The name Jagadananda Ghosh may not ring a bell but he & Dr. Charles E. "Snuffy" Myers co-authored a number of papers on PCa & 5-LOX when they were at UVA (Charlottesville, VA) in the 1990s. Seems that Ghosh is still looking at 5-LOX - this time in the context of Xtandi resistance:
"... even after initial good response, enzalutamide-resistant prostate cancer (ERPC) develops which eventually leads to widespread metastasis. Management of ERPC is extremely difficult because available therapeutic regimen cannot effectively kill and eliminate ERPC cells."
"We investigated the effects of pharmacological and genetic inhibition of 5-lipoxygenase (5-Lox) on cell proliferation, apoptosis and invasive potential of enzalutamide-resistant prostate cancer cells."
"Our findings indicate that inhibition of 5-Lox may emerge as a promising new approach to effectively kill ERPC cells sparing normal cells and suggest that development of a long-term curative therapy of prostate cancer may be possible by killing and eliminating ERPC cells with suitable 5-Lox-inhibitors."
5-LOX is one of the enzymes produced when NF-kB is activated. Along with COX-1 & COX-2, etc, the enzymes target the omega-6 fatty acid arachidonic acid to produce inflammatory metabolites.
A number of us use supplements based on Boswellic Acid to inhibit 5-LOX. Here is a thread from 4 years back:
Pharmacological and Genetic Targeting of 5-lipoxygenase Interrupts c-Myc Oncogenic Signaling and Kills Enzalutamide-Resistant Prostate Cancer Cells via Apoptosis
1 Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, 48202, United States.
2 Vattikuti Urology Institute, Henry Ford Health System, Detroit, MI, 48202, United States. jghosh1@hfhs.org.
3 Henry Ford Cancer Institute, Henry Ford Health System, Detroit, MI, 48202, United States. jghosh1@hfhs.org.
PMID: 32313135 DOI: 10.1038/s41598-020-62845-8
Abstract
Much of the morbidity and mortality due to prostate cancer happen because of castration-resistant prostate cancer (CRPC) which invariably develops after anti-androgenic therapy. FDA-approved enzalutamide is commonly prescribed for CRPC which works by blocking androgen receptor function. However, even after initial good response, enzalutamide-resistant prostate cancer (ERPC) develops which eventually leads to widespread metastasis. Management of ERPC is extremely difficult because available therapeutic regimen cannot effectively kill and eliminate ERPC cells. Though the mechanism behind enzalutamide-resistance is not properly understood, over-activation of c-Myc has been found to be a common event which plays an important role in the maintenance and progression of ERPC phenotype. However, direct-targeting of c-Myc poses special problem because of its non-enzymatic nature and certain amount of c-Myc activity is needed by non-cancer cells as well. Thus, c-Myc has emerged as an elusive target which needs to be managed by novel agents and strategies in a cancer-specific way. We investigated the effects of pharmacological and genetic inhibition of 5-lipoxygenase (5-Lox) on cell proliferation, apoptosis and invasive potential of enzalutamide-resistant prostate cancer cells. Transcriptional activity of c-Myc was analyzed by DNA-binding, luciferase-assays, and expression of c-Myc-target genes. We found that 5-Lox regulates c-Myc signaling in enzalutamide-resistant prostate cancer cells and inhibition of 5-Lox by Quiflapon/MK591 or shRNA interrupts oncogenic c-Myc signaling and kills ERPC cells by triggering caspase-mediated apoptosis. Interestingly, MK591 does not affect normal, non-cancer cells in the same experimental conditions. Our findings indicate that inhibition of 5-Lox may emerge as a promising new approach to effectively kill ERPC cells sparing normal cells and suggest that development of a long-term curative therapy of prostate cancer may be possible by killing and eliminating ERPC cells with suitable 5-Lox-inhibitors.
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Boswellia powder is a strong anti inflammatory herbal remedy. I use Boswellia powder daily along with other one dozen herbs and spices. Last week ,My C reactive protein came
0.2 and ESR came 5. Inflammation very well controlled and indirectly cancer well controlled. (PSA 0.2) Consider this inexpensive powder as your complementary med.
Hi there, how much Boswellia powder do you take per day, and where can I get it, for husband, preferably the most economical although not compromising effectiveness.... ALSO -- what other herbs and spices do you use? Thanks so much!
I bought on Amazon...TNV vitamins brand Boswellia 1200 mg per capsule. I take one cap a day.
As for my list of herbs and spices...Its a long list. I am on NO medicine at this time for last 3 months as part of OFF period of Intermittent Androgen therapy . my PSA remains 0.2 and T remains below 5....C reactive protein 0.2
My list includes an early morning drink of boiled 4 type of leaaves (soursoup, Sweet potato, Guava and holy basil leaves...added turmeric,ginger,blackpepper powder)..five drops of Manuka honey to take away bitterness.
Thats my starting drink of the day. Black+Green tea is second drink of the day.
Then, rest of the day...in a large cup of Fatfree yogurt..a pinch of Black cumin seed, Boswellia, Rosemary,organo,parsley, Giloy powder, Grape seed powder, pomegrandae seed powder, Quercetin and bromelain powder...
This Special cup of Yogurt with all these goodies is part of my breakfast. (11 am)
I have a plastic container in which small bottles of all herbs and spices are arranged
with labels on top of each. This is my "concoction box" Waiting to see how it goes in future...for now, I am doing well. At bedtime, 33 mg of CBD oil (without THC)
Interesting how so many of these helpful supplements are helpful for joint problems, given the pain my husband complained about the most was in his joints, esp his knees, and that it wold 'move around'.
I wonder if this would supplement would work as well with other --alutamides??
Perhaps it might be a good idea to use with Bicalutamide or the newer 'lutamide' drugs, but 5-LOX remains a good target regardless.
***
For those who are not impressed with supplements based on plant extracts mentioned in the Bible, BigPharma is very interested in 5-LOX inhibition & there are pharma alternatives.
Minocycline, which I am already using at a low dose for PCa:
"Minocycline Inhibits 5-lipoxygenase Expression and Accelerates Functional Recovery in Chronic Phase of Focal Cerebral Ischemia in Rats" [1]
Zileuton "is a 5-lipoxygenase inhibitor, primarily used for the prophylaxis and treatment of chronic asthma" [2]
Darbufelone: "Dual Inhibition of COX-2/5-LOX Blocks Colon Cancer Proliferation, Migration and Invasion in Vitro" [3]
***
The 'three wise men' brought gifts of gold, frankincense and myrrh, which suggests that frankincense and myrrh were highly valued.
"Frankincense and myrrh are both resins extracted from trees in the Burseraceae family, also known as the torchwood or incense family. Frankincense comes from the dried sap of Boswellia trees, while myrrh comes from the lifeblood of the Commiphora. Extracting the sap is a tenuous dance—you must injure the tree without killing it. If done properly, the wound will stimulate a process called "gummosis," which is exactly what it sounds like: the tree tries to gum up the damage, and you can carve off the resulting ooze for your own uses." [4]
& yes, there are some myrrh PCa studies [5]
It's interesting that the phytochemicals that might be useful as complementary therapy. including the polyphenols, are all involved in protection against phyto-injury, & that they all seem to have properties that translate to higher forms of life.
I was only reading yesterday that the oil does not contain AKBA.
"While boswellic acids are a major component of the resin, the steam or hydro distilled frankincense essential oil does not contain any boswellic acid as these components are non-volatile and too large to come over in the steam distillation process (the essential oil is composed mainly of the much lighter monoterpene and sesquiterpene molecules with small amounts of diterpenoid components being the upper limit in terms of molecular weight)." [1]
Nala would know what that all means.
So I would certainly keep using the oil, but also the patented 5-LOXIN:
"5-LOXIN® is a registered trademark of P.L. Thomas-Laila Nutra LLC and is used under license." [2]
Here is what I found at Lef.org Patrick is this what you use?
What is the "AprèsFlex"?
5-LOX Inhibitor with AprèsFlex®
100 mg, 60 vegetarian capsules | #01639
Promotes joint, cell & arterial health.
5-LOX Inhibitor with AprèsFlex® is made with a standardized Boswellia serrata extract that promotes a healthy inflammatory response and absorbs 52% better than standard boswellia extracts.
Compounds in Boswellia extract have been shown to bind directly to 5-LOX, an enzyme that transforms fatty acids into inflammatory factors like leukotriene B4.. A compound in boswellia called AKBA is the key to this beneficial action. Each 100 mg vegetarian capsule of 5-LOX Inhibitor with AprèsFlex® is standardized to provide 20% of active AKBA from boswellia.
AprèsFlex® absorbs 52% more than standard boswellia extract and is standardized for the active AKBA compound.
5-LOX Inhibitor with AprèsFlex® Benefits
Made with standardized Boswellia serrata extract
Promotes a healthy inflammatory response by inhibiting 5-LOX enzyme
Supports joint health, arterial health & healthy cell division
Better-Absorbed Boswellia
Boswellia is an extract that can inhibit inflammatory factors to support joint and arterial health. In this supplement, we use a standardized form of boswellia called AprèsFlex® that absorbs into the blood 52 percent more than previously available boswellia extracts. Each vegetarian capsule of 5-LOX Inhibitor with AprèsFlex® provides 100 mg of this innovative extract.
Dear Patrick, thanks a lot for your many, many great contributions.
May I ask you 2 questions:
1. Since I started ADT at the end of Nov. 2019, and Zytiga / Prednison middle of February 2020, I´m interested in your view on Zytiga in this context. Is my understanding correct that what is mentioned for Enzalutamide in this paper is also valid, and helpful, for Zytiga? In other words, is the inhibitions of 5-Lox, via Boswellia Serrata extract (ideally 5-LOXIN), also prudent in my situation?
2. If you would be in my situation (mentioned above), what would you recommend to do to stay as long a possible castration sensitive, and what would you try to avoid under all circumstances?
In the Enza study, the target was c-myc, but c-myc cannot be safely inhibited directly. However, inhibition of upstream 5-LOX generation did the trick. It's important, in my view, since c-myc is mentioned as a problem in over 700 papers (over 100 have "c-myc" in the title.)
In a paper published in October [1] - "C-MYC, HIF-1α, ERG, TKT, and GSTP1: An Axis in Prostate Cancer?":
"We found that high c-myc level was significantly associated with HIF-1α elevated expression ... in our 72 samples."
HIF-1α [Hypoxia-inducible factor 1-alpha] is commonly induced in drug resistance.
So I think that the authors may have hit on a general approach - & it would be potentially useful for Zytiga users.
The 2nd question is difficult since I can't give medical advice.
But I think that those who have been following my posts know that I have been using testosterone [T] for 15 of the 16 years since diagnosis. I have had some bone mets, & still have a very small one at S1 (untreated), yet I continue to wake up each morning in good shape & spirits. The reason, I feel, is that T interupts the path to CRPC. It sort of resets the clock.
In late 2018, I decided to swich from my homegrown approach to Sam Denmeade's (Johns Hopkins) BAT (Bipolar Androgen Therapy). I had to tailor it a bit, though.
I mention this because most men on Abi (Zytiga) or Enza (Xtandi) continue until drug resistance occurs. Abi & Enza are not curative & such palliative therapies promote the appearance of difficult "treatment emergent" mutations. But there are few options out there.
What would I "try to avoid under all circumstances?" Inflammation. Abnormal coagulation.
Hello Patrick, or others, what dose for Boswellia powder do you use? Or what dose of whatever else mentioned? And where do you get it? Similar question for those using the Life Extension preparation. Most economical is helpful although I do not want to compromise quality,. Thanks! Husband has become resistant to enzalutamide, perhaps it's too late but just heard about this.... He has mcrpc, docetasel first and then enzalutamide next didn't do the job. He still feels fine, extensive and increasing bone mets but not in his organs according to scan this week, we're fighters. Thanks!!!
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Ketones inhibit PCa, in the lab of course, but still...
evolutionary theory for Pca resistance
Hexose-6-phosphate dehydrogenase blockade reverses enzalutamide resistance
