Saturday, April 21, 2018

Everything Cures Melanoma - Installment #10

So....just to keep y'all up to date on the latest and greatest, I keep reporting all things (well...almost all....some things are just too far fetched to make even THIS list!!!) peeps are looking at to "Cure" melanoma.  Here's a link to the last installment:  Everything Cures Melanoma!!! (And yes, we're up to installment #9 - with no actual cure!)

Now, there's this.....

Chrysin, a natural and biologically active flavonoid suppresses tumor growth of mouse B16F10 melanoma cells: In vitro and In vivo study. Sassi, Maatouk, El Gueder, et al. Chem Biol Interact. 2018 Jan 15.

Chrysin (5,7-dihydroxyflavone) is a natural and biologically active compound which has many biological activities as an anticancer agent. The current report is aimed at finding out whether the antitumor potential of chrysin, evidenced in vitro and in vivo, is linked or not to its effect on immunological mechanisms of melanoma-bearing mice. Chrysin-treated B16F10 cells were analyzed for their metabolic rate and apoptotic potentials. In vivo, BALB/c mice received a subcutaneous injection of B16F10 melanoma cells prior to antitumor treatments with chrysin (50 mg/kg b.w) for 14 days and 21 days. The results showed that chrysin inhibited cancer cell growth at a dose-dependent manner by inducing apoptosis and cell cycle arrest at G2/M phase. Moreover, chrysin suppressed melanoma tumor growth at an average of 60% (after 14 days of treatment) and 71% (after 21 days of treatment) compared to the tumor-bearing group. Furthermore, chrysin treatment increased the cytotoxic activity of NK, CTL and macrophages. The findings showed that chrysin antitumor action on the murine melanoma model was very promising, suggesting that chrysin could be a potentially good candidate for future use in alternative anti-melanoma treatments.

So, at least in 70% of poor little mice given melanoma, chrysin, found in honey and most often extracted from blue passion flowers, melanoma tumor growth was suppressed after about a month of treatment.

Oridonin inhibits migration, invasion, adhesion and TGF-β1-induced epithelial-mesenchymal transition of melanoma cells by inhibiting the activity of PI3K/Akt/GSK-3β signaling pathway. Li, Wang, Shen, et al. Oncol Lett. 2018 Jan;15.

Epithelial-mesenchymal transition (EMT) has been reported to play pivotal roles in tumor invasion and metastasis. Inhibition of EMT may exert beneficial effects in regulating metastasis. Oridonin (ORI), an active diterpenoid compound isolated from Rabdosia rubescens, was found to be a potent anti-metastatic agent. However, the possible involvement of ORI in the EMT in malignant melanoma is unclear. The present study found that ORI inhibited cell migration, invasion, and adhesion in A375 and B16-F10 melanoma cells. The transforming growth factor-β1 (TGF-β1)-induced EMT was also inhibited in ORI-treated cells, as reflected in the upregulation of E-cadherin, and downregulation of vimentin and Snail. Similar results were observed in A375 and B16-F10 melanoma cells treated with ORI. Furthermore, pre-treatment with ORI blocked the TGF-β1-induced phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase (Akt)/glycogen synthase kinase (GSK)-3β signaling pathway activation. These effects mimicked PI3 kinase inhibitor LY294002 treatment. ORI interfered with the PI3K/Akt/GSK-3β pathway, and reversed TGF-β1-induced EMT, which suppressed the invasion and metastasis of melanoma cells. Taken together, the present study demonstrated that ORI inhibits melanoma cells migration, invasion, and adhesion and TGF-β1-induced EMT through the PI3K/Akt/GSK-3β signaling pathway. These findings suggest that ORI is a promising anti-metastasis agent for melanoma.

In this study, oridonin (ORI) extracted from a herb (the isodon plant) kept melanoma cells in a petri dish from getting their groove on!!!  Apparently it has had various uses in Japan, China, and Korea as a herbal remedy and was examined here as well:  Oridonin, a diterpenoid extracted from medicinal herbs, targets AML1-ETO fusion protein and shows potent antitumor activity with low adverse effects on leukemia in vitro and in vivo. Blood Journal, 2007.

Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice. Kokolus, Zhang, Sivik, et al. Oncoimmunology. 2017 Dec 21.

Immunotherapy has expanded treatment options for cancers with historically poor outcomes, yet a significant proportion of patients still fail to achieve durable clinical benefit. We defined the contribution of β-adrenergic receptor (βAR) signaling, a component of the stress response, on success of immunotherapy for melanoma since the use of antagonists (β-blockers) is associated with improved clinical outcomes in some cancers. We show that metastatic melanoma patients who received immunotherapy had improved overall survival if they also received pan β-blockers. This retrospective analysis is reinforced by results showing that βAR blockade enhances the control of murine melanoma growth by anti-(α)PD-1 checkpoint blockade. However, this effect was most significant when β-blocker was combined with dual αPD-1 + high dose interleukin-2 therapy and was reproduced by selective blockade of β2ARs. These results identify a novel strategy that can be quickly introduced to potentially increase the number of patients who benefit from immune-based therapies.

I first reported on Propranolol use in melanoma back in 2014 here: Kill melanoma....with snake venom or Vietnamese sophora root...beta-blockers...not so much!  Where it was noted that: "Beta-blockers were prescribed after malignant melanoma diagnosis to 20.2% of 242 patients who died from malignant melanoma and 20.3% of 886 matched controls.  Contrary to some previous studies, beta-blocker usage after malignant melanoma diagnosis was not associated with reduced risk of death from melanoma in the UK population based study."  In the report above, researchers state that they saw improved OS in melanoma peeps who were simultaneously given immunotherapy, as was the case for more poor little melanoma affected mice.  They do point out that the effect was greater when melanoma peeps (or maybe they mean the's not clear) were also given high dose IL-2 with their anti-PD-1/beta blocker cocktail! 

Antioxidative and Anti-Melanogenic Activities of Bamboo Stems (Phyllostachys nigra variety henosis) via PKA/CREB-Mediated MITF Downregulation in B16F10 Melanoma Cells. Choi, Jo, Yang, et al. Int J Mol Sci. 2018 Jan 30.

Phyllostachys nigra var. henosis, a domestic bamboo species, has been attracting much attention; its bioactive compounds (especially in the leaf) show antioxidant, anti-inflammatory, and anti-obesity activities. Little information is available on the antioxidative and anti-melanogenetic activities of the bioactive compounds in bamboo stems. The anti-melanogenic and antioxidative activities of the EtOAc fraction (PN3) of a P. nigra stem extract were investigated in a cell-free system and in B16F10 melanoma cells. PN3 consisted of a mixture of flavonoids, such as catechin, chlorogenic acid, caffeic acid, and p-coumaric acid. The antioxidant activity (2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS)), and hydroxyl radical scavenging) was evaluated, as well as the inhibition of reactive oxygen species (ROS) produced by the Fenton reaction. PN3 showed in vitro tyrosinase inhibition activity with the half maximal inbihitory concentration (IC50) values of 240 μg/mL, and in vivo cytotoxic concentration ranges > 100 μg/mL. The protein expression levels and mRNA transcription levels of TYRTRP-1, and MITF were decreased in a dose-dependent manner by the treatment with PN3. PN3 interfered with the phosphorylation of intracellular protein kinase A (PKA)/cAMP response element-binding protein (CREB), demonstrating potent anti-melanogenic effects. PN3 could inhibit PKA/CREB and the subsequent degradation of microphthalmia-associated transcription factor (MITF), resulting in the suppression of melanogenic enzymes and melanin production, probably because of the presence of flavonoid compounds. These properties make it a candidate as an additive to whitening cosmetics.

Hmmm....  The "whitening/anti-melanomagenetic" properties of compounds found in bamboo stems make this interesting given what we know about vitiligo improving the prognosis for those with melanoma.  Wonder if pandas ever get melanoma!!!???

RK1, the first very short peptide from Buthus occitanus tunetanus inhibits tumor cell migration, proliferation and angiogenesis.   Kjammessi, Ben Mabrouk, El Fessi-Magouri, Krarrat.  Biochem Biophys Res Commun. 2018 Jan 20.

Scorpion toxins have been the subject of many studies which explore their pharmacological potential toward diverse molecular targets, known to monitor key mechanisms in cancer such as proliferation, migration and angiogenesis. The few peptides from scorpion venom that have an anti-tumor effect are generally cytotoxic. Herein, we present the first description of a short 14 amino acid peptide (called RK1), purified from the venom of Buthus occitanus tunetanus, with the particular capabilities, among different other scorpion peptides, to inhibit cell proliferation, migration and angiogenesis of U87 (Glioblastoma) and IGR39 (Melanoma). Moreover, RK1 is a first peptide derived from scorpion venom exhibiting a potential anti-tumoral activity with no manifest toxicity. Our results suggest that, in terms of its primary structure, RK1 is unique compared to a variety of known peptides purified from scorpion venoms. In addition, RK1 is the first natural peptide able to abolish completely the proliferation of cancer cells. The Chicken chorioallantoic membrane model revealed that RK1 strongly inhibits ex-vivo vascular growth. RK1 could open new perspective for the pharmaceutical application of short scorpion venom peptides in anticancer activity and may represent the first member of a new group of scorpion peptides

So a little scorpion venom can do in melanoma and glioblastoma cells in a petri dish!  And the RK1 peptide noted here, can do that without any collateral toxicity.  That's cool!!  But what the heck is a "Chicken chorioallantoic membrane"????  Reckon it would be tasty fried up with hot sauce????  Coming soon to the KFC near you!!  Just watch!

Propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR/p70S6K signaling pathway in melanoma cells. Shang, Feng, Cuj, et al. Oncol Lett. 2018 Jan;15.

Propofol is an intravenous anesthetic, which is widely used in clinical anesthesia induction and maintenance and is critical in the sedation of patients. However, the functions and mechanisms of propofol on apoptosis of melanoma cells remain unclear. The present study investigated whether propofol promotes cell apoptosis and suppresses the HOX transcript antisense RNA (HOTAIR)-mediated mechanistic target of rapamycin (mTOR) pathway in melanoma cells. B16F10 cells were cultured with different concentrations (0-10 µM) of propofol for 24 or 48 h. Proliferation and apoptosis of B16F10 cells were detected using MTT assay and flow cytometry. The pcDNA 3.1(-)-HOTAIR and pcDNA 3.1(-)-control plasmids were transfected into B16F10 cells using Lipofectamine 2000. In the present study, treatment with propofol significantly reduced viability, and induced apoptosis and caspase-3 activity in melanoma cells. Propofol treatment significantly inhibited HOTAIR expression and the expression of phosphorylated (p)-mTOR and p- p70S6K protein in melanoma cells. Overexpression of HOTAIR significantly increased viability of melanoma cells, and increased HOTAIR, p-mTOR and p-p70S6K protein expression in melanoma cells. These results indicated that propofol promotes apoptosis and suppresses the HOTAIR-mediated mTOR signaling pathway in melanoma cells.

In this study, once again, in the petri dish, melanoma cells couldn't get their groove on when treated with proprofol.  That's good!  Of course, the rest of the body can't get its groove on either if one is given too much propofol!!!!

Thai Water Lily Extract Induces B16 Melanoma Cell Apoptosis and Inhibits Cellular Invasion Through the Role of Cellular Oxidants. Aimvijarn, Palipoch, Okada, Suwannalert. Asian Pac J Cancer Prev. 2018 Jan 27.

Melanoma is a cancer that is associated with a high capacity of invasion. Oxidative stress is recognized as cancer growth and progression. The phytochemical pigments of natural products show either anti-oxidant or pro-oxidant activity from the redox system. In addition, the phytophenolics also prevent cancer cell proliferation and progression. This study aims to investigate the effects of Thai water lily on cell apoptosis and cellular invasion through the role of cellular oxidants in B16 melanoma cells.  The cytotoxicity and cell apoptosis of Thai water lily extract treating B16 cells were performed by using the MTT and Annexin V/PI-flow cytometry methods, respectively. In addition, cellular oxidants and cancer cell invasion were also obtained by using DCFH-DA and Boyden chamber assays, respectively.  Thai water lily, Nymphaea stellate extract was shown to be markedly toxic to B16 melanoma cells with IC50 = 814 μg/ml. The extract at 800 and 1,000 μg/ml demonstrated pro-oxidant activity relating to the cell apoptosis. The low concentrations of the extract at 200 and 400 μg/ml showed the anti-oxidant function associated with the inhibitory effect of melanoma cell invasion.  Thai water lily extract may play an important role in bioactive work as a chemo preventive agent on the modulation of cellular oxidative stress-induced apoptosis and suppressed cancer cell invasion.
Again, in the petri dish, Thai water lily extracts seemed to inhibit melanoma cell invasion.  That's sounds very fierce and calming all at the same time!!!

Lectin Isolated from Japanese Red Sword Beans (Canavalia gladiata) as a Potential Cancer Chemopreventive Agent. Une, Nonaka, and Akiyama.  J Food Sci. 2018 Feb.

In this study, we investigated the chemical and biological profile of lectin isolated from Japanese red sword beans (Canavalia gladiata; RSBs). RSB lectin was purified using maltamyl-Sepharose 4B and subjected to amino acid composition and partial amino acid sequencing analyses, and evaluated for blood and carbohydrate specificity, mitogenic activity, splenic natural killer (NK) cell activity, and its effect on B16 melanoma cell proliferation, compared with Concanavalin A (Con A). The amino acid composition and sequences of RSB lectin were similar to those of Con A. RSB lectin showed specificity to mannose, glucose, maltose, methyl-D-mannoside, and thyroglobulin, but not rhamnose, using mouse, sheep, and rabbit erythrocytes. Compared with Con A, RSB lectin showed low resistance to proteases and to temperatures greater than 70 °C, but high mitogenic activity for mouse splenic cells. Notably, while treatment with RSB lectin and Con A (0.01 and 0.1 μg/mL) promoted similar levels of splenic NK cell activity, which were higher than that observed in the control (0 μg/mL) and interleukin 2 (IL-2) (25 U)-treated populations, RBS lectin exerted a significantly stronger antiproliferative effect than Con A at a concentration of 125.0 μg per well. Overall, our results show that RSB lectin might exert immunological effects on mouse splenic cells and could thus be used as a potential cancer chemopreventive agent.  Japanese red sword bean (RSB) is a tropical perennial legume consumed in many Asian countries. RSB lectin shows specificity to mannose, glucose, maltose, methyl-d-mannoside, and thyroglobulin, but not to rhamnose, using mouse, sheep, and rabbit erythrocytes. RSB lectin exhibits similarities to Concanavalin A in amino acid composition and sequence, shows mitogenic activity for mouse splenic cells and strong antiproliferative activity for B16 melanoma cells, and also enhances the activity of splenic natural killer (NK) cells against YAC-1 cells. Thus, RSB lectin has the potential to be used as a bioactive protein in medical research.

I like beans!!!  Sounds like something I could get behind!

Bioaccessible selenium sourced from Se-rich mustard cake facilitates protection from TBHP induced cytotoxicity in melanoma cells. Jaiswal, Prakash, Prahu, Tejo Prakash. Food Funct. 2018 Apr 12.

Selenium (Se) is an essential dietary supplement that resolves inflammatory responses and offers antioxidant cytoprotection. In this study, we present the data on the cytoprotective effect of Se-rich mustard protein isolated from mustard cultivated in seleniferous soils in Punjab, India. The concentrations of total Se in mustard seed, oil-free mustard cake, and mustard protein were 110.0 ± 3.04, 143.0 ± 5.18, and 582.3 ± 6.23 μg g-1, respectively. The cytoprotective effect of Se-rich mustard protein was studied on tert-butyl hydroperoxide (TBHP)-induced cytotoxicity in a mouse melanoma cell line (B16-F10). When compared with TBHP treated cells (where no viable cells were found), Se-rich protein made bioaccessible through simulated gastrointestinal digestion protected melanoma cells from cytotoxicity with decreased levels of oxidative stress resulting in 73% cell viability. Such an effect was associated with a significant increase in glutathione peroxidase activity as a function of bioaccessible Se and its response towards cytoprotection.

So, this is a bummer.  For all the good things that curcumin (derived from mustard seeds) is supposed to do for melanoma peeps...we now have to worry if the mustard seeds used were grown in selenium rich soil!!  GAH!!!!!

Helix aspersa maxima mucus exhibits antimelanogenic and antitumoral effects against melanoma cells. Ellijimi, Ben Hammouda, Othman, et al. Biomed Pharmacother. 2018 May.

Snail secretion is currently revolutionizing the world of cosmetics and human skin care. The efficacy of snail secretion in wounds healing has been proven both in vitro and by clinical studies. However, the potential anti-tumor effect of snail secretion was poorly investigated. In this report, our in vitro study showed that Helix aspersa maxima species snail slime (SS) could not only treat melanogenesis but also endowed with anti-tumoral activity against human melanoma cells. Indeed, SS reduced melanin content and tyrosinase activity on B16F10 cells with IC50 values of 288 μg/mL and 286 μg/mL, respectively, without altering cell viability. This effect was also observed, at a lesser extent, on human melanoma IGR-39 and SK-MEL-28 cell lines. On another hand, SS specifically inhibited the viability of IGR-39 and SK-MEL-28 cells associated to an apoptotic effect highlighted by PARP cleavage. It is worth to note that SS did not affect the viability of B16F10 cells and non tumorigenic HaCaT cells. Interestingly, this extract was found to inhibit migration and invasion of both human melanoma cells through reducing the expression of Matrix metalloproteinase MMP2. Snail slime also exerted a high inhibitory effect on IGR-39 cell adhesion through blocking the function of α2β1 (45%), αvβ3 (38%) integrins and by reducing the expression levels of αv and β1 integrins. The presented results shed light on the potential anti-melanoma effect of SS and support its use against skin diseases.

Wow!!!  Snail slime???  Really???  Well, if it works, okay!!!  Hope we won't have to eat it!!!

Hang in there, my melanoma peeps!!  Thanks to all the researchers (esp the ones who had to deal with snail slime!!!), petri dishes and melanoma mice!  Maybe something wonderful is in the offing!!! - c

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