Clorgyline & MAOA redux. {Treatment-Induced Neuroendocrine Prostate Cancer [NEPC].}

[pjoshea13]

It has taken 4 years since my post "Clorgyline & MAOA" [1], but the new Chinese paper "Monoamine oxidase A drives neuroendocrine differentiation in prostate cancer"[2] might revive interest in Clorgyline [3].

"Neuroendocrine transdifferentiation (NED) of prostate cancer (PCa) is the main cause of failure of androgen receptor inhibitor treatment."

"Emerging evidence indicates that elevated monoamine oxidase A (MAOA) contribute to the proliferation, cell stemness, and bone metastasis in PCa."

"Here, we generated an enzalutamide-induced NED cell model to assess the role of MAOA during NED. Overall, MAOA expression was significantly increased upon Enz long-term exposure and was required for neuroendocrine marker expression. In particular, Enz was found to induce NED via the MAOA/mTOR/HIF-1α signaling axis."

"Further analyses revealed that the MAOA inhibitor clorgyline(CLG) may bring multiple benefits to CRPC patients, including better therapeutic effect and delays NED."

-Patrick

[1] healthunlocked.com/advanced...

[2] pubmed.ncbi.nlm.nih.gov/353...

Biochem Biophys Res Commun

. 2022 Mar 23;606:135-141. doi: 10.1016/j.bbrc.2022.03.096. Online ahead of print.

Monoamine oxidase A drives neuroendocrine differentiation in prostate cancer

Xue Shui 1 , Xuehua Ren 2 , Rong Xu 3 , Qinghua Xie 4 , Yaohua Hu 1 , Jing Qin 3 , Han Meng 3 , Caiqin Zhang 3 , Jumei Zhao 5 , Changhong Shi 6

Affiliations collapse

Affiliations

1 Division of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China; School of Basic Medical Sciences, Medical College of Yan'an University, 580 Bao-Ta Street, 716000, Yanan, China.

2 Shaanxi Stem Cell Engineering and Technology Research Center, College of Veterinary Medicine, Northwest A&F University, Yangling, 712100, China.

3 Division of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China.

4 Division of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China; Animal Experiment Center, Guangzhou University of Chinese Medicine, 510000, Guangzhou, Guangdong, China.

5 School of Basic Medical Sciences, Medical College of Yan'an University, 580 Bao-Ta Street, 716000, Yanan, China. Electronic address: [e-mail].

6 Division of Cancer Biology, Laboratory Animal Center, Fourth Military Medical University, 710032, Xi'an, Shaanxi, China. Electronic address: [e-mail].

PMID: 35349822 DOI: 10.1016/j.bbrc.2022.03.096

Abstract

Neuroendocrine transdifferentiation (NED) of prostate cancer (PCa) is the main cause of failure of androgen receptor inhibitor treatment. However, the molecular mechanisms underlying the development of NEPC, especially treatment-induced NEPC, remain unclear. Emerging evidence indicates that elevated monoamine oxidase A (MAOA) contribute to the proliferation, cell stemness, and bone metastasis in PCa. Here, we generated an enzalutamide-induced NED cell model to assess the role of MAOA during NED. Overall, MAOA expression was significantly increased upon Enz long-term exposure and was required for neuroendocrine marker expression. In particular, Enz was found to induce NED via the MAOA/mTOR/HIF-1α signaling axis. Further analyses revealed that the MAOA inhibitor clorgyline(CLG) may bring multiple benefits to CRPC patients, including better therapeutic effect and delays NED. These findings suggest that MAOA may be an important target for the development of anti-NED therapies, thereby providing a novel strategy for the combined application of CLG and AR inhibitors in the clinic.

Keywords: Monoamine oxidase A; Neuroendocrine differentiation; Prostate cancer.

Copyright © 2022 Elsevier Inc. All rights reserved.

***

[3] en.wikipedia.org/wiki/Clorg...

[MateoBeach]

Interesting. However, MAO Inhibitors can be problematic to manage. Since the pathway is via mTOR perhaps good mTOR inhibition, such as my intermittent rapamycin, among others, will cover this base too.

[noahware]

I don't think clorgyline is readily available in the US, but an MAOI that would be is Nardil (phenelzine). I believe some clinical trials with this, for PC, have been done or are in progress... and I think those are for PC prior to NED, so there may be benefit for some men at any stage.

Does anyone know it if there are any studies/theories on use of MAOIs in conjunction with Lu177?

[pjoshea13 in reply to noahware]

Note:

clinicaltrials.gov/ct2/show...

Terminated (low enrollment)

clinicaltrials.gov/ct2/show...

Active, not recruiting

Both using Phenelzine Sulfate.

Published papers for <prostate phenelzine>:

"The MAO inhibitors phenelzine and clorgyline revert enzalutamide resistance in castration resistant prostate cancer"

ncbi.nlm.nih.gov/pmc/articl...

"MAOA inhibitor phenelzine efficacious in recurrent prostate cancer"

nature.com/articles/s41585-...

"Phase 2 Trial of Monoamine Oxidase Inhibitor Phenelzine in Biochemical Recurrent Prostate Cancer"

ncbi.nlm.nih.gov/pmc/articl...

"Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells"

ncbi.nlm.nih.gov/pmc/articl...

-Patrick

[Hidden]

I take 60 mg/day of phenelzyne (Nardil). I used it for depression in 94-95 so know that I do good with the sides (no food restrictions needed for me - not the case for many people). So, in 2019 I went back to the past.

1. Chemotherapy-Induced Monoamine Oxidase Expression in Prostate Carcinoma Functions as a Cytoprotective Resistance Enzyme and Associates with Clinical Outcomes

ncbi.nlm.nih.gov/pmc/articl...

2. USC researchers use decades-old antidepressant to combat prostate cancer – Ellison Institute for Transformative Medicine

ellison.usc.edu/2020/03/03/...

3. Phase 2 trial of monoamine oxidase inhibitor phenelzine in biochemical recurrent prostate cancer – PubMed

pubmed.ncbi.nlm.nih.gov/321...

4. USC study shows MAO-A may be effective in treating prostate cancer

news.usc.edu/146963/usc-stu...

5. Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells – PubMed

pubmed.ncbi.nlm.nih.gov/306...

6. Loss of MAOA in epithelia inhibits adenocarcinoma development, cell proliferation and cancer stem cells in prostate | Oncogene

nature.com/articles/s41388-...

7. Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells

ncbi.nlm.nih.gov/pmc/articl...

8. 1950s depression pill could be used to treat prostate cancer | Daily Mail Online

dailymail.co.uk/health/arti...

9. MAOA promotes prostate cancer cell perineural invasion through SEMA3C/PlexinA2/NRP1–cMET signaling | Oncogene

nature.com/articles/s41388-...

10. Adherence to antidepressant medications is associated with reduced premature mortality in patients with cancer: A nationwide cohort study – PubMed

pubmed.ncbi.nlm.nih.gov/313...

11. Antidepressants protect bones from metastatic prostate cancer – PubMed

pubmed.ncbi.nlm.nih.gov/283...

12. Phase II Trial Results Show Promise for Phenelzine in Prostate Cancer

cancernetwork.com/view/phas...

13. Antidepressant shows promise in treating recurrent prostate cancer

news.usc.edu/166277/antidep...

14. Effect of Monoamine oxidase A (MAOA) inhibitors on androgen-sensitive and castration-resistant prostate cancer cells

ncbi.nlm.nih.gov/pmc/articl...

15. Effects of the monoamine oxidase inhibitors pargyline and tranylcypromine on cellular proliferation in human prostate cancer cells

ncbi.nlm.nih.gov/pmc/articl...

[GeorgeGlass in reply to Hidden]

Why did you hide your name?

[Captain_Dave]

I thought that quercetin was an MAO inhibitor.

[pjoshea13 in reply to Captain_Dave]

ncbi.nlm.nih.gov/pmc/articl...

[LearnAll in reply to Captain_Dave]

No.

[FRTHBST in reply to Captain_Dave]

Yes, Quercitin and many other flavonoids are MAO inhibitors.

integrativepharmacology.com...

researchgate.net/publication

/41805982_Natural_Monoamine_oxidase_inhibitors_A_Review

Common supplements, including resveratrol, -many others have some activity in this direction. From the first reference : The most potent inhibitors have the lowest IC50 values (the concentration required to achieve 50% inhibition of enzyme activity). Flavonoids like quercetin and its analog kaempferol, and the stilbene resveratrol, were relatively effective against MAO-A, based on the above data.

[LearnAll in reply to FRTHBST]

Thanks..I was not aware of this. BTW...Most of these natural substances...I eat every single day. Also, a herb, St Johns Wort also has some MAO inhibitor effect.

[GeorgeGlass in reply to FRTHBST]

How much Quercetin do you take daily?

[FRTHBST in reply to GeorgeGlass]

I've been taking 200mg tablets of a product, Isoquercitin. 2 tablets 3 x day. This is an old but good post, miss Patrick's sharp eye and constant searching intelligence.

[GeorgeGlass in reply to FRTHBST]

I go back to much older posts by using search feature. Much of the usefulness didn’t change much over the years, unless it’sa cutting edge treatment. Patrick is an excellent source of knowledge and original thinker.

[FRTHBST in reply to GeorgeGlass]

My dosage was perhaps not expressed clearly, each tablet is 200mg, so each day would be 1200mg. I'll have to do more retrospective searching- so much to learn and it's impossible to absorb all of the useful information in one go.

[GeorgeGlass in reply to FRTHBST]

Thanks. It’s impossible to act on most of the information as well. The government should have s department of cancer instead of a department of education and irs. Lots of good research going on but production and distribution is limited, which is why so many are seeking supplements.

[DenDoc]

Thanks for sharing. May be an important addition to current treatment.

[LearnAll]

The connection between Anti Depressant medicines and improved prognosis in prostate Cancer is very interesting.In my previous post ,I did present the papers which illustrate that antidepressant meds such as Sertraline, Imipramine , phenelzine etc...all tend to inhibit growth of stem cells and delay resistance by some yet unknown mechanism.

Meds like Sertraline (SSRI family) are do not have major serious side effects, Imipramine (tricyclic family) cause dry mouth, constipation, blurry vison and sometimes urinary retention. MAO inhibitors such as Phenelzine requires avoidance of tyramine containing foods such as BEER, favabeans, Cheese etc. so these are difficult to use . The foods which contain tyramine can cause severe rise in blood pressure if used with Phenelzine.

SSRIs such as prozac,Paxil,Zoloft, lexapro are safer choices of all anti depressant meds.

[Canoehead in reply to LearnAll]

Now I’m concerned. You capitalized “BEER.” I hope that means it’s an acronym (we use a lot of those around here) for some obscure chemical and not to emphasize the need to avoid one of my favorite beverages. LOL

[LearnAll in reply to Canoehead]

Sorry..dear beer drinker....MAO inhibitors react with tyramine which is an ingredient in Beer and can cause dangerous elevation in blood pressure...This is called Cheese reaction because Cheese has tyramine too.

[j-o-h-n in reply to Canoehead]

A smile to offset your tears......

A brewery worker named Lee

Drowned in a vat of brewski.

I regretfully say

He’d not drowned right away;

He climbed out five times just to pee.

Good Luck, Good Health and Good Humor.

j-o-h-n Thursday 03/31/2022 3:30 PM DST

[pjoshea13 in reply to j-o-h-n]

Ah, the old Guiness brewery joke. -Patrick

[j-o-h-n in reply to pjoshea13]

I saw it while Hoping around and Barley found it..... Geez Patrick you're older than you look..........

Good Luck, Good Health and Good Humor.

j-o-h-n Thursday 03/31/2022 3:50 PM DST

[Medline]

Serotonin is produced by neuroendocrine prostatic cells, and the enzymatic degradation of serotonin is mainly served by MAO-A.

pubmed.ncbi.nlm.nih.gov/150...