"Inflammation. [4] How to Change the ... - Advanced Prostate...

Advanced Prostate Cancer

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"Inflammation. [4] How to Change the Numbers"

pjoshea13•

8 years ago•8 Replies

This is my final post on inflammation. Earlier posts:

"Inflammation. [1] Neutrophil-to-Lymphocyte Ratio [NLR]"

"Inflammation. [2] Albumin & C-Reactive Protein [CRP]"

"Inflammation. [3] SedRate, Fibrinogen, IL-6, TNFalpha"

The literature tends to treat subclinical inflammation as an artifact of serious disease. It has prognostic value, I suppose, in that one can identify patients who are going to do badly, but tests are pointless if they do not lead to a preemptive therapeutic response, when called for.

The big question is whether changing the inflammation numbers can change the outcome of the disease.

Inflammation is part of the normal response to pathogens. The central player in the response is Nuclear Factor-kappaB [NF-kB]. NF-kB is bound to a protein [IkB] in healthy cells, & remains so even during normal cell death (apoptosis). But when faced with widespread viral or bacterial insult, cell death might outstrip the body's ability to replace them. This would be a disaster in the case of a vital organ. The primary purpose of NF-kB is to place a moratorium on cell death in such events.

An enzyme [IKKα] separates NF-kB from its protein, & it is then free to travel to the nucleus. When activated, NF-kB is responsible for the production of a large number of cell survival proteins. Some of these are enzymes that will act on arachidonic acid (an omega-6) contained in the lipid raft of the cell, to form inflammatory metabolites -prostaglandins, thromboxanes & leukotrienes.

Because NF-kB puts a hold on cell death, the "intent", if you will, is that it be activated only during a crisis, but not long-term. Unfortunately, there are a number of debilitating inflammatory diseases where NF-kB is chronically activated: arthritis, inflammatory bowel disease, & so on. And, of course, cancer.

The reason why tackling inflammation in PCa could improve the prognosis, is that NF-kB is the logical target, & NF-kB triggers a number of survival paths associated with aggressive growth.

[1] Natural inhibitors of NF-kB.

[1a] Tom Gilmore (the Gilmore Lab), Bostom University, maintains a NF-kB site. One of the pages lists inhitors, with links to studies [1ai].

[1ap] Apigenin.

[1api] (2015 - U.S.)

"IKKα has been implicated as a key regulator of oncogenesis and driver of the metastatic process; therefore is regarded as a promising therapeutic target in anticancer drug development. In spite of the progress made in the development of IKK inhibitors, no potent IKKα inhibitor(s) have been identified. Our multistep approach of molecular modeling and direct binding has led to the identification of plant flavone apigenin as a specific IKKα inhibitor. Here we report apigenin, in micro molar range, inhibits IKKα kinase activity, demonstrates anti-proliferative and anti-invasive activities in functional cell based assays and exhibits anticancer efficacy in experimental tumor model. We found that apigenin directly binds with IKKα, attenuates IKKα kinase activity and suppresses NF-ĸB/p65 activation in human prostate cancer PC-3 and 22Rv1 cells much more effectively than IKK inhibitor, PS1145."

[1apii] (2016 - Turkey)

"The expressions of NF-κB p105/p50, PI3K, Akt and the phosphorylation of pAkt were decreased after apigenin treatment."

[1cof] Coffee.

[1cofi] (2016 - Norway)

"Coffee inhibits nuclear factor-kappa B in prostate cancer cells and xenografts."

[1cur] Curcumin.

[1curi] (2004 - U.S.]

"Curcumin sensitizes prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand/Apo2L by inhibiting nuclear factor-kappaB through suppression of IkappaBalpha phosphorylation."

[1curii] (2002 - U.S.)

"Our results show that curcumin down-regulates transactivation and expression of AR, activator protein-1 (AP-1), nuclear factor-kappaB (NF-kappaB), and CREB (cAMP response element-binding protein)-binding protein (CBP)."

[1curiii] (2001 - U.S.)

"Treatment of cells with curcumin, a chemopreventive agent, suppressed both constitutive (DU145) and inducible (LNCaP) NF-kappaB activation, and potentiated TNF-induced apoptosis."

"Overall, our results suggest that NF-kappaB and AP-1 may play a role in the survival of prostate cancer cells, and curcumin abrogates their survival mechanisms."

[1gar] Garlic.

[1gari] Diallyl Trisulfide (DATS) (2008 - U.S.)

"DATS inhibited angiogenesis (as measured by CD31-positive and factor VIII-positive blood vessels and hypoxia-inducible factor-1alpha, vascular endothelial growth factor, and interleukin-6 expression) and metastasis [matrix metalloproteinase (MMP)-2, MMP-7, MMP-9, and MT-1 MMP expression], which were correlated with inhibition in AKT and nuclear factor-kappaB activation."

[1k2] Vitamin K2 [VK2].

[1k2i] (2013 - U.S.)

"Our investigations show that VK2 is able to suppress viability of androgen-dependent and androgen-independent prostate cancer cells via caspase-3 and -8 dependent apoptosis. We also show that VK2 treatment reduces androgen receptor expression and PSA secretion in androgen-dependent prostate cancer cells. Our results also implicate VK2 as a potential anti-inflammatory agent, as several inflammatory genes are downregulated in prostate cancer cells following treatment with VK2. Additionally, AKT and NF-kB levels in prostate cancer cells are reduced significantly when treated with VK2."

[1lyc] Lycopene. (from tomatoes)

[1lyci] (2013 - Italy)

"... lycopene reduced the Ras-dependent activation of nuclear factor-kappaB (NF-κB)."

[1lycii] (2016 - U.K.)

"Lycopene acts through inhibition of IκB kinase to suppress NF-κB signaling in human prostate and breast cancer cells."

[1mag] Magnolia.

[1magi] Honokiol (2016 - U.S.)

"Honokiol affects multiple signaling pathways, molecular and cellular targets including nuclear factor-κB (NF-κB), STAT3, epidermal growth factor receptor (EGFR), cell survival signaling, cell cycle, cyclooxygenase and other inflammatory mediators, etc."

[1pip] Piperine (from black pepper)

[1pipi] (2013 - U.S.)

"Interestingly, treatment of LNCaP, PC-3 and DU-145 prostate cancer cells with piperine resulted in reduced expression of phosphorylated STAT-3 and Nuclear factor-κB (NF-kB) transcription factors."

[1pom] Pomegranate.

[1pomi] (2008 - U.S.)

"Pomegranate extract inhibits androgen-independent prostate cancer growth through a nuclear factor-kappaB-dependent mechanism."

[1qrci] (2011 - India)

"Quercetin inhibits invasion, migration and signalling molecules involved in cell survival and proliferation of prostate cancer cell line (PC-3)."

"Quercetin inhibits cell survival factor β-catenin, NF-κB and also proliferative signalling molecules ..."

[1sil] Silibinin (from milk thistle)

[1sili] (2016 - U.S.)

"... molecular studies identified monocyte chemotactic protein-1 (MCP-1) as the key component of CCM that promotes PCA invasiveness, whereas silibinin treatment strongly reduced MCP-1 expression in CAFs by inhibiting the DNA-binding activity of MCP-1 transcriptional regulators-nuclear factor-kappaB and AP-1."

[1silii] (2014 - U.S.)

"Silibinin inhibits prostate cancer cells- and RANKL-induced osteoclastogenesis by targeting NFATc1, NF-κB, and AP-1 activation in RAW264.7 cells."

[1siliii] (2010 - China)

"Silibinin reverses epithelial-to-mesenchymal transition in metastatic prostate cancer cells by targeting transcription factors."

"... we found that silibinin could inhibit the nuclear factor kappaB (NF-kappaB) p50 translocation via the up-regulation of I kappaB alpha protein ..."

[1urs] Ursolic acid. (from holy basil, etc.)

[1ursi] (2011 - Singapore)

"... our results from experimental and predictive studies suggest that UA mediates its anti-tumor effects through suppression of NF-κB and STAT3 pathways in prostate cancer."

[1ursii] (2012 - Singapore)

"Ursolic acid inhibits the initiation, progression of prostate cancer and prolongs the survival of TRAMP mice by modulating pro-inflammatory pathways."

"... we found that UA down-regulated activation of various pro-inflammatory mediators including, NF-κB, STAT3, AKT and IKKα/β phosphorylation"

[1zyf] Zyflamend.

[1zyfi] (2009 - U.S.)

"Zyflamend in men with high-grade prostatic intraepithelial neoplasia: results of a phase I clinical trial."

"Immunoreactive staining demonstrated a reduction in NF-kappaB in the 18-month samples "

[2] Pharmaceutical inhibitors of NF-kB.

[2met] Metformin.

[2meti] (2015 - U.S.]

"We show that NF-kappaB is a downstream molecule of N-cadherin and metformin regulates NF-kappaB signaling via suppressing N-cadherin."

[2metii] (2013 - Canada)

"Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-κB activation."

"... metformin prevented the translocation of NF-κB to the nucleus and inhibited the phosphorylation of IκB and IKKα/β, events required for activation of the NF-κB pathway."

[2sim] Simvastatin

[2simi] (2013 - Korea)

"Simvastatin induces apoptosis in castrate resistant prostate cancer cells by deregulating nuclear factor-κB pathway."

[2tax] Taxotere.

[2taxi] Taxotere + DIM

"Importantly, luciferase assays showed a significant reduction of survivin-Luc and NF-kappaB-Luc activity in prostate cancer cells exposed to DIM and Taxotere."

[3] Conclusion.

I excluded many studies involving more obscure polyphenols, but, in general, if something is a polyphenol, it is an inhibitor of NF-kB.

The common polyphenols are well-tolerated, even at high doses. They are protective in slightly different ways, & there may be synergy.

My personal view is that inflammation can be controled via a mix of polyphenols, but that some men will need much higher doses than others. A simple blood test can be used to determine/monitor the dose.

-Patrick

[1a] people.bu.edu/gilmore/nf-kb...

[1ai] people.bu.edu/gilmore/nf-kb...

[1api] ncbi.nlm.nih.gov/pubmed/264...

[1apii] ncbi.nlm.nih.gov/pubmed/275...

[1cofi] ncbi.nlm.nih.gov/pubmed/264...

[1curi] ncbi.nlm.nih.gov/pubmed/152...

[1curii] ncbi.nlm.nih.gov/pubmed/122...

[1curiii] ncbi.nlm.nih.gov/pubmed/117...

[1gari] ncbi.nlm.nih.gov/pubmed/187...

[1k2i] ncbi.nlm.nih.gov/pubmed/240...

[1lyci] ncbi.nlm.nih.gov/pubmed/206...