Everything cures melanoma...redux....#5?????

Lord knows I have covered 'most' everything that folks have tested and came away saying would cure melanoma:  coffee, curcumin, strawberry extract, wine, doxycycline, beta blockers, snake venom, shitakes, eggplant, potatoes, tomatoes, cimetadine, NSAID's, Vitamin D, Vietnamese Sophora root, exercise, sandalwood...I did leave off sea urchin snot....just seemed a bridge too far!!!!  Here are those posts if you'd like to see the data for yourself:

From 2013:  Everything cures melanoma, so why do we have it?

Be Better in 2013: Jump up, jump around and get down!

2014: Red, red wine boosts radiation effect

Also from 2014:  For melanoma: eat that curry again we just don't know why!

2015: Everything kills melanoma: Take 4

Now we have these reports touting the benefits of dill and parsley, coffee and curcumin again, anti-cholesterol meds and stress control! Here you go:

Efficient Synthesis of Glaziovianin A Isoflavone Series from Dill and Parsley Extracts and Their in Vitro/in Vivo Antimitotic Activity.  Semenov, Tsyganov, Semenova, et al.  J Nat Prod. 2016 Apr 21. 

A concise six-step protocol for the synthesis of isoflavone glaziovianin A (GVA) and its alkoxyphenyl derivatives 9 starting with readily available plant metabolites from dill and parsley seeds was developed. The reaction sequence involved an efficient conversion of the key intermediate epoxides 7 into the respective β-ketoaldehydes 8 followed by their Cu(I)-mediated cyclization into the target series 9. The biological activity of GVA and its derivatives was evaluated using a panel of seven human cancer cell lines and an in vivo sea urchin embryo assay. Both screening platforms confirmed the antimitotic effect of the parent GVA (9cg) and its alkoxy derivatives. Structure-activity relationship studies suggested that compounds 9cd and 9cf substituted with trimethoxy- and dillapiol-derived B-rings, respectively, were less active than the parent 9cg. Of the evaluated human cancer cell lines, the A375 melanoma cell line was the most sensitive to the tested molecules. Notably, the target compounds were not cytotoxic against human peripheral blood mononuclear cells up to 10 μM concentration. Phenotypic readouts from the sea urchin assay unequivocally suggest a direct microtubule-destabilizing effect of isoflavones 9cg, 9cd, and 9cf.

Higher Caffeinated Coffee Intake Is Associated with Reduced Malignant Melanoma Risk:  A Meta-analysis study.  Liu, Shen, Shi, Cai, PLoS One.  2016 Jan 27.

Several epidemiological studies have determined the associations between coffee intake level and skin cancer risk; however, the results were not yet conclusive. Herein, we conducted a systematic review and meta-analysis of the cohort and case-control studies for the association between coffee intake level and malignant melanoma (MM) risk.  Studies were identified through searching the PubMed and MEDLINE databases (to November, 2015). Study-specific risk estimates were pooled under the random-effects model.  Two case-control studies (846 MM patients and 843 controls) and five cohort studies (including 844,246 participants and 5,737 MM cases) were identified. For caffeinated coffee, the pooled relative risk (RR) of MM was 0.81 for those with highest versus lowest quantity of intake. In the dose-response analysis, the RR of MM was 0.955 for per 1 cup/day increment of caffeinated coffee consumption and linearity dose-response association was found. Strikingly, no significant association was found between the decaffeinated coffee intake level and MM risk.  This meta-analysis suggested that caffeinated coffee might have chemo-preventive effects against MM but not decaffeinated coffee. However, larger prospective studies and the intervention studies are warranted to confirm these findings.


Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism.  Yang, Bai, Xiong, et al.  Nature. 2016 Mar 16. 

CD8⁺ T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8⁺ T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8⁺ T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8⁺ but not CD4⁺ T cells. This is due to the increase in the plasma membrane cholesterol level of CD8⁺ T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8⁺ T cells were better than wild-type CD8⁺ T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.

Curcumin:  A new candidate for melanoma therapy?  Mirzaei, Naseri, Reazee, et al.  Int J Can.  2016 Jun 9.  

Melanoma remains among the most lethal cancers and, in spite of great attempts that have been made to increase the life span of patients with metastatic disease, durable and complete remissions are rare. Plants and plant extracts have long been used to treat a variety of human conditions; however, in many cases, effective doses of herbal remedies are associated with serious adverse effects. Curcumin is a natural polyphenol that shows a variety of pharmacological activities including anti-cancer effects, and only minimal adverse effects have been reported for this phytochemical. The anti-cancer effects of curcumin are the result of its anti-angiogenic, pro-apoptotic, and immunomodulatory properties. At the molecular and cellular level, curcumin can blunt epithelial-to-mesenchymal transition and affect many targets that are involved in melanoma initiation and progression (e.g. BCl2, MAPKS, p21 and some microRNAs). However, curcumin has a low oral bioavailability that may limit its maximal benefits. The emergence of tailored formulations of curcumin and new delivery systems such as nanoparticles, liposomes, micelles and phospholipid complexes has led to the enhancement of curcumin bioavailability. Although in vitro and in vivo studies have demonstrated that curcumin and its analogues can be used as novel therapeutic agents in melanoma, curcumin has not yet been tested against melanoma in clinical practice. In this review, we summarized reported anti-melanoma effects of curcumin as well as studies on new curcumin formulations and delivery systems that show increased bioavailability. Such tailored delivery systems could pave the way for enhancement of the anti-melanoma effects of curcumin.

Association of stress coping strategies with immunological parameters in Melanoma Patients.  Trapp, Trapp, Avian, et al.  Acta Derm Venereol. 2016 Jun 9.

In this exploratory case control study the association between stress coping strategies and lymphocyte subpopulations was calculated in 18 non-metastatic melanoma patients and 18 controls with benign skin diseases. Coping strategies were assessed using the German version of the stress-coping questionnaire (SVF 120). While in the control group patients showed significant negative correlations of lymphocyte subpopulations (CD3+, CD4+, CD8+, CD19+, CD45+ cells) with coping strategies that refer to defence, in melanoma patients significant positive correlations between lymphocyte subpopulations (CD3+, CD4+, CD19+, CD45+ cells) were found with regard to coping strategies that are characterized by diversion from stress and focusing on stress-compensating situations. The present data, in melanoma patients and controls, show contrary correlations between stress coping strategies and lymphocyte subpopulations. The interconnection between stress coping and immunologic alterations in malignant melanoma is a field deserving further multiprofessional investigation in order to provide new therapeutical approaches in the treatment and understanding of melanoma patients.

Supercritical Fluid Extract of Spent Coffee Grounds Attenuates Melanogenesis through Downregulation of the PKA, PI3K/Akt, and MAPK Signaling Pathways.  Huang, Wei, Siao, et al.  Evid Based Complement Alternat Med. June 2016.

The mode of action of spent coffee grounds supercritical fluid CO2 extract (SFE) in melanogenesis has never been reported. In the study, the spent coffee grounds were extracted by the supercritical fluid CO2 extraction method; the chemical constituents of the SFE were investigated by gas chromatography-mass spectrometry (GC-MS). The effects of the SFE and its major fatty acid components on melanogenesis were evaluated by mushroom tyrosinase activity assay and determination of intracellular tyrosinase activity and melanin content. The expression level of melanogenesis-related proteins was analyzed by western blotting assay. The results revealed that the SFE of spent coffee grounds (1-10 mg/mL) and its major fatty acids such as linoleic acid and oleic acid (6.25-50 μM) effectively suppressed melanogenesis in the B16F10 murine melanoma cells. Furthermore, the SFE decreased the expression of melanocortin 1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase, tyrosinase-related protein-1 (TRP-1), and tyrosinase-related protein-2 (TRP-2). The SFE also decreased the protein expression levels of p-JNK, p-p38, p-ERK, and p-CREB. Our results revealed that the SFE of spent coffee grounds attenuated melanogenesis in B16F10 cells by downregulation of protein kinase A (PKA), phosphatidylinositol-3-kinase (PI3K/Akt), and mitogen-activated protein kinases (MAPK) signaling pathways, which may be due to linoleic acid and oleic acid.
 
While most of these...coffee, curcumin, and becoming a bit more zen most certainly....are likely to do no harm, do keep this word of warning in mind should you be determine to cure yourself:   Combining alternative and conventional treatments can be a risky business!

For what it's worth! - c

For melanoma...eat that curry...again!!! We just don't know why!

I've posted articles here before, regaling the benefit of curcumin (Turmeric- the yellow part of mustard and curry).  Curcumin has long been proven to eradicate melanoma...at least in a petri dish. And while that's nice and all...how am I supposed to get my melanoma cells in that dish???!!!  Well, this study took that up a notch!

Curcumin Intake Affects md RNA Dignature in Murein Melanoma with mmu-miR-205-5p Most Significantly Altered.  Dahmke, et al.  PLoS One. Dec 2013.

"Melanoma is the most aggressive form of skin cancer with an estimated 48,000 deaths per year worldwide. The polyphenol curcumin derived from the plant Curcuma longa is well known for its anti-inflammatory and anti-cancerogenic properties.  Accordingly, dietary intake of the compound may be suitable for melanoma prevention.  However, how this compound affects basic cellular mechanisms in developing melanoma still remains elusive. Therefore, the aim of this study was to investigate for the first time the impact of oral curcumin administration on the miRNA signature of engrafting melanoma."  So...ratties (real rats...this time) were given melanoma tumors on their sides.  But, they were fed their regular chow OR a curcumin diet two weeks prior to the tumor cell injection and until the experiment was stopped. "Curcumin significantly reduced the growth of the flank tumors.  Furthermore, the miRNA expression signature in tumors was substantially altered by curcumin intake with mmu-miR-205-5p over 100 times higher expressed when compared to controls."

Well!  You go my little real live curcumin eating ratties with your altered mmu-miR-205-5p!!!!  I'm gonna see if I can alter mine, too!!! Curry with a side of mustard, anyone? - c

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."