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AMPK activation via Metformin enhances survival of clinically dormant residual ER+ Breast tumor cells.  

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ljb
 ljb
(@ljb)
Joined: 5 months ago
Posts: 2
22/09/2020 3:43 pm  

https://www.biorxiv.org/content/10.1101/2020.01.21.914382v1.full

 

Hi, Daniel

Please be sure to see this paper. 

I & my wife is so embarrassed after reading this paper.

The question is, should she continue to take Metformin?
I know you're busy, but please reply to me back.

(My wife had diagnosed to Hormone-positive breast cancer 3rd stage A, had surgery in 2017, radiation therapy, and no chemo.
Tamoxifen oral medication has been in use since January 2018 until September 2020, and additional treatments are available.
I received Leuplin S.C.Inj. every three months for two years from the spring of 2018 and in January 2020 Leuplin Inj.The treatment has been suspended.I did what the hospital told me to do.
My wife is 48 years old and 168 cm tall and weighs 64 kg.)

 

I look forward to hearing from you.
Thank you, Daniel.

This topic was modified 1 month ago by ljb

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Daniel
(@daniel)
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23/09/2020 12:23 am  

Dear @ljb,

 
Thank you for your very good question.
 
The article you mention is very interesting. It suggests that AMPK activation by metformin promotes survival of dormant ER+ breast cancer cells. AMPK was often debated in literature on if it is good or bad to be activated. On the other hand, Metformin has been often shown to be beneficial in cancers, while being an AMPK activator. As you know the literature (and various studies including case reports) is overwhelmingly supporting Metformin benefits.
 
So these facts make the results in this article unexpected and an interesting challenge. After getting into the details of the literature, I think I found the answer to the puzzle. But first I will go a bit through the facts:
 
The article above states the following:
 

- dormant tumor cells exhibited markers of increased respiration and dependency upon FAO (fatty acids oxidation)

- it shows that there is an increased numbers of mitochondria and mitochondrial elongation in dormant tumors, increased levels and activity/respiration of mitochondria during hormone deprivation
- it shows that FAO activity is increased during hormone deprivation
- increase in FAO and mitochondria activity are a result of AMPK activation during the cellular stress conditions
- in estrogen stimulated cells Metformin strongly inhibits the tumor growth
- in estrogen deprived cells (with lower AMPK activation), Metformin activates AMPK and helps the cells survive by increasing mitochondria bio-genesis and FAO
- when FAO inhibitors are applied, the cell survival is halted
- the conclusion here is that Metformin helps against tumors when they are not treated with hormonal treatments, but may help their survival during hormone deprivation
 
On the other hand, from literature, we know that:
- Metformin shows anticancer effects in many types of cancer 
- one major mechanism to do that is via mitochondria inhibition
- another major mechanism responsible for its anticancer action is blood glucose reduction
- yet another major mechanism responsible for its anticancer action is its insulin reduction (that can be a growth signal)
- indeed Metformin is also an AMPK activator (triggered by e.g. energy depletion or the superoxide level increased due to the respiration inhibition), that in turn activates FAO and inhibits FAS (fatty acid synthesis). This also leads to the reduction of the level of lipid droplets stored into the cell, and could be the reason why Metformin may help loose weight. 
- the AMPK inhibition leads to activation of autophagy as well as mitochondria biogenesis
 
My analysis:
- the results in the article above do not make sense, based on the info we have available, since Metformin should inhibit mitochondria activity and not lead to an increased activity of mitochondria and facilitation of FAO
- so there must be something else that we are not aware of
- first we should be aware that in this article they used a metformin dose that "did not significantly alter levels of serum insulin, serum free fatty acids, or blood glucose". This means that two important anti-cancer mechanisms related to Metformin have been removed from the experiment. This means that we also nee to only look at AMPK activation and respiration inhibition
- after spending a good amount of time searching in the literature. here is what I think is the key that can explain the above results:
 
According to the above two articles, fatty acids revert the inhibition of respiration caused by the antidiabetic drug metformin to facilitate their mitochondrial β-oxidation.
 
This is totally new to me and it uncovers a very important aspect about how to maximise the benefits of using Metformin against cancer.
 
So what happens is that Metformin inhibits respiration, but when exposed to fatty acids that effect is gone (or partially gone) and we are only left with AMPK activation that stimulates:
- FAO (fatty acid oxidation) increase 
- Mitochondrial Biogenesis
This is not what we want as also shown by the article above. 
 
(Remember that in these experiments we do not look at Metformin anti cancer benefits related to glucose reduction and insulin reduction).
 
This may explain why Metformin sometimes works and sometimes not in reducing the growth of tumors. Therefore combining Metformin with FAO inhibitors may be the way towards an increased anti-cancer effectiveness.
 
Based on the article above, in ER+ breast cancer I would consider combining the following:
1. Mitochondria inhibitors of various complexes, such as discussed here https://www.cancertreatmentsresearch.com/a-list-of-mitochondria-inhibitors/
2. Mitochondria inhibitors of its biogenesis, such as Doxycicline
3. FAO inhibitors, such as Ranolazine - FDA-approved for angina treatment
Here is a longer list of FAO inhibitors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240910/
 
Metformin is a drug that I like a lot and has so many anti-cancer properties but in this case I would skip it (and other AMPK activators or FAO activators) or use-it in one month cycles.

I will check to see if I can find more FAO inhibitors.

I hope this helps.

 

Kind regards,
Daniel

 

 

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ljb
 ljb
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Posts: 2
24/09/2020 6:25 pm  

@daniel

안녕 다니엘
다시 한번 당신의 정성어린 답변에 감사드린다

1.나도 Metformin(이하 MFM)이 혈당을 감소시켜주고 혈중 인슐린 level을 낮추어줌으로써 항암효과를 가지는것으로 알고있다. 그런데 그 약물이 항암효과를 가지는 기전중 가장 중요한 부분은 Mito.Com.I 억제(=OXPHOS 억제)에 의한 Mito.Resp.억제라고 알고 있었다.암세포에서 Mito.억제에 대한 보상성 feedback(?)으로 AMPK가 활성화되고 뒤따라 FAO가 활성화되더라도, FAO에서 나온 Acetyl CoA가 결국 TCA cycle을 거치고 ETC로 들어가 ATP가 만들어지는것이니, 그러한 보상성 feedback 과정에 의한 후속적인 ATP생성 또한 MFM에 의해서 계속 차단될 것이라고 생각했다.
2.MFM의 항암작용중 다른 기전인 혈당 감소와 혈중 인슐린 level 감소는 반드시 MFM이라는 약물만 가지고서 얻을수 있는 효과가 아니지 않는가?
저탄수화물 식이나 다른 종류의 약물(eg., SGLT2 억제제) 등등으로서도 가능하지 않는가?
방금의 내 질문이 맞다면, Metformin이란 약물이 항암효과를 가지는 기전중에서 OXPHOS억제에 의한 Mito.Resp.감소/inhibition이 가장 의미있고 중요한 것이 아닌가?
3.당신의 답변글에 올려져있는 ScienceDirect 논문에서의 내용을 보면, Mito.FAO는 Mito.Com.I 억제를 역전시키고 ("or~이 아니라 "and") CPT 억제까지 풀어주게 되면 촉진된다고 나와있다. 또한 논문의 제목에서처럼 세포내(Mito.내?) 지방산이 있어야 (많아져야?) 그 지방산에 의해서 Metformin에 의한 Mito.  Resp.억제 작용이 되돌려진다고 되어있다.여기서 언급되는 지방산은 식이에서 오는 것인가 아니면 de novo FAS에 의해서 오는 것인가 아니면 두가지(식이 와 생체내 de novo FAS) 모두에서 오는것인가?
FAO에 기질로 쓰일 지방산의 공급원으로서, De novo FAS에 의한 지방산 공급의 비중이 훨씬 더 크거나 거의 전적이라고 한다면 Metformin과 PPI등으로 FAS를 억제하게 되면 FAO에 들어가게 될 FA는 많이 줄어들 것이고,
혹은 식이섭취와 de novo FAS가 비슷한 비중으로 FA공급원이 된다면 MFM 과 PPI 복용과 함께 저지방 식이법을 추가하여 세포내(Mito.내?)로의 지방산 유입을 줄여줌으로써 지방산 증가가 MFM의 Mito.Resp.억제 작용을 되돌리는 것을 막아줄수 있지 않겠는가?
결국 그렇다면 간간히 말하자면 세포내(혹은 Mito.내?)로의 지방산의 유입만 줄여주게 된다면 MFM의 호흡억제 작용은 그대로 유지되지 않겠는가?
4. 오메가 3 도 불포화지방산이고 올리브오일에도 지방산이 풍부하다고 알고있다. 이런 성분의 보충제(오메가 3 보충제 및 올리브오일 및 올리브잎 추출물 등)를 많이 섭취할 시에 세포내로 지방산의 유입을 증가되어서 MFM의 Mito.Resp.억제 작용을 되돌리는 (결코 우리가 원하지 않는) 경우는 생기지 않는가?
5. Ranolazine은 Statin과의 약물 상호작용으로 근병증 유발위험도가 높아진다고 알고있다. 당신이 알다시피 Statin은 항암작용 약물로 정말 중요하기에 도저히 복용하지 않을수가 없고 근병증 또한 환자의 일상을 아주 힘들게 할게 되므로, Ranolazine은 구할수 있다 하더라도 같이 복용하지는 못하지 않겠는가?
6. Trimetazidine이라는 성분(우리나라에서 generic name Vastinan)이 FAO의 부분적인 억제제라고 알고있다. 이 약물은 현재 전 세계적으로 많이들 쓰이고 있다고 알고있다(나의 지식으로는 다른 약물들보다 safety profile이 좋기에 그럴것이라고 안다). 이약물을 FAOI로 복용하는것은 효과적이지 못할것이라 예측되는가?
7. 당신도 알고 있는 유명한 책인 " How to Starve Cancer? " 의 저자인 Jane이 만든 암세포 대사 치료 Metro Map 삼각형에서 보면 FAOI로 독시싸이클린이 나오고 있다.(물론 FAOI로서 그 약물 옆에 Mildronate도 적혀있다) 내가 며칠간 구글을 통해서 아무리 검색을 해 보아도 독시싸이클린이 FAOI 작용이 있다는 자료는 찾을수가 없었다. 독시싸이클린이 FAOI로 작용할수 있는것이 맞는 것인가? (아내는 독시싸이클린 100mg 1T qd 복용은 거의 1년간 해 왔으며 다행히 그 용량과 용법으로는 큰 부작용이 없었었기에, 독시싸이클린이 FAOI로 효과적일수 있다는 Jane의 Metro Map 내용이 정확히 맞기를 바란다)
8. Avocatin B에 관한 정보 및 구입가능한 인터넷싸이트를 알려주어서 너무나 고맙다
9. 당신은 내가 포럼에 올린 논문(혹은 article)에서 사용된 MFM의 용량 및 농도가 혈중 인슐린 및 FFA 및 혈당을 의미있게 바꾸어 줄수 있는 농도가 아니라고 한다. 그런데 나의 영어실력 및 해석실력이 너무 짧아서인지 나는 그렇게 생각하질 않았다. 당연히 당신은 나보다 훨씬 더 영어라는 언어에 아주 익숙하고 영어논문에 전문적이며 심지어 물리학 박사이기에 당신의 분석과 해독이 맞았다고 본다. (당신의 논문 분석을 보고서 내가 감히 그 내용에 반박하는 것이 절대로 아니다~기분 나쁘게 받아들이지 말라)
그렇다면, 그 논문에서의 MFM농도에서 그런 결과가 나왔다면 실제 흔히들 추천하는 MFM 복용량(1500~2000mg/day)으로 복용시에는 인체내에서 더 높은 혈중농도/조직농도가 형성될 것이고 그 효과가 달라질 것이기에 그 논문에서의 결과만을 온전히 받아들일 수는 없다는 것 아닌가?
10. 만약 결국 어쨌던지간에 그녀가 MFM 복용을 망설인다면, MFM 을 복용함과 동시에  Avocatin B 와  Trimetazidine 복용을 같이 하는것은 나쁜 선택이 될까 궁금하다

너무 많은 것을 물어보아서 정말 미안하다
그리고 내 지식 및 영어실력이 짧아서 질문이나 글의 내용이 전문가인 당신에게는 건방지거나 무례하다고 느껴질수도 있겠으나 내가 너무 아는것이 없고 영어실력이 짧아서 그런것임을 이해해 달라. 절대 당신을 믿기 때문에 당신의 귀한 의견을 듣고자 함이니 나의 글 표현 방식에 제발 기분 나빠하지 말아달라.
늘 성심껏 도와주어서 당신에게 진심으로 고맙다


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Daniel
(@daniel)
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25/09/2020 1:51 am  

Dear @ljb ,

I just translated your text. Thank you for your questions. There are some very good questions, and in order to be able to answer all I would need to spend more time to investigate, and for example search more for FAO inhibitors and check a little more. I find this subject very interesting and this is why I want to spend a little more time before addressing your questions.

Thanks you for your understanding and patience.

Below, I will add the translation of your text so that I can read it latter.

Kind regards,
Daniel 

 

 

Hello daniel

Once again thank you for your polite response

  1. I also know that Metformin (hereinafter referred to as MFM) has anti-cancer effects by reducing blood sugar levels and lowering blood insulin levels. However, it was known that the most important part of the mechanism by which the drug has anticancer effect is inhibition of Mito.Resp. by inhibition of Mito. Even if AMPK is activated and FAO is subsequently activated, Acetyl CoA from FAO eventually goes through the TCA cycle and enters ETC to make ATP, so I think that subsequent ATP generation by such a reward feedback process will also be blocked by MFM did.
  2. Among the anticancer effects of MFM, aren't the other mechanisms of reducing blood sugar and reducing blood insulin levels that can be obtained only with drugs called MFM?
    Isn't it possible with a low-carb diet or other types of drugs (eg, SGLT2 inhibitors)?
    If my question is correct, isn't Mito.Resp. reduction/inhibition by OXPHOS inhibition the most significant and important among the mechanisms that Metformin has anticancer effect?
  1. Looking at the content in the ScienceDirect paper posted in your reply, Mito.FAO is promoted by reversing Mito.Com.I inhibition ("or" but "and") and even releasing CPT inhibition. In addition, as in the title of the paper, it is said that the presence of fatty acids in the cells (in Mito?) (must be more?) is reversed by the fatty acids in the inhibition of Mito. Resp. by Metformin. The fatty acids mentioned here come from diet Is it from de novo FAS or is it from both (diet and in vivo de novo FAS)?

    As a source of fatty acids to be used as a substrate in FAO, if the proportion of fatty acid supply by De novo FAS is much greater or almost entirely, if FAS is suppressed with Metformin and PPI, the amount of FA that will enter FAO will decrease a lot.
    Alternatively, if dietary intake and de novo FAS are the source of FA with similar proportions, MFM and PPI intake and a low-fat diet are added to reduce the influx of fatty acids into the cells (Mito. Wouldn't it be possible to prevent it from reversing the action?
    In the end, if so, if you only reduce the influx of fatty acids into the cells (or Mito?), will not the respiratory inhibitory action of MFM remain the same?

  2. Omega 3 is also an unsaturated fatty acid, and it is known that olive oil is also rich in fatty acids. When a large intake of these supplements (such as omega 3 supplements and olive oil and olive leaf extract) increases the influx of fatty acids into the cells, thereby reversing the mito.Resp. inhibitory action of MFM (which we never want). Does not occur?
  3. Ranolazine is known to increase the risk of inducing myopathy due to drug interactions with Statin. As you know, Statin is really important as an anticancer drug, so we can't help but take it, and myopathy also makes the patient's daily life very difficult. So even if Ranolazine is available, why not take it together?
  4. Trimetazidine (generic name Vastinan in Korea) is known to be a partial inhibitor of FAO. I know that this drug is being used a lot all over the world (I know it will be because it has a better safety profile than other drugs to my knowledge). Is it expected that taking this drug as FAOI will not be effective?
  5. From the Cancer Cell Metabolism Therapy Metro Map triangle created by Jane, the author of the famous book "How to Starve Cancer?" you know, FAOI is doxycycline (of course, as FAOI, Mildronate is written next to the drug). No matter how much I searched through Google for a few days, I couldn't find any data that Doxycycline had FAOI action. Is it correct that Doxycycline can act as FAOI? (My wife has been taking doxycycline 100mg 1T qd for almost a year, and fortunately, there were no major side effects with the dosage and administration, so I hope that Jane's Metro Map content that Doxycycline can be effective as FAOI is exactly correct)
  6. Thank you so much for providing information on Avocatin B and available online sites.
  7. You say the doses and concentrations of MFM used in my forum article (or article) are not those that can significantly alter blood insulin and FFA and blood sugar. However, I didn't think so because my English and interpretation skills were too short. Obviously, you are much more familiar with the language of English than I am, specialized in English papers, and even a Ph.D. in physics, so I think your analysis and decoding are correct. (It is absolutely not that I dare refute the contents of your thesis analysis-do not take it offended)
    If that is the case, then, if such a result was obtained from the MFM concentration in the paper, a higher blood concentration/tissue concentration in the human body would be formed and the effect would be changed when taken at the actual recommended MFM dose (1500~2000mg/day). Isn't it that you cannot fully accept the results of that thesis?
  8. In the end, if she hesitates to take MFM anyway, I wonder if taking Avocatin B and Trimetazidine at the same time taking MFM would be a bad option.

I'm really sorry for asking so many things

Also, because my knowledge and English are short, it may feel impolite or rude to you, who is an expert in the content of questions or writings, but please understand that it is because I do not know too much and my English is short. Because I absolutely trust you, I want to hear your valuable opinions, so please don't be offended by the way I express my writing.

I sincerely thank you for always helping me out.

 


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Daniel
(@daniel)
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25/09/2020 2:19 am  

@ljb You will probably like this https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593549/ although the results are a little strange because Valproic Acid is known as beta-oxidation inhibitors https://www.nature.com/articles/pr1992399 and https://repub.eur.nl/pub/129244/

This post was modified 1 month ago by Daniel

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Jcancom
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Joined: 3 years ago
Posts: 507
25/09/2020 4:06 am  

Sorry to bud in, though D referenced a version of the cancer stem cell eradication treatment. I want to highlight a newer version as seen below that uses a triple combination DAV that appears quite impressive. Vitamin C acts to promote mitochondrial biogenesis which is then obstructed by  doxy and azithro at the protein translation level leaving rho zero mitochondria. Very smart! rho zero mitochondria cancer stem cells essentially would create non-viable cells. They would be extremely vulnerable to almost any glycolytic stress. This appears to be a very powerful anti-cancer strategy that those on forum should be more aware of. Attacking cancer stem cells is a powerful approach to directly addressing the driving force of cancer propagation. 

 

ljb, thank you for posting! It is especially helpful that you kept the Korean font so that it was easy to recognize your nationality.

Might you be aware of 3-BP development in South Korea and elsewhere in Asia? It is not easy breaking through the internet language barrier in order to assess the current 3-BP situation.

There is quite a bit of excitement now that South Korea has acquired ownership of 3-BP intellectual property. GLab has posted several cancer patient success stories using 3-BP. Are you aware of South Korean clinics that offer 3-BP treatment? Might you be aware of the rough timeline that has been announced for 3-BP's entry into the clinic in South Korea?

Different nations have different regulatory stances to 3-BP treatment. Are you aware of how different Asian nations are managing 3-BP access? For instance, do Asian typically accept the concept of Right to Try? Best Wishes, J 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022456/pdf/biomolecules-10-00079.pdf

Doxycycline, Azithromycin and Vitamin C (DAV): A potent combination therapy for targeting mitochondria and eradicating cancer stem cells (CSCs)

 

"It is important to note Doxycycline and Azithromycin are not direct OXPHOS inhibitors, but instead are inhibitors of mitochondrial protein translation.  Vitamin C acts as a mild pro-oxidant and can stimulate the production of free radicals, driving mitochondrial biogenesis, secondary to mitochondrial oxidative stress and the anti-oxidant response."

 

https://www.aging-us.com/article/101905/text

Anti-mitochondrial therapy. Vitamin C can act as a pro-oxidant, via the production of free radicals. The ascorbate radical is normally very stable, but becomes highly reactive in the presence of metal ions, including iron (Fe). As mitochondria are rich in iron, they could become a key target of the pro-oxidant effects of Vitamin C, sequentially driving first mitochondrial oxidative stress and then mitochondrial biogenesis. However, the use of inhibitors of mitochondrial protein translation, together with Vitamin C, would ultimately prevent CSC mitochondria from fully recovering, leading instead to CSC eradication. Additional experimentation will be required to further test this hypothesis.

 

Summary diagram highlighting the mechanism(s) of action related to the triple combination of Azithromycin, Doxycycline and Vitamin C. This approach effectively results in the synergistic eradication of CSCs, using vanishingly small quantities of antibiotics. It is important to note Doxycycline and Azithromycin are not direct OXPHOS inhibitors, but instead are inhibitors of mitochondrial protein translation. The 2 metabolic targets are the large mito-ribosome and the small mito-ribosome. Azithromycin inhibits the large mitochondrial ribosome as an off-target side-effect. In addition, Doxycycline inhibits the small mitochondrial ribosome as an off-target side-effect. Vitamin C acts as a mild pro-oxidant and can stimulate the production of free radicals, driving mitochondrial biogenesis, secondary to mitochondrial oxidative stress and the anti-oxidant response. Vitamin C is also thought to act as an inhibitor of the glycolytic enzyme GAPDH (Glyceraldehyde 3-phosphate dehydrogenase). However, here, we did not observe any inhibition of glycolysis, when Vitamin C was tested alone.

 

 


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