.

RESULTS: High frequency of coffee drinking (>once daily), compared with low-frequency consumption of coffee (≤7 times weekly) was associated with a protective effect for cutaneous melanoma (OR 0.46; 95 % CI 0.31-0.68) after adjusting for sex, age, education, hair colour, common nevi, skin phototype, and sunburn episodes in childhood. When stratified by GSTM1 and GSTT1 genotype, the protective effect of coffee was extremely high for subjects with both GSTM1 and GSTT1 null polymorphisms (OR 0.01; 95 % CI 0.0003-0.54).

CONCLUSIONS: Our results show a protective effect of coffee consumption for cutaneous melanoma, in particular for those with homozygous deletion for GSTM1 and GSTT1.

Doxycycline inhibits the adhesion and migration of melanoma cells by inhibiting the expression and phosphorylation of focal adhesion kinase (FAK). 

Sun T, Zhao N, Ni CS, Zhao XL, Zhang WZ, Su X, Zhang DF, Gu Q, Sun BC.  Source: Department of Pathology, Tianjin Medical University, Tianjin 300070, PR China.Cancer Lett. 2009 Nov. Epub 209 May 30.

Abstract:  Doxycycline has been found to induce apoptosis and to inhibit the growth of a variety of tumor cells, in addition to its use as an antibiotic. However, the mechanism of its actions, especially at the molecular level, remains unknown and needs to be resolved. A crucial step possibly lies in the early period of doxycycline administration, which leads to a series of cascading effects depicting the consequential biological action of doxycycline on tumor cells. The present study focuses on the early-stage effects of doxycycline administration, specifically at the stages of treatment (before 16h). In this paper, we report that doxycycline inhibits the adhesion and migration of melanoma cells. Afterwards, the cells undergo apoptosis (aniokis). Remarkably, doxycycline also inhibits the expression and phosphorylation of focal adhesion kinase (FAK), a protein tyrosine kinase involved in the regulation of cell adhesion and migration. We further demonstrate that doxycycline down-regulates the activities of MMP-2 and MMP-9, and its effects are stronger than those of an Integrin beta1 antibody. Finally, we suggest that doxycycline might exert its anti-tumor effects by inhibiting FAK signaling pathway. These results provide an insight into the possible mechanisms that underlie the multiple drug actions of doxycycline. The potential use of doxycycline in anti-tumor treatment is promising and warrants further studies.

Activation of c-Jun N-terminal kinase is essential for mitochondrial membrane potential change and apoptosis induced by doxycycline in melanoma cells.

Shieh JM, Huang TF, Hung CF, Chou KH, Tsai YJ, Wu WB.  Source:  Department of Internal Medicine, Chi-Mei Medical Center, Tainan, Taiwan.  Br J Pharmacol. 2010 Jul.

Abstract

BACKGROUND AND PURPOSE: Tetracyclines were recently found to induce tumour cell death, but the early processes involved in this cytotoxic effect remain unclear.

EXPERIMENTAL APPROACH: Viability of human and mouse melanoma cells was determined by MTT assay and flow cytometry. Kinase/protein/caspase activation was measured by Western blotting and mitochondrial membrane potential (DeltaPsi(m)) was analyzed by fluorescence microscopy and flow cytometry.

KEY RESULTS: Human and mouse melanoma cells were treated with doxycycline or minocycline but only doxycycline was cytotoxic. This cell death (apoptosis) in A2058 cells involved activation of caspase-3, -7 and -9 and contributed to inhibition, by doxycycline, of matrix metalloproteinase (MMP) activity and migration of these cells. Doxycycline induced intra-cellular reactive oxygen species (ROS) production, apoptosis signal-regulated kinase 1 (ASK1), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation at an early stage of treatment and induced mitochondrial cytochrome c release into cytosol and DeltaPsi(m) change during apoptosis. The JNK inhibitor/small interference RNA inhibited doxycycline-induced JNK activation, DeltaPsi(m) change and apoptosis, but did not affect ASK1 activation, suggesting a role of ASK1 for JNK activation in melanoma cell apoptosis. Two ROS scavengers reduced doxycycline-induced JNK and caspase activation, and apoptosis. Taken together, the results suggest the involvement of a ROS-ASK1-JNK pathway in doxycycline-induced melanoma cell apoptosis.

CONCLUSIONS AND IMPLICATIONS: We have shown a promising cytotoxic effect of doxycycline on melanoma cells, have identified ROS and ASK1 as the possible initiators and have demonstrated that JNK activation is necessary for doxycycline-induced melanoma cell apoptosis.

Curcumin-induced antiproliferative and proapoptotic effects in melanoma cells are associated with suppression of IκB kinase and nuclear factor κB activity and are independent of the B-Raf/mitogen-activated/extracellular signal-regulated protein kinase pathway and the Akt pathway

Doris R. Siwak M.S., Shishir Shishodia Ph.D., Bharat B. Aggarwal Ph.D., Razelle Kurzrock M.D.^†,*  Article first published online: 11 JUL 2005

Abstract

BACKGROUND Nuclear factor-κB (NF-κB) plays a central role in cell survival and proliferation in human melanoma; therefore, the authors explored the possibility of exploiting NF-κB for melanoma treatment by using curcumin, an agent with known, potent, NF-κB-inhibitory activity and little toxicity in humans.

METHODS Three melanoma cell lines (C32, G-361, and WM 266-4), all of which had B-raf mutations, were treated with curcumin, and the authors assessed its effects on viability ((3-[4,5-dimethylthiazol-2-yl]2,5-diphenyltetrazolium bromide assay) and apoptosis (flow-cytometric analysis of annexin V/propidium iodide-stained cells). Curcumin-treated cells also were examined for NF-κB binding activity (electrophoretic mobility shift assay) and for the activity of its upstream regulator, IκB kinase (IKK) (immune complex kinase assay). In addition, relevant signaling, as reflected by B-Raf kinase activity (kinase cascade assay), and steady-state levels of activated, downstream effectors, as reflected by mitogen-activated signal-regulated protein kinase (MEK), extracellular signal-regulated protein kinase (ERK), and Akt phosphorylation levels (immunoblots), were assessed.

RESULTS  Curcumin treatment decreased cell viability of all 3 cell lines in a dose-dependent manner (50% inhibitory concentration = 6.1–7.7 μM) and induced apoptosis.  However, curcumin did not inhibit the activities of B-Raf, MEK, or ERK, and Akt phosphorylation was enhanced. Furthermore, in the presence of curcumin, the Akt inhibitor 1L-6-hydroxymethyl-chiro-inositol 2-[(R)-2-O-methyl-3-O-octadecylcarbonate] no longer suppressed Akt phosphorylation.

CONCLUSIONS  Curcumin has potent antiproliferative and proapoptotic effects in melanoma cells. These effects were associated with the suppression of NF-κB and IKK activities but were independent of the B-Raf/MEK/ERK and Akt pathways. Cancer 2005.

Cimetidine for treatment of melanomas in three horses.

Goetz TE, Ogilvie GK, Keegan KG, Johnson PJ.  Source:  Department of Veterinary Clinical Medicine, College of Veterinary Medicine, University of Illinois, Urbana 61801. J AM Vet Med Assoc. 1990

Abstract: Cimetidine, an H2 histamine antagonist, was used in the clinical management of progressive, multifocal melanomatosis in 3 adult gray horses. Prior to treatment, the tumors had increased rapidly in size and number in 2 horses (duration of 6 and 27 months, respectively) and slowly in the third horse (duration of 48 months). All 3 horses were treated with cimetidine (2.5 mg/kg of body weight, PO, q 8 h) for 2 months to 1 year. During treatment, the number and size of the melanomas decreased substantially (50 to 90%). The progression of the disease was halted in 2 horses and controlled in the third horse, which is still being treated with cimetidine (1.6 mg/kg, PO, q 24 h). The horses in which treatment was terminated have not been treated for 31 and 41 months, respectively, during which time the melanomas have not increased in number or size.

 

Nonsteroidal anti-inflammatory drugs and the risk of skin cancer:  A population-based case-control study. 

By:  Johannesdottir, Chang, Mehnert, et al.  In:  Cancer, 2012, May 29. [Epub]

Knowing that Nonsteroidal anti-inflammatory drugs (NSAIDS....like aspirin, ibuprofen, etc.) may prevent the development of cancer by inhibiting cyclooxygenase (COX) enzymes, these folks from Denmark looked at NSAID use and the risk of squamous cell carcinoma, basal cell carcinoma, and melanoma.  They looked at all cases of those diseases from 1991 through 2009 in northern Denmark. (Squamous = 1,974, basal = 13, 316, and melanoma = 3,242).  They matched 10 population controls (n=178,655) to each case by age, gender, and county of residence.  Use of NSAIDs was noted via a prescription data base.  FINDINGS:  After a great deal of incidence rate ratios and confidence interval statistical shenanigans....they determined that "NSAID ever use compared with nonuse was associated with a decreased risk of squamous cell and melanoma, especially for long-term use and high-intensity use.  NSAID use was not associated with a reduced risk of basal cell.  All estimates of reduced risk were driven primarily by the use of nonselective NSAIDs and older COX-2 inhibitors."

 

Oral ingestion of Lentinula edodes mycelia extract...in mice   

From:  Cancer Science, March, 2011
By:  Tanaka, Ishikawa, Matsui, et al., The Japanese Cancer Association.

Poor little mice "were inoculated subcutaneously in the footpad with B16 melanoma and fed L.E.M. extract [shiitake mushroom juice].  Ingestion of L.E.M. extract significantly inhibited tumor growth, and this in vivo anti-tumor effect was not observed in nude mice, suggesting a T cell-dependent mechanism. In addition, ingestion of [shiitake juice] led to significant restoration of H-2K(b)-restricted and melanoma-reactive T cells in the spleen and draining lymph nodes of melanoma bearing mice....furthermore, an in vitro assay revealed than an immunosuppressive activity of CD4(+) T cells from melanoma-bearing mice was canceled by ingestion of [shiitake juice].  Our results indicate that oral ingestion of L.E.M. extract restores immune responses of class 1-restricted and melanoma-reactive CD8(+) T cells in melanoma-bearing mice, presumably by a mitigation of regulatory T cells-mediated immunosuppression."