Everything Cures Melanoma!!! (And yes, we're up to installment #9 - with no actual cure!)

Yes, I look forward to the day when I can make that announcement with no sarcasm and cease to make these crazy lists!  Here's the link to the last installment:  Everything Cures Melanoma....#8  Sigh.  Until then....

We have known for sometime that psychotropic agents like Thorazine kills melanoma.  Now:

Psychotropic agent thioridazine elicits potent in vitro and in vivo anti-melanoma effects. Jiang, Chen, Shen, et al. Biomed Pharmacother. 2017 Nov.

Psychotropic agents have been shown anti-tumor potential in recent years. In the present study, our in vitro pharmacological data indicated that thioridazine inhibited melanoma cells proliferation. The growth-arresting effect of thioridazine was accompanied by autophagy induction, as shown by immunoblotting of increased LC3II. Besides, certain apoptotic events had also occurred after thioridazine exposure. The in vivo anti-melanoma effect of thioridazine was confirmed by showing that intraperitoneally injection of thioriazine remarkably retarded tumor growth and reduced tumor vasculature. Our results imply that thioridazine might be an available therapeutic agent for melanoma patients with no better options.

Of course, that does leave the tiny little hiccup of having to take psychotropic agents...among other things!!!

Antimelanomic Effects of High- and Low-Molecular Weight Bioactive Subfractions Isolated from the Mossy Maze Mushroom, Cerrena unicolor (Agaricomycetes). Statkiewicz, Matuszawska, Jaszek.  Int J Med Mushrooms. 2017

Three bioactive fractions isolated from Cerrena unicolor cultures-crude endopolysaccharide (c-EPS), laccase, and a subfraction of low-molecular weight secondary metabolites-were used to determine potential cytotoxic effects on the mouse melanoma B16-F10 cell line (American Type Culture Collection CRL-6475). The results obtained prove that all examined fractions exhibited activity against the investigated tumor cells. In addition, an evident immunomodulatory effect of the c-EPS fraction was observed. Our results show that the levels of 2 cytokines (tumor necrosis factor-a and chemokine ligand 2) in mouse inner medullary collecting duct mIMCD-3 cells (American Type Culture Collection CRL-2123) stimulated by c-EPS were significantly higher. A lipopolysaccharide model was used at the same concentration (10 μg/mL) as a positive control.

Yes, mossy maze mushrooms look like lichen I see on trees everywhere....but there you go!  Wanted you to see it just in case you thought anti-melanoma effects were limited to Shiitakes! (If you're interested in that one, check out this post from 2012: Shiitakes - Much ado about mushrooms!)  And speaking of lichen....

The Polysaccharide Extracted from Umbilicaria esculenta Inhibits Proliferation of Melanoma Cells through ROS-Activated Mitochondrial Apoptosis Pathway. Sun, Li, Zhang, et al. Biol Pharm Bull. 2018;41.

Cooked!

Raw as found in nature...

Melanoma is one of the most aggressive skin cancers with an increasing rate of morbidity. Umbilicaria esculenta is an edible lichen and its main component of extracts-polysaccharide (PUE) has shown significant antitumor effects in a variety of cancer types such as stomach adenocarcinoma. However, whether it has an anti-melanoma effect and the underlying mechanism has not been revealed. In this article, we showed that PUE extracted from Umbilicaria esculenta could inhibit the growth of A875 and A375 melanoma cells but without obvious toxicity to normal vascular endothelial cells. The generation of reactive oxygen species (ROS) in A875 cells was significantly elevated when treated with PUE for 24h. In addition, the expression of caspase-3 and -9 also increased as compared to the controlled group which resulted in the apoptosis of A875 melanoma cells. In the meantime, when pre-treated with N-acetylcysteine (NAC), the ROS scavenger, PUE induced apoptosis and cell death could be reversed via suppression of elevated generation of ROS and ROS-mediated caspase-9 expression. In summary, our study demonstrated that PUE extracts from Umbilicaria esculenta have a potent anti-melanoma effect through the induction of ROS and caspases-3 and -9. It could provide a promising strategy of melanoma therapy with the components from the extracts of natural and edible plants such as lichen Umbilicaria esculenta.

The more you know!!!  Apparently pretty delicious and part of Korean cuisine!

Dietary Crocin Reverses Melanoma Metastasis. Bakashi, Lukmanul, Sam, and Javid. J Biomed Res. 2017 Nov 1.

Crocus sativus and its bioactive constituent crocin are well known for anti-tumor potential in different models. However, the efficacy of crocin on in-vivo melanoma metastasis is not yet reported. In this study, melanoma metastatic model was developed by tail vein injection of B16F-10 cells in to C57BL/6 mice. Metastatic mice treated with two different doses of crocin (250 and 500 µg/kg of bodyweight) for 10 days and parameters such as lung metastasis inhibition, mean survival time, lung hydroxyproline, uronic acid and hexosamine levels were analyzed after 21 days of treatment. Then blood was collected and serum gamma glutamyl transpeptidase (g-GGT), sialic acid, tumor necrosis factor alpha (TNF-a), interleukin 10 (IL-10), IL-6, IL-2, and TIMP-1 levels were measured. Further, a lung histological examination was done in crocin treated metastatic mice. Subsequently hallmark metastatic parameters such as matrix metalloproteases (MMPs), extracellular regulated kinase 2 (ERK2), vascular endothelial growth factor (VEGF), and K-ras gene expression were investigated in the lungs of crocin treated metastatic mice. Further, in-vitro adhesion, invasion and migration of B16F-10 cells were examined after 24 h of crocin (5 and 10 µg/mL) treatment. Administration of crocin to tumor bearing C57BL/6 mice reduced the lung metastasis by 85%. Elevated levels of hydroxyproline, uronic acid, hexosamine, serum sialic acid andg-GGT in metastatic control were found to be significantly reduced in crocin treated mice. Crocin also inhibited expression of MMP-2, MMP-9, ERK-2, K-ras, and VEGF. Crocin reduced the ability of B16F-10 cells invasion, migration and adhesion by upregulating E-cadherin expression. In conclusion, crocin elicited marked anti-metastatic potential by regulating the metastasis induced biomarkers.

And what, you might ask, is Crocus Sativus.....that so helpfully cured these poor little mice???

Yep, my favorite Harbinger of Spring....the pretty, tiny, unassuming crocus that grows from bulbs.

It is not clear from the report if they are referring to using the bulbs, leaves, petals, or the super pricey saffron threads harvested from the crocus.  If it's the saffron threads themselves...that may set your bank account back just as much as immunotherapy!!!

Ciprofloxacin-mediated induction of S-phase cell cycle arrest and apoptosis in COLO829 melanoma cells. Beberok, Wrzesniok, Minecka, et al. Pharmacol Rep. 2017 Jul 16.

Low effectiveness of anti-melanoma therapies makes it necessary to search for new drugs that could improve or replace the standard chemotherapy. Fluoroquinolones are a group of synthetic antibiotics, used in the treatment of wide range of bacterial infections. Moreover, this class of antibiotics has shown promising anti-tumor activity in several cancer cell lines. The aim of this study was to examine the effect of ciprofloxacin on cell viability, apoptosis and cell cycle distribution in COLO829 melanoma cells.  Cell viability was evaluated by the WST-1 assay. Cell cycle distribution and apoptosis in cells exposed to ciprofloxacin was analyzed by the use of fluorescence image cytometer NucleoCounter NC-3000.  Ciprofloxacin decreased the cell viability in a dose- and time-dependent manner. For COLO829 cells treated with ciprofloxacin for 24 h, 48 h and 72 h the values of IC₅₀ were found to be 0.74 mM, 0.17 mM and 0.10 mM, respectively. The oligonucleosomal DNA fragmentation was observed when the cells were exposed to ciprofloxacin in concentration of 1.0 mM for 48 h and 72 h. At lower ciprofloxacin concentrations (0.01 mM and 0.1 mM) cells were arrested in S-phase suggesting a mechanism related to topoisomerase II inhibition. Moreover, it was demonstrated that ciprofloxacin induced apoptosis as a result of mitochondrial membrane breakdown.  The obtained results for COLO829 melanoma cells were compared with data for normal dark pigmented melanocytes and the use of ciprofloxacin as a potential anticancer drug for the treatment of melanoma in vivo was considered.

So this is all rather old, in terms of how melanoma treatment is addressed, but in the petri dish it seems cipro  decreased the viability of melanoma cells.  Okay.  Plus...there's this....

The effect of ciprofloxacin on the growth of B16F10 melanoma cells. Jaber, Jallad, Abdelnoor. J Cancer Res Ther. 2017 Oct-Dec;13.

The antitumor effect of ciprofloxacin has been widely assessed in-vitro, and positive results have been reported. The aim of this study was to investigate the influence of ciprofloxacin treatment on the growth of B16F10 melanoma cells both in-vitro and in-vivo.

Groups of C57BL/6 female mice challenged with B16F10 melanoma cells were kept untreated or were treated with sterile water, intraperitoneal ciprofloxacin, or ciprofloxacin through drinking water for 10 days. The serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA 1 and 3 h after the last dose of ciprofloxacin. Mice were monitored for an additional 10 days for survival assessment. Moreover, B16F10 melanoma cells were cultured in 24-well plates and exposed to different concentrations of ciprofloxacin (10-1000 μg/ml). Viability was determined, after 24 and 48 h, using trypan blue.

The serum levels of VEGF significantly decreased in ciprofloxacin-treated mice when compared to the controls. None of the control mice survived beyond day 8, whereas 16.67% of those treated with ciprofloxacin survived up to 18 days. In addition, the viability of B16F10 melanoma cells, in-vitro, significantly decreased with increasing concentrations of ciprofloxacin after 24 and 48 h.

Ciprofloxacin seems to exhibit antitumor activity both in-vivo and in-vitro. This effect might be explained by several mechanisms such as directly inducing cancer cell death or altering the immune response through the modification of the normal microbiota.

So in little mice and petri dishes, ciprofloxin, a fairly common antibiotic "exhibits antitumor activity".  Though their commentary about "altering the immune response through the modification of the normal microbiota" is NOT a good thing if you believe this report:  Antibiotic use MAY decrease effectiveness of immunotherapy?????  Not to mention the more recent: Science magazine: Precision medicine using microbiota Researchers really need to learn to communicate and discuss their results!!!

Non Polar compounds of Persian Gulf Sea Cucumber Holothuria parva Selectively Induce Toxicity on Skin Mitochondria isolated from animal Model of Melanoma. Arast, Seyed, Nazemi, et al. Cutan Ocul Toxicol. 2017 Dec 12.  

Melanoma is a highly aggressive and deadly cancer with a poor prognosis given its drug resistance. A defect in apoptosis is one of the key mechanisms that contribute to drug resistance in Melonama. An important sea marine animal is the Holothuria parva, also known as the sea cucumber, which has various pharmacological activities. Compounds obtained from sea cucumbers have shown to have anticancer activity through induction of apoptosis singling.

In the present study, selective toxicity and apoptotic effect of three extracts of Holothuria parva (H. parva) were assessed on skin mitochondria isolated from mouse animal models of melanoma. The mitochondria was isolated from melanoma cells via differential centrifuges and treated with various concentrations (250, 500 and 1000 µg/ml) of metanolic, diethyl ether and n-hexane extracts of H. parva.

All the applied concentrations (250, 500 and 1000 µg/ml) of three extracts of H. parva increased the reactive oxygen species (ROS) generation only in the skin mitochondria isolated from melanoma cells group (In comparison to the control group). Additionally, all three extracts (250, 500 and 1000 µg/ml) induced swelling within the mitochondria, the collapse of the mitochondrial membrane potential (MMP) and the release of cytochrome c from the mitochondria. Flow-cytometry analysis demonstrated that n-hexane and diethyl ether extracts of H.parva selectively and progressively induced apoptosis only on melanoma but not healthy control skin cells group

Given these results, the potentially bioactive compounds found in H. parva render it a strong candidate for further research in molecular identification and confirmatory in-vivo studies. Clinical trials are also warranted in the general process of novel drug discovery for the treatment of melanoma cancer.

I feel it is important to note that this little feller' is not just any ol' sea cucumber.  No!  He is a Persian Sea Cucumber Holothuria Parva!!!  Just in case you were going to make a sea cucumber slurry to sprinkle on the random melanoma mitochondria you have sitting around in your petri dishes!!!

MMP-Inhibitory Effects of Flavonoid Glycosides from Edible Medicinal Halophyte Limonium tetragonum. Bae, Karadeniz, Oh, et al. Evid Based Complement Alternat Med. 2017 Sep 20.

Limonium tetragonum has been well-known for its antioxidative properties as a halophyte. This study investigated the antimetastasis effect of solvent-partitioned L. tetragonum extracts (LTEs) and isolated compounds on HT1080 mouse melanoma cell model with a focus on matrix metalloproteinase (MMP) activity and TIMP and MAPK pathways. Upregulation and stimulation of MMPs result in elevated degradation of extracellular matrix which is part of several complications such as metastasis, cirrhosis, and arthritis. The anti-MMP capacity of LTEs was confirmed by their MMP-inhibitory effects, regulation of MMP and TIMP expression, and suppression of MAPK pathway. Among all tested LTEs, 85% aq. MeOH and n-BuOH were found to be most active fractions which later yielded two known flavonoid glycosides, myricetin 3-galactoside and quercetin 3-o-beta-galactopyranoside. Anti-MMP potential of the compounds was confirmed by their ability to regulate MMP expression through inhibited MAPK pathway activation. These results suggested that L. tetragonum might serve as a potential source of bioactive substances with effective anti-MMP properties.

Hey!  I swear this is the same as the pretty, paper-like, stiff, long-lasting, long stemmed flower that is in mixed bouquets you can get from Wally World!!!  Hmmm.....  

Oral treatment with a rattlesnake native polypeptide crotamine efficiently inhibits the tumor growth with no potential toxicity for the host animal and with suggestive positive effects on animal metabolic profile. Campeiro, Marinovic, Carapeto, et al. Amino Acids. 2017 Dec 12.

The efficacy of crotamine as antitumoral was first demonstrated by daily intraperitoneal (IP) injections of low doses of this toxin in an animal model bearing melanoma tumors. Significant inhibition of tumor growth and increased lifespan of mice bearing tumor was also noticed after 21 consecutive days of this daily IP administration of crotamine. However, due to the limited acceptance of treatments by IP route in clinical conditions [No, I can see that injecting stuff into your abdomen wouldn't be the preferred route for drug consumption by many!!!] herein, we evaluated the antitumor effect of this native polypeptide employing the oral route. The efficacy of crotamine in inhibiting the melanoma growth in vivo, even after passing through the gastrointestinal tract of the animal, was confirmed here. In addition, biochemical biomarkers and also histopathological analysis showed both the absence of any potential toxic effects in tissues or organs of the animal in which the highest accumulation of crotamine is expected. Interestingly, a reduction of weight gain was observed mainly in animals with tumor treated with crotamine by IP route, but not by oral administration. Albeit, oral administered crotamine was able to significantly decrease the body weight gain of healthy animals without tumor. Taking advantage of this same experimental animal models receiving crotamine by oral route, it was possible to show metabolic changes as the increased capacity of glucose clearance, which was accompanied by a reduction of the total cholesterol, and by increased high-density lipoprotein levels, both observed mainly in the absence of tumor. Triglycerides and low-density lipoprotein were also significantly decreased, but only in the absence of tumor. Taken together, these data suggest a clear trend for metabolic positive effects and mischaracterize unhealthy condition of animals, with or without tumors, treated with crotamine for 21 days. In addition, this study confirmed the efficacy of crotamine administered by oral route as antitumor agent, which besides the additional advantage of administration convenience and decreased risk of toxic effects, allowed the serendipitous observation of several positive metabolic effects on treated animals.

Damn, while croatamine helped mice with melanoma a little, this shiz is the new lipitor...producing weight loss and decreased cholesterol in mice who did NOT have tumors!!!!  Just when you think injecting snake venom into the abdomen of little mice or putting it in their kibble couldn't get any weirder!  Mother Nature...what do you think of that kink in your food chain????

Well!!!  All of that is a lot of business, isn't it????  (Not to mention all the ground that is covered in the prior posts!!!!)  I never say NEVER!!!  Ha!  Here's hoping.....as I nibble my lichen, pop my cipro and thorazine, with a glass of red wine and dine on curry over saffron flavored rice with a bit of kimchi and mustard on the side!!!  After dinner coffee, anyone???  - c