Statins + Dipyridamole?

[pjoshea13]

New cell study below [1].

Bottom-line: PCa resistance to statins can be blocked by Dipyridamole. Might be an important finding.

Dipyridamole "is a medication that inhibits blood clot formation" [2]. (which in itself is useful for PCa)

{"Dipyridamole is used to dilate blood vessels in people with peripheral arterial disease and coronary artery disease

"Dipyridamole has been shown to lower pulmonary hypertension without significant drop of systemic blood pressure

"It inhibits formation of pro-inflammatory cytokines (MCP-1, MMP-9) in vitro and results in reduction of hsCRP in patients.

"It inhibits proliferation of smooth muscle cells in vivo and modestly increases unassisted patency of synthetic arteriovenous hemodialysis grafts.

"It increases the release of t-PA from brain microvascular endothelial cells

"It results in an increase of 13-HODE and decrease of 12-HETE in the subendothelial matrix (SEM) and reduced thrombogenicity of the SEM.

"Pretreatment it reduced reperfusion injury in volunteers.

"It has been shown to increase myocardial perfusion and left ventricular function in patients with ischemic cardiomyopathy.

"It results in a reduction of the number of thrombin and PECAM-1 receptors on platelets in stroke patients.

"cAMP impairs platelet aggregation and also causes arteriolar smooth muscle relaxation. Chronic therapy did not show significant drop of systemic blood pressure.

"It inhibits the replication of mengovirus RNA.

"It can be used for myocardial stress testing as an alternative to exercise-induced stress methods such as treadmills."}

"The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear."

"High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR ..."

"Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells."

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/310...

Mol Metab. 2019 Apr 10. pii: S2212-8778(19)30088-2. doi: 10.1016/j.molmet.2019.04.003. [Epub ahead of print]

An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer.

Longo J1, Mullen PJ2, Yu R1, van Leeuwen JE1, Masoomian M3, Woon DTS4, Wang Y5, Chen EX2, Hamilton RJ4, Sweet JM3, van der Kwast TH3, Fleshner NE4, Penn LZ6.

Author information

1

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada.

2

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada.

3

Department of Pathology, Laboratory Medicine Program, University Health Network, Toronto, Ontario, M5G 2C4, Canada.

4

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Division of Urology, Department of Surgical Oncology, University Health Network & University of Toronto, Toronto, Ontario, M5G 2M9, Canada.

5

Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, V6H 3Z6, Canada; Department of Experimental Therapeutics, BC Cancer Research Centre, Vancouver, British Columbia, V5Z 1L3, Canada.

6

Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 1L7, Canada. Electronic address: [e-mail].

Abstract

OBJECTIVE:

The statin family of cholesterol-lowering drugs has been shown to induce tumor-specific apoptosis by inhibiting the rate-limiting enzyme of the mevalonate (MVA) pathway, HMG-CoA reductase (HMGCR). Accumulating evidence suggests that statin use may delay prostate cancer (PCa) progression in a subset of patients; however, the determinants of statin drug sensitivity in PCa remain unclear. Our goal was to identify molecular features of statin-sensitive PCa and opportunities to potentiate statin-induced PCa cell death.

METHODS:

Deregulation of HMGCR expression in PCa was evaluated by immunohistochemistry. The response of PCa cell lines to fluvastatin-mediated HMGCR inhibition was assessed using cell viability and apoptosis assays. Activation of the sterol-regulated feedback loop of the MVA pathway, which was hypothesized to modulate statin sensitivity in PCa, was also evaluated. Inhibition of this statin-induced feedback loop was performed using RNA interference or small molecule inhibitors. The achievable levels of fluvastatin in mouse prostate tissue were measured using liquid chromatography-mass spectrometry.

RESULTS:

High HMGCR expression in PCa was associated with poor prognosis; however, not all PCa cell lines underwent apoptosis in response to treatment with physiologically-achievable concentrations of fluvastatin. Rather, most cell lines initiated a feedback response mediated by sterol regulatory element-binding protein 2 (SREBP2), which led to the further upregulation of HMGCR and other lipid metabolism genes. Overcoming this feedback mechanism by knocking down or inhibiting SREBP2 potentiated fluvastatin-induced PCa cell death. Notably, we demonstrated that this feedback loop is pharmacologically-actionable, as the drug dipyridamole can be used to block fluvastatin-induced SREBP activation and augment apoptosis in statin-insensitive PCa cells.

CONCLUSION:

Our study implicates statin-induced SREBP2 activation as a PCa vulnerability that can be exploited for therapeutic purposes using clinically-approved agents.

Copyright © 2019 University Health Network. Published by Elsevier GmbH.. All rights reserved.

KEYWORDS:

Dipyridamole; Drug repurposing; Mevalonate pathway; Prostate cancer; Statins; Tumor metabolism

PMID: 31023626 DOI: 10.1016/j.molmet.2019.04.003

[2] en.wikipedia.org/wiki/Dipyr...

[Graham49]

Interestingly, Jane McLelland in her book "How to Starve Cancer" states that dipyridamole was one of the drugs she used to beat cancer.

[pjoshea13 in reply to Graham49]

Graham,

Thanks for pointing that out. I think that most who reject standard care do crazy stuff, but embracing standard care when the odds go below a certain point, forces one to contemplate alternatives. Jane McLelland, dealing with several cancers - although clearly not PCa - was drawn to some of the topics that I have written about. Nothing crazy about her response to impossible odds, IMO. -Patrick

From: healthinsightuk.org/2019/03...

... note highlighted section ...

"This post is ... by someone who has near zero qualifications for taking on the august and powerful oncology establishment. Jane McLelland is a former physiotherapist, one-time competitive yachtswoman and the author of a recently published book called ‘How to Starve Cancer’. It’s a passionate, brave and gripping medical detective story.

Jane’s most obvious achievement is that she’s still alive. Twenty years ago, she was diagnosed with stage IV lung cancer – life expectancy measured in months – but here she still is, promoting her book and sharing her discoveries about the biochemistry of cancer and how they can be used to destroy it. Not information oncologists were concerned about in 1999. Few are interested now.

Cheap drugs with anti-cancer effects

But more than identifying cancer’s ignored vulnerabilities, she has mapped the terrain of cancer in a new way that make clear why various complementary and alternative cancer treatments can work – diets, supplements, hyperbaric oxygen, intravenous vitamin C – and how they might be combined more effectively.

What she has added to this mix is the discovery of research on a variety of old drugs with anti-cancer properties that had never been used clinically for that purpose. She found out all about them and how they might benefit her and then made a case for why her doctors should allow her to take them experimentally. More than a decade later the use of cheap, promising drugs is just beginning to be explored by a few radical oncologists.

Jane’s cancer saga, began with two serious failures of standard ‘care’: a missed diagnosis of cervical cancer, followed some years later by a failure to spot metastasised stage IV lung cancer, for which the average survival time is three months.

She quickly realised that the conventional concentration on genes and eradicating the tumour at all costs – especially to the patients – meant that many other possibilities were being ignored. What about the various natural growth factors which had been co-opted by the cancer? They were linked to inflammation and to metabolic changes which involved the way the body used fuel. So why not try to reduce inflammation and make fuel from food harder to obtain? What about starving cancer?

A bloody-minded Sherlock Holmes

‘Oncologists ignore the general health of their patients,’ she writes, explaining her approach. ‘Cancer is a systemic disease; markers are detectable in the blood, so it affects the whole body. It is not just some ‘lump’ to be excised.’

This led her to a strategic and tactical approach. She became part medical Sherlock (maybe Shelock) Holmes ‘piecing together clues and trying to make sense of a confusing and complex picture’; part senior manager of herself, trying to head off trouble by taking logical, rather than the standard steps. Both require bloody-mindedness and an appetite for a master’s degree level of understanding of biochemical research.

Faced with the prospect of an operation on her lungs to remove the tumour in 1999, she suggested to her oncologist that it would make sense to take an aspirin-type anti-inflammatory drug called a cox-2 inhibitor because the enzyme it blocked – cox 2 – was part of the system that allowed tumours to hook into a nearby blood supply (angiogenesis).

It also made sense because it would reduce the inflammation that operations are known to cause. However, it still encountered the TINA-type response {There Is No Alternative} to any non-standard suggestion: without a massively expensive RCT we can’t do it. Later she found that anti-inflammatory drugs can also cut the risk of cancer metastasising (spreading).

Ways to make chemo more effective ignored

This research lead her to natural and herbal versions and non-drug remedies to make it more difficult for cancers to hook up to a blood supply. But a new problem loomed; her medical team was keen to get her on chemotherapy after the operation. But she’d already had it for her previous cancer and her research had revealed the damage it could do to her immune system.

So again, she became managerial and proposed taking various supplements that had some evidence they could make chemo more effective, making it possible to give less, so reducing the hit on her immune system. This also was resisted.

These rebuffs did nothing, however, to deter Jane from trying other logical angles. She included intermittent fasting and stress reduction techniques in her regime to bring down the level of the stress hormone cortisol (having cancer treatment is very stressful) which also damps down the immune response.

Her overall strategy would have been regarded as intelligent and plausible in any other field. ‘I wanted the terrain, the area around the cancer cell, to be as inhospitable as possible and for the rest of my body to be functioning as well as it could.’

A particularly impressive bit of medical detective work was to propose that raised levels of glucose and insulin from a high carbohydrate diet would help cancer grow. Glucose would provide its first choice of fuel while the insulin would ensure more of it got into the tumour cells. She was looking for a drug or supplement to bring glucose down. We now know the diabetes drug metformin does this and so does the ketogenic diet, but she was way ahead of her time. Some diehards are still denying this idea, even while metformin is being researched as a treatment. [Link]

The herbal extract that answered her prayers

While trawling through health journals, however, Jane discovered another option: a traditional Chinese herbal extract called berberine, which seemed the answer to several of her prayers. It lowered blood glucose, reduced inflammation and targeted hostile gut parasites. It also was particularly effective against her type of tumour, which had features in common with psoriasis. Oh, and it also increased the effectiveness of chemotherapy.

But none of this dedicated and successful medical sleuthing budged her doctors; she was still getting high-dose chemo, although only for six months, followed by three months at a lower level.

She survived it and the tumour shrank, presenting her with a fresh management challenge, putting together a new protocol: ‘To detox to get rid of any remnants of chemotherapy and to rebuild my gut, which I assumed would be badly damaged.’ Other goals included: exercise more; enjoy life; start a new business.

She added a few more supplements and began vitamin C therapy, having carefully investigated it and found how well it fitted with so many of the other things she was doing. Her regular blood tests confirmed her cancer markers were down but her diet, especially, required constant vigilance.

Tumour fights back with blood cancer

‘Could I never let my hair down again?’ she despaired. ‘Was my future to live on a knife edge, checking foods, unable to go out and allow myself a couple of cheeky drinks?’

Then disaster struck. Four years after the operation, she discovered that her red blood cells were clumping together in sticky columns knows as rouleaux. She learned they were common in cancer patients because tumours cause the release of abnormal clotting factors, greatly increasing the risk of heart attacks and strokes.

‘It’s an unspoken side-effect of treatment and a leading cause of death among patients,’ Jane writes. ‘Around 25% of cancer patients die of cardiovascular events which are never directly attributed to the cancer, so they are not included in the statistics.’

The standard treatment would be yet another round of chemotherapy, of course, because there is nothing else – but she was not about to damage her immune system and guts again. Besides which, she discovered, chemo would also push up her risk of developing clots in her blood vessels!

Jane discovers a cheap off-patent treasure

Instead, her first move was to draw on the material on anti-inflammatories and their effect on blood clotting she had already gathered. The rouleaux broke up a little. But further tests showed that she had developed a form of leukaemia called myelodysplasia ; average survival time 18 months to two years. It was quite probably the result of the heavy chemo had had on her immune system. Once again, she faced the challenge of putting together her own protocol and once again the medical journals came to the rescue.

Whichever angel looks after researchers was clearly on duty because she noticed a reference to an old, off-patent drug called dipyridamole. It was an antiplatelet (platelets are involved in clotting) drug for cardiovascular problems, but it also had anti-cancer effects, which had been ignored.

But the dipyridamole discovery triggered something else. This was when the idea of using old cheap drugs that have anti-cancer effects started to take off for her. The material Jane found on dipyridamole reported an unbelievable range of effects directly relevant to her situation and, very likely to the thousands of cancer patients who also develop clotting issues.

It could stop blood clots forming, stop platelet aggregation (forming sticky clumps), work together with aspirin and magnesium to thin the blood, restore the balance of the immune system and ‘starve’ cancer cells by preventing them getting the material needed to make the DNA for the new cells they were constantly building.

Making up a personalised drug cocktail

Dipyridamole’s huge potential set Jane off on the search for other old anti-cancer drugs that could be added to the combination of natural supplements and complementary treatments she was already using

The first she found was one of the early statin drugs called Lovastatin. Statins are normally given to cut heart attack risk by reducing cholesterol production, but Jane came across research showing that combining Lovastatin with an anti-inflammatory drug used for arthritis, caused cancer cells to self-destruct (apoptosis).

She was now able to assemble a radical and totally unorthodox combination to keep her cancer at bay. It didn’t depend on one super new powerful drug to hit genetic targets in a tumour, instead it was a ‘guerrilla warfare approach of hitting cancer with lots of bullets from different directions.’ And it was astoundingly cheap.

The statin would starve the cancer of the cholesterol needed to build the walls of new cancer cells and the anti-inflammatory would damp down the inflammation that fuelled tumour growth. Meanwhile, the dipyridamole would starve the cancer of the proteins needed to make new DNA and Jane’s diet would keep the supply of the fuels the tumour relied on – fat and glucose – as low as possible.

Markers for cancer in her blood plunge

This was highly unorthodox and perhaps her most impressive achievement was persuading her regular doctors to prescribe the drugs for her madly off-piste experiment.

The results, however, were remarkable. Several of the markers showing levels of cancer activity, which had been sky high only a few months early, had dropped back into the normal range. A few years later a Canadian group published lab research showing the deadly effect a combination of statins and dipyridamole could have on cancer cells.

If this were a movie script, that would be cue for credits, but we are only half way through the book. Jane, as well as building a business and working to help others, has continued her explorations of cancer metabolism and compiled a remarkable cancer ‘Metro Map’. It reveals the multiple supply lines and a variety of treatment combinations that can take them out.

Cancer TINA with its three antique treatments dating back, in the case of chemotherapy, to World War I, has never seemed more untrue.

Her Facebook Group Jane McLelland Off Label Drugs for Cancer

howtostarvecancer.com/the-b...

[Graham49 in reply to pjoshea13]

Thanks Patrick, IMO what we all could do with are oncologists with the Sherlock Holmes mentality of Jane McLelland and adequate time to devote to each patient. I guess it's not likely to be the norm any time soon!

[HOPEFULSPOUSE in reply to pjoshea13]

We just started reading her book yesterday when it arrived. So interesting.

We were living in the UK when my husband was diagnosed in 2013 and several of the DRs she thanks in the Acknowledgements section were ones we had consulted with early on.

My biggest takeaway from the book as well as our own experience is that no one DR is a substitute for the patient maintaining vigilance and taking control of their care regimen. Sherlock Holmes approach for sure. We keep finding bits from different DRs and on this site (Thank you Patrick for your informative posts) and thankfully have a good team to call on that is generally supportive of the info we present.