NSAID's and cancer (Colon and melanoma specifically!) ~

Much has been written in the literature regarding NSAID use and melanoma. NSAID's are drugs like aspirin, ibuprofen, naproxen, and lots of prescription ones, that block COX enzymes.  Enzymes that produce prostaglandins which lead to inflammation, pain and fever when left to do their own thing.  By blocking the enzyme, NSAID's reduce the prostaglandins and the unpleasantness they cause.  I first reported on them in 2012!  Here is a break down of how they might work in melanoma world from 2015:  An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!! 
Here are a zillion additional reports:  NSAID's - do they help or not? 
Basically, the data (and reports) cover:
"YES!!!  NSAID's make immunotherapy work better!"   "NSAID's increase survival in melanoma patients."  "No, NSAID's make no difference."

Though these drugs are not to be trifled with despite being accessible over the counter, most data says at worst they "do no harm".  Given the aches and pains immunotherapy causes, I've long said you would be hard pressed to find a patient on immunotherapy who did NOT partake in the use of NSAID's!!  I know I certainly took my share of advil during my treatment!!!  Now, there's this:

The Impact of Nonsteroidal Anti-Inflammatory Drugs, Beta Blockers, and Metformin on the Efficacy of Anti-PD-1 Therapy in Advanced Melanoma.  Wang, McQuade, Rai, et al.  Oncologist.  2019 Nov 29.

Anti-programmed cell death protein-1 (anti-PD-1) therapy has greatly improved outcomes of patients with melanoma; however, many fail to respond. Although preclinical studies suggest a potentially synergistic relationship with anti-PD-1 therapy and certain concurrent medications, their clinical role remains unclear. Here, we retrospectively evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other drugs in 330 patients with melanoma treated with anti-PD-1 therapy from four academic centers. In the cohort, 37% of patients used NSAIDs including aspirin (acetylsalicylic acid; ASA; 47%), cyclooxygenase (COX)-2 inhibitors (2%), and non-ASA/nonselective COX inhibitor NSAIDs (59%). The objective response rates (ORRs) were similar in patients with NSAID (43.4%) and no NSAID (41.3%) use with no significant difference in overall suvival (OS). There was a trend toward improved progression-free survival (PFS) in patients who took NSAIDs (median PFS: 8.5 vs. 5.2 months). Most patients (71.3%) took NSAIDs once daily or as needed. Multivariate analysis did not reveal an association with NSAID use with ORR, PFS, or OS. Concurrent use of metformin or beta blockers did not affect ORR, PFS, or OS. Our study found no conclusive association of concurrent NSAID or other medication use with improved outcomes in patients with melanoma treated with anti-PD-1 therapy. Larger and more systematic analysis is required to confirm these findings.

Given my current condition, it is pertinent that my 2015 report started with this quote:
 "NSAID's, including aspirin, decrease the incidence and mortality from colon cancer in humans by 45% to 50%."  DuBois, Cancer Research, 56(4), 1996.

Now, there's this - The Association between NSAID use and Colorectal Cancer Mortality: Results from the Women's Health Initiative

Which notes:  "Randomized trial evidence demonstrates that non-steroidal anti-inflammatory drug (NSAID) use, particularly long-term use, reduces the incidence of colorectal neoplasia. Recent data also suggests an inverse association between NSAID use and death due to colorectal cancer (CRC). We examined the association between NSAID use and CRC mortality among 160,143 post-menopausal women enrolled in the Women's Health Initiative. Women provided details on medication use at baseline and three years after enrollment. Overall, NSAID use at baseline was not associated with CRC mortality. However, women who reported NSAID use at both baseline and year-three experienced reductions in CRC mortality compared to non-users.  Results suggest that NSAID use is associated with lower CRC mortality among post-menopausal women who use these medications more consistently over time. Our results support prolonged NSAID use in post-menopausal women for the prevention of poor CRC outcomes."

I have discussed all of this with my various docs.  They didn't have too much to say or contribute on the subject one way or another.  However, I was given their blessing to start an aspirin regimen of one baby aspirin (81mg) per day.  So, I did!  For what it's worth! - c

Old Stuff from the newest ASCO - NLR association with response and survival in advanced melanoma, SRS with targeted or immunotherapy for melanoma brain mets, COX2 inhibitors (NSAID's) and improved response to anti-PD-1 therapy in melanoma

Yeah.  Most of this jazz, is NOT news.

I have been yelling about NLR and its relationship to response in melanoma patients FOREVER!!!  Here are only a million prior reports:  Better melanoma outcomes with a lower NLR, neutrophil-to-lymphocyte ratio! (Again...) Now, this:

Association of baseline neutrophil-to-lymphocyte ratio (NLR) with response and survival in advanced melanoma (MEL) receiving PD-1 inhibitors.  2019 ASCO.  Hemadri, Lin, Lin, et al.   J Clin Oncol 37, 2019 (suppl; abstr 9571)

Background: Inflammation is an adverse prognostic factor in cancer. Neutrophil-to-lymphocyte ratio (NLR) is an easily derived biomarker of systemic inflammation. Several studies have demonstrated that elevated NLR is linked with adverse prognosis in patients (pts) receiving immunotherapy including PD-1 inhibitors. To evaluate the prognostic utility of NLR, we performed a retrospective evaluation of NLR and other covariates in stage IV cutaneous MEL. Methods: Stage IV cutaneous MEL pts who received anti PD-1 therapy at the University of Pittsburgh between 2014-2018 were included in this analysis. PD-1 blockade was continued until progression or intolerable toxicity. Tumor assessment was performed at baseline and every 12 weeks and response classified per RECIST v1.1. Clinical and demographic data were obtained. Baseline NLR was defined based on values at the first treatment date. Descriptive statistics were created for all covariates. Kaplan Meier and Cox proportional hazard regression were performed to assess how variables related to response (ORR), overall survival (OS) and progression free survival (PFS) measured in months (mos). Results: 172 pts with advanced MEL were evaluated. Elevated NLR was associated with poorer PFS and OS and ORR at all cutoffs (NLR greater than/= to 2 to NLR greater than/= to 5) with NLR greater than/= to 5 having the greatest discriminative value. ORR steadily declined with increasing NLR: NLR greater than/= to 1 (ORR 64%), NLR greater than/ = to 2 (ORR 61%), NLR greater than/= to 3 (ORR 52%), NLR greater than/= to 4 (ORR 43%), NLR greater than/ = to 5 (ORR 43%). Elevated NLR was associated with poorer PFS (median 21.5 mos vs. 5.2 mos) and OS (median 35.4 mos vs. 10.6 mos). In a multivariate model, elevated NLR  was independently associated with poorer OS/PFS separate from ulceration, performance status and elevated LDH. There was no evidence of an age-related increase or decrease in NLR. Conclusions: Baseline NLR was independently associated with response, PFS and OS in the largest retrospective series of advanced MEL pts treated with PD-1 blockade. NLR independent of other factors predicted poorer PFS and OS at NLR cutoffs (NLR greater than/= to 3 to NLR greater than/= to 5), although NLR greater than/+ to 5 segregated pts best. NLR is an inexpensive and easily obtained real-world biomarker that has a high value in predicting outcomes to PD-1 blockade.

Once again, elevated NLR was associated with worse outcomes across the board, including PFS, OS, and ORR - in melanoma patients treated with immunotherapy - even when separated from ulceration, patient status, and elevated LDH.  This is a cheap and easy test that might aid patients and docs in their selection of treatment options!  

When dealing with brain mets, we have learned that when systemic therapy (targeted or immunotherapy) is combined with radiation (SRS) the response is better than with either treatment option alone.  Here are a zillion reports: Radiation combined with systemic therapy in melanoma treatment - 2015 forward  Now, this:

First-line stereotactic radiosurgery combined with systemic targeted and immune checkpoint inhibitor therapy in melanoma patients with newly diagnosed brain metastases.  2019 ASCO.  Heumann, Wu, Ye, ..., Weber, Pavlick, et al.  J Clin Oncol 37, 2019 (suppl; abstr e13577)

Background: Of solid tumors, melanoma has the highest propensity for central nervous system spread with historic median survivals of 5-8 months following brain metastasis diagnosis. We evaluated the impact of systemic BRAF targeted and immune checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and assessed patient treatment burden associated with prolonged survival. Methods: We retrospectively reviewed the demographics, disease characteristics, therapeutic regimens, overall survival, and first-year cumulative incidence of comorbid disease for patients with de novo MBM treated between 2013 and 2017 at a major melanoma referral center. Results: Among 123 newly diagnosed MBM patients:  65% were male, 24% were 50 years old or less, 50% were BRAF mutated, 63% had multiple intracranial lesions at diagnosis. Locally, 73% received SRS as first-line treatment.Systemically, 73% received ICI, 46% received BRAF targeted therapy, and 12% received neither. With median follow up of 11 months (mo), total cohort median OS was 13.2 mo, 20.5 mo for BRAF mutated patients, 10.8 mo for BRAF wild-type patients. Median OS for first-line SRS was 31.0 mo (47% 3-year OS) when combined with both ICI and BRAF targeted therapy, 17.5 mo (31% 3-year OS) when combined with ICI monotherapy, and 6.1 mo (22% 3-yr OS) with neither systemic therapy. SRS and BRAF targeted therapy were associated with improved OS. BRAF status, ICI therapy, intratumoral hemorrhage were not significant prognosticators for OS.At one-year follow-up, comorbid conditions with the greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage, deep vein thrombosis, major depressive disorder, and pneumonia. Patients averaged one inpatient visit every 4.5 mo (1 week average length of stay), and 2 advanced imaging studies (MR/CT/PET-CT) per month following MBM diagnosis. Conclusions: In one of the largest reported MBM series, survival has improved markedly for patients receiving first-line brain radiosurgery combined with BRAF targeted therapies and immunotherapies. Simultaneously, longer life expectancy comes with increasing incidences of comorbid conditions reflecting an evolving complexity of and need for coordination of care for patients with MBM. 

Wait for it...  Folks with melanoma brain mets did better when they were treated with targeted therapy or immunotherapy combined with radiotherapy, than with either of the treatments as single agents!

COX inhibitors, your basic NSAID's ~ think aspirin or advil ~ have long been a topic of discussion as they relate to responses from immunotherapy.  In this post from 2015, An aspirin a day...keeps melanoma at bay....and makes immunotherapy work better!!!!, I noted, "...here's the deal:   To back up a step -  NSAIDs block an enzyme, cyclooxygenase (also called: COX1 and COX2).  Blocking those enzymes, blocks the production of prostaglandins.  Soooo..... These researchers used genetically modified mice to research the role of prostaglandins in blocking immune rejection of tumors.  Aspirin and similar NSAIDs stop the production of prostaglandins, thereby allowing immune cells to kill tumors more easily and enhancing the checkpoint inhibitors like anti-PD1 (nivo/opdivo and pembro/keytruda), anti-PDL1, and anti-CTLA4 (ipililmumab).  Researchers note:

• Prostaglandins in tumors interferes with immune cell function.
• Blocking cyclooxygenase in tumors restores immune cell function.
• The cyclooxygenase blockers (NSAIDs) increase the action of checkpoint inhibitors.
• This mechanism is shared by mouse and human tumor systems.

My thoughts:  While you can find conflicting reports regarding effects of NSAIDs and this latest study was done with real ratties (ie the 4 legged kind!!), the benefit of COX inhibitors in the form of NSAIDs sounds like a pretty common sense, low risk, and reliable finding to aid patients' results from immunotherapy.  I am certain that my study did NOT control for NSAID use, but I imagine it is a pretty rare anti-PD1 patient who does not utilize ibuprofen to deal with arthralagias and other aches and pains the therapy produces!!  I know I certainly lived on advil and benadryl to deal with my rashes and beat up joints.  Of course, the next step will be an examination of the application in human ratties....  So, time will tell.  But, I think I'll keep taking my ibuprofen....unless Bentie makes me switch to aspirin!!!"

Then there was some back and forth in this composite of many posts and articles in 2018:  Aspirin, NSAID's, and melanoma  Now, there's this:

Evaluating the role of the COX2/PGE2 pathway in anti-melanoma immunity.  2019 ASCO.  Ferreira, Krybaeva, et al.  J Clin Oncol 37, 2019 (suppl; abstr e14114)

Background: Checkpoint inhibitors such as anti-PD1 (aPD1) have revolutionized treatment of metastatic melanoma. However, a large subset of patients receiving such treatment fails to respond to aPD1 monotherapy due to mechanisms such as PD-L1 upregulation within the tumor and T cell exhaustion in the tumor microenvironment. The PGE2/COX2 signaling pathway is one of the pathways implicated in T cell exhaustion and PD1/PD-L1 upregulation and thus represents an attractive pharmacologic target to enhance effects of aPD1 therapy due to the availability and safety of inhibitors such as aspirin or NSAIDs. There is evidence that PGE2/COX2 pathway inhibitors act synergistically with aPD1 therapy in murine melanoma and breast cancer models. Here we aimed to further characterize this synergism using the YUMMER (Yale University Mouse Melanoma Exposed to Radiation) 1.7 model, an irradiated, syngeneic cell line originating from BrafV600E; Pten-/-; and Cdkn2a-/- genetically engineered mouse melanomas. YUMMER1.7 cells implanted into the flanks of C57BL6/j mice show reproducible but partial responses to intraperitoneal aPD1 therapy and thus serves as an ideal platform to study whether concurrent PGE2/COX2 pathway blockade may result in additive effects to aPD1 therapy. Methods: 6-7 week old male C57BL6/j mice (n = 20) were injected with 500K YUMMER1.7 cells and treated with aPD1 therapy alone starting on day 7 after tumor implantation (n = 10) or with aPD1 therapy starting on day 7 in addition to ibuprofen dissolved in drinking water at a concentration of 1 mg/mL started on the day of tumor implantation (n = 10). Using an average daily water consumption estimate of 6 mL/day, this translates to a human equivalent of roughly 1200 mg/day, a moderate dose of ibuprofen. Tumor growth was monitored and tracked to an endpoint of 1cm3. Results: Tumor volume at day 17 significantly differed between the two groups. Survival curves were significantly different between the two groups (p < 0.0001); all tumors treated with aPD1 alone grew to endpoint by day 32, while all tumors treated with aPD1 + ibuprofen regressed with 8 out of 10 showing complete regression by day 32. Conclusions: We have shown that ibuprofen strongly synergizes with aPD1 therapy in a murine model of melanoma, complementing existing evidence. This suggests that PGE2/COX2 inhibitors such as NSAIDs, which are over-the-counter agents with a well-studied safety profile, may serve as a promising means of enhancing the response to aPD1 therapies such as nivolumab in melanoma patients who initially fail aPD1 monotherapy.

Well, okie dokie then!  Not sure just taking anti-PD-1 with an aspirin is going to work for folks who failed anti-PD-1 in the first place, especially since I think it would be a hard task to find a melanoma peep on anti-PD-1 who hasn't had to dip into the NSAID bottle of choice in order to survive the assorted aches and pains that come with that therapy!  But what do I know?????

There is beauty still...

... even if we come through the storm looking something like a Dr. Seuss flower!  - c

Aspirin, NSAID's, and melanoma

I first posted on this bunch of mess in 2012!!!!  (I'm getting old and in melanoma land ~ or any other land, really ~ that is AWESOME!!!!)   Here's a link to a complete re-cap:  Sooo....advil works for SOME melanoma patients?????  As you can see from these posts:  Aspirin and other NSAID's decrease rates of melanoma!!  Well, maybe!!!  Advil and such make immunotherapy work better in treating melanoma.  Oh, perhaps not....or just for certain peeps! 
Hmmmm......  Now, there's this....

Post-diagnosis aspirin use and overall survival in patients with melanoma.  Wallace, Li, et al.  J Am Acad Dermatol. 2018 Jan 6.   

Mouse studies show that tumor-derived prostaglandins and platelets promote melanoma progression and immune-evasion. [To] Determine if aspirin confers longer survival in patients with melanoma - A retrospective cohort study of 1,522 patients at Indiana University Health (IUH) diagnosed with melanoma between 2000 and 2014 and followed up through September, 2016.

Aspirin use was associated with longer overall survival in univariate analysis and after controlling for age, sex, stage, and treatment modalities. Aspirin use was not associated with survival in patients with in situ and stage I melanoma, but was associated with better survival in stages II and III. No statistical significance was observed in stage IV patients. In turn, patients using aspirin before diagnosis were less likely to be diagnosed in stages III or IV disease. Observational study. Aspirin could provide a survival advantage in melanoma. Clinical trials investigating the therapeutic potential of aspirin are warranted.

In this study, researchers in Indiana reviewed the files of 1,522 melanoma patients diagnosed at their university between 2000 and 2014 and followed them through September of 2016.  Aspirin use was NOT associated with survival in patients with Stage I and in situ melanoma.  However, aspirin WAS associated with better survival for Stage II and III patients, while no statistical difference was found in Stage IV patients.  However, patients who used aspirin BEFORE they were diagnosed were found less like to "be diagnosed in Stages III or IV disease". 

Hmmm.....You gotta love it when a new study only adds more confusion (or is that confirmation?????) to a yes/no situation!!!  Oh, well.  Melanoma provides no easy answers.  Low dose aspirin daily rarely hurts and helps some in a variety of ways.  Not something I've every partaken in....though advil has been an almost daily drug since taking anti-PD-1 for 2 1/2 years.  I think you'd be hard pressed to find immunotherapy patients who haven't been simultaneously "contaminated with" NSAID use, given the aches and pains the treatment produces.  Anyhow....still not sure what all this really means...if anything.  Be sure to talk to your doc about all your over the counter medicines and before starting a legit ASA regimen!  For what it's worth..... - 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

COX-2 expression correlates with PD-L1 expression on melanoma cells - or....how NSAID's like aspirin and advil might help melanoma patients????

COX-2 expression in melanoma cells is what has given the hope (??? data) that the use of NSAID's (advil, aspirin, etc) might enhance the response from immunotherapy in melanoma patients as noted in this post (with links to others within):  Sooo....advil works for SOME melanoma patients?????

COX-2 expression positively correlates with PD-L1 expression in human melanoma cells. Botti, Fratangelo, Cerrone, et al. J Transl Med. 2017 Feb 23.

The resistance to PD-1/PD-L1 inhibitors for the treatment of melanoma have prompted investigators to implement novel clinical trials which combine immunotherapy with different treatment modalities. Moreover is also important to investigate the mechanisms which regulate the dynamic expression of PD-L1 on tumor cells and PD-1 on T cells in order to identify predictive biomarkers of response. COX-2 is currently investigated as a major player of tumor progression in several type of malignancies including melanoma. In the present study we investigated the potential relationship between COX-2 and PD-L1 expression in melanoma.

Tumor samples obtained from primary melanoma lesions and not matched lymph node metastases were analyzed for both PD-L1 and COX-2 expression by IHC analysis. Status of BRAF and NRAS mutations was analyzed by sequencing and PCR. Co-localization of PD-L1 and COX-2 expression was analyzed by double fluorescence staining. Lastly the BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines were used to evaluate the effect of COX-2 inhibition by celecoxib on expression of PD-L1 in vitro.

BRAF^V600E/V600K and NRAS^Q61R/Q61L were detected in 57.8 and 8.9% of the metastatic lesions, and in 65.9 and 6.8% of the primary tumors, respectively. PD-L1 and COX-2 expression were heterogeneously expressed in both primary melanoma lesions and not matched lymph node metastases. A significantly lower number of PD-L1 negative lesions was found in primary tumors as compared to not matched metastatic lesions. COX-2 expression significantly correlated with PD-L1 expression in both primary and not matched metastatic lesions. Furthermore, in melanoma tumors, cancer cells expressing a higher levels of COX-2 also co-expressed a higher level of PD-L1. Lastly, inhibition of COX-2 activity by celecoxib down-regulated the expression of PD-L1 in both BRAF^V600E A375 and NRAS^Q61R SK-MEL-2 melanoma cell lines.  

COX-2 expression correlates with and modulates PD-L1 expression in melanoma cells. These findings have clinical relevance since they provide a rationale to implement novel clinical trials to test COX-2 inhibition as a potential treatment to prevent melanoma progression and immune evasion as well as to enhance the anti-tumor activity of PD-1/PD-L1 based immunotherapy for the treatment of melanoma patients with or without BRAF/NRAS mutations.

Breaking it down:  This report supports the notion that there is a relationship between COX-2 and PD-L1 expression in melanoma. Therefore, if we could block COX-2 we would reduce PD-L1 expression in melanoma cells and make anti-PD-1 drugs more effective. That's the theory anyway!!   - c

Sooo....advil works for SOME melanoma patients?????

I first reported on the supposed benefits of NSAID's ability to decrease cancer risk in 2012:  NSAID's and risk of skin cancer

Then last year (with much pandemonium in various news outlets this year) it was published that NSAID's reduced the bad boys - myeloid derived suppressor cells (MDSCs) and made anti-PD1 work better. 

Here's one post from 2015:  An Aspirin a day keeps melanoma at bay

And another from 2016:  Celecoxib: The stuff that's in NSAID's work synergistically with anti-PD1

Then at ASCO, they poured cold water over the whole thing.  See the last article in this post:  ASCO 2016: NSAID's many not aide response to anti-PD1 after all! 

But now, there's this: 

Differential expression of cyclooxygenase-2 in metastatic melanoma affects progression free survival.  Panza, De Cicco, Ercolano, et al.  Oncotarget. 2016 Aug 1.

The possible correlation between cyclooxygenase-2 (COX-2) expression and disease progression in melanoma is still a matter of debate. Analysis of COX-2 expression in 45 lymph node melanoma metastases demonstrates a significant correlation between the percent of expression and progression free survival (PFS). A positive COX-2 expression ≥10% (COX-2high), as opposite to a positive expression ≤9% (COX-2low), translated into a striking significant reduction of PFS of about 3 years. The reduction in PFS correlated neither with BRAFV600E nor with NRASQ61 expression in the analyzed samples. This concept was reinforced by the finding that tumour development in COX-2-/- mice was almost blunted. Similarly, inhibition of COX-2 protein expression in human melanoma cell lines, by using siRNAs technology as well as selective inhibition of COX-2 activity by celecoxib, reduced cellular proliferation and invasiveness. In conclusion we show that COX-2high is a negative prognostic factor in metastatic melanoma. Our study also clarifies that the uncertainty about the role of COX-2 in metastatic malignant melanoma, found in the current relevant literature, is probably due to the fact that a threshold in COX-2 expression has to be reached in order to impact on cancer malignancy. Our findings suggest that COX-2 expression may become an useful diagnostic tool in defining melanoma malignancy as well as argue for a possible therapeutic use of NSAID as add on therapy in selected cases.

For what it's worth!!! - c

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