Aspirin, metformin and propranolol

[kaptank]

Below I have copied a letter to the British Medical Journal in 2012 by a Scottish doctor whose name I did not keep. It was a response to an editorial on findings about aspirin and cancer. It may be of interest to some of our correspondents.

Re: Aspirin and cancer prevention

Reply to BMJ Editorial of 7.4.2012

ASPIRIN AND CANCER PREVENTION

Has the Medical profession accidentally stumbled onto a relatively inocuous cure for cancer?

Long term use of Aspirin, Metformin and the non selective BETA adrenergic receptor blocker Propranolol are all associated with lower cancer incidence, metastases and death.

Ref 1,2,3,4 and 5.

I believe the main mechanism linking thee drugs in inhibition of tumour Glycolysis.

You said in your Editorial of 7.4.12

“The study’s findings suggest low dose Aspirin should be considered in the treatment of some patients with cancer” and “the findings of 2 recent studies suggest daily low dose Aspirin could reduce cancer related outcomes”.

Otto Warburg found in the 1920s that cancer cells used 10 times more glucose because they get their energy from aerobic glycolysis rather than mitochondrial respiration. Switching off aerobic glycolysis and switching on mitochondrial respiration will lead to apoptosis : cancer cell death.

In your editorial you wrote that cancer metastases were reduced and that low dose Aspirin should be considered as a treatment for some cancers.

Aspirin was shown to block 5 enzymes of the glycolytic pathway.

Ref 6.

Aspirin reduced risk of adenocarcinoma with metastases at initial diagnosis and risk of metastasis on subsequent follow up of patients initially without metastases.

Ref 7

Empirically Metformin therapy gives a 31% to 37% reduction in relative risk of cancer, and improved prognosis in those found to have cancer.

Ref 8. Ref 2.

Metformin activates the AMP activated protein kinase pathway, a major sensor of the energetic status of the cell, which has been proposed as a promising therapeutic target in cancer treatment.

Metformin also inhibits the ability of Mitochondria to burn lactate and other products of glycolysis. New Scientist 17.9.2011.

Metformin delays uptake of glucose from the intestinal tract, decreases insulin resistance and inhibits hepatic and renal gluconeogenesis (Glucomet Data Sheet).

Propranolol users were significantly less likely to present with a T4 (odds ratio 0.24) or N2/N3/M1 (odds ratio 0.20). Cumulative probability of breast cancer specific mortality was significantly lower (hazard ratio = 0.19).

These results provide evidence in humans suggesting inhibiting the beta adrenergic pathway can reduce breast cancer progression and mortality.

Glycolysis is mediated through Beta 2 adrenergic receptor sites.

Ref 9

These drugs almost certainly act against cancer in other ways too, but the raw empirical data call for urgent trials of these drugs to be used together in randomised controlled trials as a cancer treatment at the very least in people otherwise offered only palliative chemotherapy.

My second question is can the medical profession do this when these drugs cost only pennies, and nearly all research is paid for by the Pharmaceutical Companies that expect to make large profits on expensive drugs.

REFERENCES

Reference 1 BMJ Editorial 7.4.2012

Aspirin & Cancer Prevention

Quote in studies Aspirin reduced the risk of cancer with distant metastases, hazard ratio 0.64.

“The study’s findings suggest low dose Aspirin should be considered in the treatment of some patients with cancer” and “the findings of 2 recent studies suggest daily low dose Aspirin could reduce cancer related outcomes”.

Reference 2

Metformin, cancer alphabet soup, and the role of epidemiology in Etiologic Research Diabetes care September 2009.

Reference 3

Metformin and Cancer Risk in Diabetic patients : A systematic review and Meta analysis Cancer Prevention and research 12th October 2010.

Reference 4

The influence of antidiabetic medications on the development and progression of prostate cancer. Cancer Epidemiology March 2012.

Reference 5

Betablockers and breast cancer mortality : a population and based study.

Journal of Clinical Oncology 2011 1st July

Reference 6

Aspirin acetylates multiple cellular proteins in HCT-116 colon cancer cells. Identification of novel targets, International Journal of Oncology 39; 1273-1283, 2011.

Reference 7

Effect of daily Aspirin on risk of cancer metastasis a study of incident cancers during randomised controlled trials. Lancet 20th March, 2012

Reference 8

Metformin in Cancer Therapy: a new perspective for an old diabetic drug published Molecular Cancer Therapy 2010 May.

Reference 9

Increased aerobic glycolysis through Beta 2 stimulation is a common mechanism involved in lactate formation during shock states. Shock October 2008 .

Competing interests: No competing interests

[TommyTV]

Otto Warburg was eventually proved wrong.

“In oncology, the “Warburg hypothesis” states that this change in metabolism is the fundamental cause of cancer. This hypothesis was eventually replaced by modern science – mutations in oncogenes and tumor suppressor genes (caused by viruses, environmental hazards, and random DNA errors) are responsible for malignant transformation. Warburg’s observations result from the mutations, and they are not the cause of cancer”.

This bad science has resulted in the crazy idea about alkaline diets, to change you body’s Ph, which is medically impossible.

[Tall_Allen]

More recent placebo-controlled studies so far proved him wrong. This isn't very surprising; observational studies often get overturned by randomized clinical trials.

There is a very large (n=11,000) randomized clinical trial in the works in the UK that should be definitive.

clinicaltrials.gov/ct2/show...

"Higher all-cause mortality was observed among apparently healthy older adults who received daily aspirin than among those who received placebo and was attributed primarily to cancer-related death."

nejm.org/doi/full/10.1056/N...

"Our data do NOT show that aspirin or levofloxacin help to decrease the incidence of prostate cancer occurrence, delay castration-resistant prostate cancer transformation, or reduce tumour-associated death. "

thelancet.com/journals/lanc...

The STAMPEDE randomized clinical trial proved that the COX-2 inhibitor, celecoxib (celebrex) had no effect on newly diagnosed metastatic prostate cancer. "Celecoxib 400 mg twice daily for up to 1 year is insufficiently active in patients starting hormone

therapy for high-risk prostate cancer, and we do not recommend its use in this setting."

thelancet.com/pdfs/journals...

[cesanon in reply to Tall_Allen]

"There is a very large (n=11,000) randomized clinical trial in the works in the UK that should be definitive.

clinicaltrials.gov/ct2/show..."

It appears the study is for non-metastatic tumors. So it might not be so definitive for many of us, or for most of us?

[Tall_Allen in reply to cesanon]

Men who have a recurrence often have undetected micrometastases. If it does nothing for preventing recurrence, what are the chances that it does anything for men who already have detectable metastases?

[kaptank]

Thanks for bringing me up to date. Yes, the Warburg effect is not the cause of cancer, but the effect is real enough - cancer cells rely on aerobic glycolysis as chief energy source and this distinguishes them from normal cells, making it a potential path to disrupt the growth of malignant cells. I agree that alkaline diets are not a great idea.

I think the jury is still out on aspirin. So far, the evidence from diabetics for metformin still seems strong even though we are still unsure as to how it works.

Nalakrats is right that propranolol is contra indicated for some heart conditions. It usually requires a prescription and your doctor should always do some simple tests and follow up if necessary before prescribing.

[pjoshea13 in reply to kaptank]

"Unlike most malignancies, prostate cancer is characterized by a slow glycolysis and low FDG avidity on PET imaging (3, 4). Other positron-emitting radiotracers, such as 18F-choline, 11C-choline, 11C-acetate and 18F-fluorodihydrotestosterone have recently been suggested as putative imaging agents for the detection of prostate tumors (5-9). Clinical evaluation of these radiotracers is presently underway and the role of PET scaning in prostate cancer is still evolving (10-12). Cell proliferation in malignant tumors is associated with increased energy requirements. If glucose consumption is not elevated in prostate cancer, alternative metabolic pathways must provide bioenergy for abnormal cell proliferation and growth. We therefore hypothesize that increased fatty acid metabolism characterizes prostate cancer, which depends on fatty acid oxidation, rather than glucose metabolism, as its dominant energy source. To test this hypothesis, as the first step, we investigated the uptake of radiolabeled glucose and fatty acid in various benign and malignant prostate cell lines."

...

"Normal and malignant prostate cells are characterized by dominant uptake of fatty acid over glucose."

ar.iiarjournals.org/content...

-Patrick

[cesanon]

You have the letter, but not the name of the author? How can that be?

[pjoshea13 in reply to cesanon]

Martyn Phipps

[pjoshea13]

here is the link: bmj.com/content/344/bmj.e24...

-Patrick

[cesanon in reply to pjoshea13]

Hmmm this all seems to make logical sense. And there is as yet no definitive controlled study proving or disproving it.

Metformin makes sense.

I had a detailed discussion with my GP and low dose aspirin continues to make sense.

If you are taking blood pressure medication, why not Propranolol?

Patrick, what do you think?

[pjoshea13 in reply to cesanon]

"Beta-blocker usage after diagnosis was not associated with cancer-specific or all-cause mortality in prostate cancer patients in this large UK study." [1]

"The use of beta blockers, including those of the non-selective type, was not associated with a decreased risk of prostate cancer and all-cause mortality." [2]

But:

"These findings indicate that beta-blocker use was associated with reduced cancer-specific mortality among prostate cancer patients taking beta-blockers." [3]

"Our findings demonstrate a possible benefit of β-blocker use for men treated with ADT, suggesting the need for investigation in larger cohorts." [4]

See: "Repurposing Drugs in Oncology (ReDO)—Propranolol as an anti-cancer agent" [5]

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/247...

[2] ncbi.nlm.nih.gov/pubmed/252...

[3] ncbi.nlm.nih.gov/pubmed/259...

[4] ncbi.nlm.nih.gov/pubmed/228...

[5] ecancer.org/journal/10/full...

[cesanon in reply to pjoshea13]

What am I missing. These two statements appear to be self contradictory. Apparently that is not so. What am I missing?

================

"The use of beta blockers, including those of the non-selective type, was not associated with a decreased risk of prostate cancer and all-cause mortality." [2]

But:

"These findings indicate that beta-blocker use was associated with reduced cancer-specific mortality among prostate cancer patients taking beta-blockers." [3]

[pjoshea13 in reply to cesanon]

Mixed results are common.

When there are many observational studies, a consensus view may be possible.

In this case, you would need to sift through the studies to determine the liklihood of benefit. beta-blockers are not currently part of my survival strategy.

-Patrick

[kaptank in reply to pjoshea13]

Thanks Patrick.

[j-o-h-n]

I guess "the guys" put a Kap on your Tank....

Good Luck, Good Health and Good Humor.

j-o-h-n Wednesday 11/14/2018 6:20 PM EST