Statins and Cancer
Dear Friends, I am currently on holiday, travelling and with little access to the computer, but recently I came across interesting information related to the use of Statins to fight cancer, and would like to share that with you as soon as possible. So I decided to allocate a day and consolidate this important information on Statins. It may not be very well written post but I hope it helps you.
This important information is related to the following:
- a Statin that seems to be the most effective against cancer of all Statins
- a specific diet that should go with it, and
- a case report of a ovarian cancer patient (a doctor) using this combo and obtaining complete remission
First, here is a little background for those new to the subject:
Statins (e.g. atorvastatin, lovastatin, simvastatin, pravastatin, pitavastatin, rosuvastatin, mevastatin, cerivastatin and fluvastatin) are a group of (FDA approved) drugs used to lower cholesterol, reducing illness and mortality in those who are at high risk of cardiovascular disease.
However, during the past years Statins have been found to also have important anticancer action, possibly related to their capability of inhibiting/reducing cholesterol production. There is a large amount of science on that (Ref.), some of which will be discussed below, as well as meta-analysis trying to validate the findings from the laboratory.
In line with all the scientific discoveries from the academic field, mevalonate pathway and cholesterol production related to that are key in cancer (Ref.), and as a results their modulation can help fight cancer. Statins are inhibiting an enzyme (HMGCR) which is essential for the synthesis of mevalonate (a precursor for the biosynthesis of cholesterol). This leads to a lower cholesterol production in cells. Cholesterol starvation in hepatocytes increases expression of LDLR, in turn facilitating uptake of LDL particles from blood, which reduces blood cholesterol (Ref.). However, note that because Statins inhibit the mevalonate pathway, they do not only prevent the synthesis of cholesterol, but also inhibit Ras/MEK/ERK and Ras/mTOR pathways, in connection to geranylgeranyl pyrophosphate (GGPP) depletion (Ref.1, Ref.2, Ref.3). GGPP is an intermediate on the mevalonate pathway, essential for the anchoring of Ras protein to the cell membranes (Ref.). (Here is a map showing where HMGCR and GGPP are located on the mevalonate pathway.).
Geranylgeranyl pyrophosphate (GGPP) depletion could be an important mechanism leading to anticancer effects since it has been demonstrated that supplementation with Geranylgeraniol (a substance found in various foods) can inhibit the anticancer effects of statins (see discussion below). Indeed, inside the cells there is a salvage pathway that converts Geranylgeraniol into Geranylgeranyl pyrophosphate (GGPP) (Ref.1, Ref.2).
In some of my previous posts I already discussed various ways to modulate mevalonate pathway and as a result cholesterol (and Geranylgeranyl pyrophosphate) (Ref.), and latter I even consolidate all those approaches in an “Anti Cholesterol Strategy” (Ref.). Yet, I never discussed Statins in more details. Now, given this recent information indicating ways to increase the effectiveness of Statins as well as a successful case report after using that approach, I think it’s time to have a dedicated post to Statins. Of-course, there is so much to write about Statins and cancer, but here I will try to stick to the aspects that are most important for their application against cancer.
Laboratory research indicates that Statins may be relevant in the fight against various types of cancer
Statins can represent useful tools to fight cancer either alone or in combination with conventional therapies including radio- and chemo-therapy, in various cancer types including:
- gastric cancer (Ref.)
- ovarian cancer (Ref.)
- head and neck cancer (Ref.)
- endometrial cancer (Ref.)
- breast cancer (Ref.1, Ref.2)
- glioblastoma (Ref.)
- prostate cancer (Ref1, Ref.2.)
- paragangliomas (Ref.)
- blood cancers (leukemia and lymphoma) (Ref.)
- colon cancer (Ref.1, Ref.2)
- pancreatic cancer (Ref.)
- hepatocellular carcinoma (Ref.)
The above are just a few examples of references, but the reader will be able to find much more references for most type of cancers, as this is a subject intensively investigated in the academic space.
So far, in real life, positive results were observed, but more moderate compared to the laboratory
Indeed, going from laboratory to real life studies, the results are sometimes mixed. Such studies are either looking at correlating the use of Statins with cancer incidence or cancer recurrence and mortality. For example, a Meta-Analysis on the association of Statins and cancer incidence did not showed a statistically significant difference induced by the use of statins (Ref.). Also, studies such as combining Statins with sorafenib in advanced hepatocellular carcinoma did not show signs of improved survival (Ref.).
Other studies on the other hand, indicated positive associations between the long-term Statins use and an improved overall survival in breast cancer patients (Ref.). Positive association between the use of Statins and the improved outcomes have also been identified in colorectal cancer (Ref.), renal cell carcinoma (Ref.), pancreatic cancer (Ref.), esophageal cancer (Ref.), prostate cancer (Ref.), ovarian cancer (Ref.) and breast cancer (Ref.). Nielsen et al. showed an association of Statins use and a reduced cancer-related mortality for 13 malignancies, e.g. pancreatic cancer and cervical cancer (Ref.).
Overall, most studies indicate a positive impact of the use of Statins on the survival of patients with various cancer types. In full resonance with these studies, Care Oncology Clinic recently reported positive results from patients using a cocktail of four re-purposed drugs including one Statin drug (Ref.). This cocktail succeeded to help double the average survival time in Glioblastoma patients.
Therefore as we can see from these results, while the research in the lab indicates that Statins can be effective tolls to fight and kill cancer cells, in reality the results are there but more moderate. While having even moderate results is highly valuable in advanced cancers, the question is how we can maximise the effectiveness of Satins so that we obtain not only slow down of tumour growth, but tumour death?
How to Make Statins Work Better Against Cancer?
It is indeed known that Statins is a group of drugs containing various drugs that have different absorption in the body and different life time in patient’s blood. In addition, as discussed below, there are other aspects that have to be considered in order to get the best out of Statins value. Here are some approaches that are expected to increase the effectiveness of Statins against cancer:
- Reduce cancer cells resistance to Statins with the help of the FDA approved drug Dipyridamole
Statins inhibit the rate-limiting enzyme of the mevalonate (MVA) pathway called HMG-CoA reductase (HMGCR). This is also the mechanism through which it is believed that statins kill cancer. However, it seems that most cells have a way to overcome the HMGCR inhibition with the help of the sterol regulatory element-binding protein 2 (SREBP2). Using Dipyridamole, a FDA approved drug, will block SREBP2 activation and thus, maintain the effectiveness of Statins (Ref.1, Ref.2).
- Use lipophilic Statins for better intracellular access
It has been suggested that lipophilic statins (e.g. atorvastatin, simvastatin, lovastatin) are more effective than hydrophilic statins (e.g. pravastatin and rosuvastatin) in cancer treatment. This may be due to the fact that lipophilic statins are able to cross the biological membranes and they have greater intracellular access (Ref.). Here is a paper classifying lipophilic or hydrophilic statins, in the “Additional file 3” (Ref.).
- Use Statins that have longer lifetime and high anti-cancer effectivness
In laboratory studies, it has been found that continual inhibition of HMGCR is necessary to induce apoptosis. However, many statins have a short half-life s due to their uptake into the liver and subsequent metabolism by cytochrome P450. What is required on the other hand is a statin that would be constantly present in the blood. Therefore, one statin to have half-life about 12h and that would be taken 2x/day every 12h would be perfect. Although I would guess that Atorvastatin would fit this requirement, according to this publication (Ref.), Pitavastatin is the only statin that fits all requirements for anti-cancer treatment.
- Indeed, this older study indicates that Pitavastatin has a better pharmacokinetic profile compared to Atorvastatin (Ref.), with the best bio availability (Ref.).
- Also, studies on pancreatic cells showed that Pitavastatin is one of the most effective anti-proliferative statins (Ref.)
So based on it’s anticancer action and based on the relatively long half-time (~12h) (Ref.) the statin of choice is Pitavastatin. If Pitavastatin is not available, the next statin I would chose is Atorvastatin given it’s very long half-time (~14 hours). If non of this two are available, the next statin would chose is Simvastatin. It is a highly lipophilic one and it is expected to have good anti-cancer action better than Atorvastatin (at least in pancreatic cancer – Ref.), but the challenge with it is that its half-time is short (~5h) (Ref.) – so in order to keep a constant level in the blood across 24 hours, a patient would have to take it every 5 hours, which is less practical. Here is a paper half life of available statins, in the “Additional file 3” (Ref.).
However, please note that for brain cancer, or brain metastasis, blood brain barrier (BBB) penetration has to also be considered. According to this study (Ref.), “Simvastatin clearly demonstrated a high potential to access to the brain, followed by fluvastatin and cerivastatin, while atorvastatin, mevastatin, rosuvastatin, and pravastatin scarcely penetrated by passive diffusion.” Out of these, Simvastatin is best as it has also the longest half-life (about 5h) compared to fluvastatin and cerivastatin.
- Use low geranylgeraniol diet while on Statin
It has been recently found that dietary geranylgeraniol, a fat found in many foods, can limit the activity of pitavastatin as a potential treatment for cancer. This finding was published in a Nature Scientific Reports journal (Ref.). Indeed, nearly 20 years ago it has also been shown that Geranylgeraniol inhibits the anti cancer effects of statins (Ref.). Therefore, during the use of statins, patients should avoid the use of foods containing high levels of geranylgeraniol, including rice, sunflower and linseed/flaxseed oil. Actually, it has been already suggested 10 years ago, that addition of geranylgeraniol can prevent cytotoxic effects of statins and with that also limiting the toxicities of statins (Ref.), and more recently geranylgeraniol has been suggested to be useful in protecting patients against the side effects of Bisphosphonates (Ref.).
- Use a dose that is high enough to kill tumours
As the authors describe here and here it is important to use a high enough dose in order to achieve anti cancer effectiveness. The dose used in lab experiments was significantly higher compared to the dose of pitavastatin (up to 4 mg) currently used to treat hypercholesterolaemia. The authors suggest that an option could be to use cycles of brief (1–2 weeks) high-dose pitavastatin therapy. This may help to minimise the incidence if myopathy (an issue that may limit the use of statins at high doses that can result sometimes in rhabodomyolysis).
- Use other inhibitors of mevalonate pathway such as
- zoledronic acid
Bisphosphonates such as Zoledronic Acid, are inhibitors of another step in mevalonate pathway. These drugs are often used to prevent development of bone metastazis in e.g. breast and prostate cancer patients. I discussed the drug in details here https://www.cancertreatmentsresearch.com/bisphosphonates/ Recently, it has been shown that Zoledronic Acid can increase the anti cancer activity of pitavastatin (Ref.). I actually suggested the combo of Statin and Bisphosphonate in an article I wrote on this website prior to the publication of this paper (Ref.) 🙂
- plant derived isoprenoids
Isoprenoids are a large family of compounds derived from isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), therefore partially a result of mevalonate pathway. The highest variety of plant isoprenoids participate in the interaction of plants with their environment (Ref.). For example, some are protecting plants against parasites while others are responsible for the colours in the plants (such as lycopene). Isoprenoids are known to inhibit HMGCR (Ref.) This is why it has been previously proposed to be used in combination with Statins (Ref.). Examples of Isoprenoids that could be useful here to modulate mevalonate pathway are tocotrienols (gamma- and delta-tocotrienol, Vitamin E) (Ref.1, Ref.2) and Lycopene (Ref.), and can be easily found online as food supplements. The anticancer action of Isoprenoids may explain the lowered cancer risk (and other cholesterol related diseases) associated with a diet rich in plant products (Ref.). I would not use Vitamin E during chemo- or radio-therapy, due to its anti-oxidant properties.
- Prednisolone: It has been recently published (2019) in another paper co-authored by Dr. Alan Richardson, that the anti-cancer activity of pitavastatin is potentiated significantly by prednisolone by augmenting inhibition of the mevalonate pathway (it’s not clear if the inhibition is due to prednisolone binding to the glucocorticoid receptor, or if prednisolone modulates SREBP as it has a ring structure mimicking sterols). In this paper, the authors state that the concentration of prednisolone used in the studies, although relatively high, is comparable to those clinically achievable using a relatively high dose of prednisolone. As a result, they suggest that “that it may be appropriate to evaluate the combination of prednisolone and pitavastatin in clinical trials.” (Ref.)
- zoledronic acid
Many of the findings above have been reported by Dr. Alan Richardson and his team, School of Pharmacy at Keele University, UK. In a report presented by ScienceDaily, Dr. Alan Richardson stated the following: “We believe we have found the answer to the paradox: for statins to be effective as a cancer therapy, the right statin needs to be used, it needs to be delivered at the right dose and interval, and diet needs to be controlled to reduce sources of geranylgeraniol, which can limit the statin’s effect on cancer cells.” (Ref.).
Yes, it Works! Successful Case Report in Humans
Here is the article that made me hurry up to write this post as it may help some readers of this website: “Doctor ‘cancer free’ after Keele University statin test“
The above article is a recent (July 2019) BBC report related to an advanced ovarian cancer patient who decided to start the experimental treatment proposed by Dr. Alan Richardson.
The patient, Dr Grace Gosar, was a terminal cancer when she started the experiment back in 2018. One year latter, tests showed no cancer cells present. “As a physician, I know my disease progression and I thought that I would be in the ground by now,” Dr Gosar said.
The treatment strategy of Dr Grace Gosar, was aligned with Dr. Alan Richardson findings, including Pitavastatin and a special diet low in geranylgeraniol. Dr. Gosar’s nephew, a biochemist, researched what foods can be allowed in her diet, and they came up with a diet containing potatoes, tomato paste and yoghurt.
While this report is at an anecdotal level, I find it very relevant given the fact that it is reported by a medical doctor (the patient) and a scientist that often publishes it’s work in a recognised journal.
It would be interesting to know what the dose of Pitavastatin was (as I suspect it was a dose >4mg/day) and if the patient used Zoledronic Acid. I will try to get in contact with the authors.
If any of the readers get in contact with Dr. Alan Richardson and/or have experience with Pitavastatin, please share that here as it may help others.
The major mechanism through which Statins are fighting cancer is believed to be related to the inhibition of HMG CoA-reductase on the mevalonate pathway (Ref.), preventing the synthesis of cholesterol, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. Other mechanisms related to anti cancer effects of Statins were also indicated, e.g.:
- mitochondria modulation (Ref.)
- TGF-β inhibition (Ref.)
- T reg cells modulation (Ref.)
- Statins are known to inhibit MCT4 (Ref.1, Ref.2, Ref.3)
- P-glycoprotein inhibition (Ref.)
- Statins Impair Glucose Uptake in Tumor Cells (Ref.)
- (Pitavastatin) Reduces inflammation / CRP (Ref.)
- inhibition of glutathione peroxidase (GPx)(Ref.), therefore having a pro-oxidant effect
In addition, cholesterol-lowering drugs known as statins have been reported to have significant anti-inflammatory properties (Ref.).
Side Effects and Toxicity
Statins have long been known to modestly increase levels of hepatic aminotransferases. These increases often resolve with continued statin therapy. Statins have rarely been associated with severe hepatic injury.
For toxicity and side effects of Pitavastatin as a function of dose please see the following FDA document https://www.accessdata.fda.gov/drugsatfda_docs/nda/2009/022363s000_MedR_P1.pdf
An issue that may limit the use of statins, particularly at high doses, is that statins have been associated with myopathy and in some cases this can result in rhabodomyolysis. Typically myopathy presents within a few months after starting or increasing the dose of a statin or after introduction of an interacting drug. When a patient reports unexplained muscle aches or weakness, it is important for the clinician to inquire about symptom characteristics. Most commonly, patients present with symptoms that are distributed proximally (eg, hip flexor region, upper chest and shoulders) and bilaterally. Nonspecific lower back pain can also be a presenting feature of statin-induced myopathy. (Ref.)
Also read this: Statin Safety and Associated Adverse Events
Inhibition of mevalonate pathway will lead to reduction of CoQ10 since CoQ10 is derived from the mevalonate pathway (Ref.). This is also the origin of some of the statins side effects. In line with this, statins side effects may be reduced with the addition of CoQ10 (Ref.).
Note: In a study on Japanese patients, Atorvastatin reduced Coenzyme Q10 level but not Pitavastatin (Ref.). I think this aspect is very interesting as it may be related to the way they inhibit melavonate pathway, but I cannot find any paper to explain why this is the case.
Source and Administration
Due to the reasons discussed above, Pitavastatin (Livalo®) is the most suitable statin. Pitavastatin is available in a generic form so it should be relatively cheap. It should be available at the pharmacy in most of the countries and released with a prescription.
The maximum dose given for hypercholesterolaemia is 4mg/day. Increasing the dose may come with side effects as described in this document. As described in this paper, in order to achieve a higher dose and limit side effects, one idea could be to could be to use cycles of brief (1–2 weeks) high-dose pitavastatin therapy. This may help avoid side effects such as myopathy that presents a few months after using high-dose statins. Regardless of the dose, I would take half the dose in the morning and half the dose in the evening, every 12 hours. I would start with a lower daily dose, e.g. at 2mg/day, for a cycle of two weeks, and stop taking the drug for the other two weeks (two weeks ON and two weeks OFF in line with what was suggested in the paper). If the tolerance to the drug is fine, next cycle I would use 4mg/day (2mg in the morning and 2mg in the evening, 12 hours apart). I would escalate the dose every cycle to maybe a max of 12-14mg/day, while having in mind that for pitavastatin, there have been cases of severe myopathy and rhabdomyolysis in clinical trials with doses from 8 mg to 64 mg (Ref.). During the use pitavastatin, I would also follow a diet that is low in geranylgeraniol. However, for the latest info on the treatment strategy the best is to have your oncologist contacting Dr. Richardson as discussed below.
Update August 7th, 2019: I recently contacted Dr. Alan Richardson (author of the papers cited above (Ref.1, Ref.2) who guided the successful ovarian cancer patient case). For the patient who wishes to try pitavastatin, Dr. Richardson agrees to be contacted by their oncologist and provide the info required to start this treatment approach. Dr. Richardson contact details are on the following webpage https://www.keele.ac.uk/pharmacy-bioengineering/ourpeople/alanrichardson/#biography Dr. Richardson will help not only with guides on the dose but also on the suitable diet focused on foods that do not contain geranylgeraniol.
If Pitavastatin is not available, the next option in my view is Atorvastatin. Typically, cancer patients use Atorvastatin 40mg/day for the first 2 weeks, followed by 80mg/day thereafter. The daily dose should also be split in two, morning and evening.
Lovastatin’s absorption increases when taken with food, whereas absorption of atorvastatin, fluvastatin, and pravastatin decreases when taken with food. Simvastatin and rosuvastatin are not affected by food intake http://www.medscape.com/viewarticle/561128
Lovastatin & Interferon – this is a very interesting treatment strategy, patented and performed at a clinic in US, with an outcome that seems to be impressive. I do not know anybody who was treated at this clinic.
Statin drugs to reduce breast cancer recurrence and mortality https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247616/
Epidemiologic studies have, variably, shown the concomitant use of statin drugs to be beneficial to cancer outcomes. Statin drugs have been FDA approved for three decades for the treatment of high cholesterol and atherosclerotic coronary artery disease and are widely used. This has engendered studies as to their influence on concomitant diseases, including cancers. In this context, statin use has been correlated, variably, with a decrease in deaths from breast cancer. However, there is no extant model for this effect, and the extent of efficacy is open to question.
The overarching goal of this article is to communicate to the reader of the potential of statins to reduce breast cancer progression and mortality. This is the use as a secondary prevention measure, and not as a therapy to directly counter active cancer. First, salient aspects of statin pharmacology, as relates to cardiovascular disease, will be discussed. Second, the basic and clinical research studies that investigate statin usage in breast cancer will be presented. Additionally, statin effects in other cancer types will be included for context. Finally, proposals for future basic and clinical research studies to determine the role of statins in breast cancer management will be presented.
The poor design of clinical trials of statins in oncology may explain their failure – Lessons for drug repurposing https://www.ncbi.nlm.nih.gov/pubmed/29936313
Statins are widely used to treat hypercholesterolaemia. However, by inhibiting the production of mevalonate, they also reduce the production of several isoprenoids that are necessary for the function of small GTPase oncogenes such as Ras. As such, statins offer an attractive way to inhibit an “undruggable” target, suggesting that they may be usefully repurposed to treat cancer. However, despite numerous studies, there is still no consensus whether statins are useful in the oncology arena. Numerous preclinical studies have provided evidence justifying the evaluation of statins in cancer patients. Some retrospective studies of patients taking statins to control cholesterol have identified a reduced risk of cancer mortality. However, prospective clinical studies have mostly not been successful. We believe that this has occurred because many of the prospective clinical trials have been poorly designed. Many of these trials have failed to take into account some or all of the factors identified in preclinical studies that are likely to be necessary for statins to be efficacious. We suggest an improved trial design which takes these factors into account. Importantly, we suggest that the design of clinical trials of drugs which are being considered for repurposing should not assume it is appropriate to use them in the same way as they are used in their original indication. Rather, such trials deserve to be informed by preclinical studies that are comparable to those for any novel drug.
An actionable sterol-regulated feedback loop modulates statin sensitivity in prostate cancer https://www.ncbi.nlm.nih.gov/pubmed/31023626
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.
Statin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma https://www.sciencedirect.com/science/article/abs/pii/S1078143914003500?via%3Dihub
Conclusions: These data suggest that statin usage at time of surgery is independently associated with improved OS and DSS in patients undergoing surgery for RCC.
Statin Use and Reduced Cancer-Related Mortality https://www.nejm.org/doi/full/10.1056/NEJMoa1201735
BACKGROUND: A reduction in the availability of cholesterol may limit the cellular proliferation required for cancer growth and metastasis. We tested the hypothesis that statin use begun before a cancer diagnosis is associated with reduced cancer-related mortality.
METHODS: We assessed mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009. Among patients 40 years of age or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins.
RESULTS: Multivariable-adjusted hazard ratios for statin users, as compared with patients who had never used statins, were 0.85 (95% confidence interval [CI], 0.83 to 0.87) for death from any cause and 0.85 (95% CI, 0.82 to 0.87) for death from cancer. Adjusted hazard ratios for death from any cause according to the defined daily statin dose (the assumed average maintenance dose per day) were 0.82 (95% CI, 0.81 to 0.85) for a dose of 0.01 to 0.75 defined daily dose per day, 0.87 (95% CI, 0.83 to 0.89) for 0.76 to 1.50 defined daily dose per day, and 0.87 (95% CI, 0.81 to 0.91) for higher than 1.50 defined daily dose per day; the corresponding hazard ratios for death from cancer were 0.83 (95% CI, 0.81 to 0.86), 0.87 (95% CI, 0.83 to 0.91), and 0.87 (95% CI, 0.81 to 0.92). The reduced cancer-related mortality among statin users as compared with those who had never used statins was observed for each of 13 cancer types.
CONCLUSIONS: Statin use in patients with cancer is associated with reduced cancer-related mortality. This suggests a need for trials of statins in patients with cancer.
Assessment of concomitant non-oncologic medication in patients with surgically treated renal cell carcinoma: impact on prognosis, cell-cycle progression and proliferation. https://www.ncbi.nlm.nih.gov/pubmed/31006846
Concomitant intake of statins and sartans identifies as an independent predictor of OS in RCC, and reduced Ki67 expression was significantly associated with statin use. Further evaluation of drug repurposing approaches with these substances in RCC appear warranted.
Statin Use Shows Increased Overall Survival in Patients Diagnosed With Pancreatic Cancer: A Meta-Analysis https://www.ncbi.nlm.nih.gov/pubmed/30973465
Statin-dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content https://www.ncbi.nlm.nih.gov/pubmed/30951369
Statins, widely used to treat hypercholesterolemia, inhibit the 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting enzyme of de novo cholesterol (Chol) synthesis. Statins have been also reported to slow tumor progression. In cancer cells, ATP is generated both by glycolysis and oxidative phosphorylation. Mitochondrial membrane potential (ΔΨ), a readout of mitochondrial metabolism, is sustained by the oxidation of respiratory substrates in the Krebs cycle to generate NADH and flavin adenine dinucleotide, which are further oxidized by the respiratory chain. Here, we studied the short-term effects of statins (3-24 h) on mitochondrial metabolism on cancer cells. Lovastatin (LOV) and simvastatin (SIM) increased ΔΨ in HepG2 and Huh7 human hepatocarcinoma cells and HCC4006 human lung adenocarcinoma cells. Mitochondrial hyperpolarization after LOV and SIM was dose and time dependent. Maximal increase in ΔΨ occurred at 10 µM and 24 h for both statins. The structurally unrelated atorvastatin also hyperpolarized mitochondria in HepG2 cells. Cellular and mitochondrial Chol remained unchanged after SIM. Both LOV and SIM decreased basal respiration, ATP-linked respiration, and ATP production. LOV and SIM did not change the rate of lactic acid production. In summary, statins modulate mitochondrial metabolism in cancer cells independently of the Chol content in cellular membranes without affecting glycolysis.
Statin drugs to reduce breast cancer recurrence and mortality https://www.ncbi.nlm.nih.gov/pubmed/30458856
Epidemiologic studies have, variably, shown the concomitant use of statin drugs to be beneficial to cancer outcomes. Statin drugs have been FDA approved for three decades for the treatment of high cholesterol and atherosclerotic coronary artery disease and are widely used. This has engendered studies as to their influence on concomitant diseases, including cancers. In this context, statin use has been correlated, variably, with a decrease in deaths from breast cancer. However, there is no extant model for this effect, and the extent of efficacy is open to question.The overarching goal of this article is to communicate to the reader of the potential of statins to reduce breast cancer progression and mortality. This is the use as a secondary prevention measure, and not as a therapy to directly counter active cancer. First, salient aspects of statin pharmacology, as relates to cardiovascular disease, will be discussed. Second, the basic and clinical research studies that investigate statin usage in breast cancer will be presented. Additionally, statin effects in other cancer types will be included for context. Finally, proposals for future basic and clinical research studies to determine the role of statins in breast cancer management will be presented.
Statin use after diagnosis is associated with an increased survival in esophageal cancer patients: a Belgian population-based study. https://www.ncbi.nlm.nih.gov/pubmed/30820714
In this large cohort of Belgian patients with esophageal cancer, statins use after diagnosis was associated with a decreased mortality.
Curbing Lipids: Impacts ON Cancer and Viral Infection https://www.ncbi.nlm.nih.gov/pubmed/30717356
Lipids play a fundamental role in maintaining normal function in healthy cells. Their functions include signaling, storing energy, and acting as the central structural component of cell membranes. Alteration of lipid metabolism is a prominent feature of cancer, as cancer cells must modify their metabolism to fulfill the demands of their accelerated proliferation rate. This aberrant lipid metabolism can affect cellular processes such as cell growth, survival, and migration. Besides the gene mutations, environmental factors, and inheritance, several infectious pathogens are also linked with human cancers worldwide. Tumor viruses are top on the list of infectious pathogens to cause human cancers. These viruses insert their own DNA (or RNA) into that of the host cell and affect host cellular processes such as cell growth, survival, and migration. Several of these cancer-causing viruses are reported to be reprogramming host cell lipid metabolism. The reliance of cancer cells and viruses on lipid metabolism suggests enzymes that can be used as therapeutic targets to exploit the addiction of infected diseased cells on lipids and abrogate tumor growth. This review focuses on normal lipid metabolism, lipid metabolic pathways and their reprogramming in human cancers and viral infection linked cancers and the potential anticancer drugs that target specific lipid metabolic enzymes. Here, we discuss statins and fibrates as drugs to intervene in disordered lipid pathways in cancer cells. Further insight into the dysregulated pathways in lipid metabolism can help create more effective anticancer therapies.
Statins enhance efficacy of venetoclax in blood cancers https://www.ncbi.nlm.nih.gov/pubmed/29899021
Statins have shown promise as anticancer agents in experimental and epidemiologic research. However, any benefit that they provide is likely context-dependent, for example, applicable only to certain cancers or in combination with specific anticancer drugs. We report that inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) using statins enhances the proapoptotic activity of the B celllymphoma-2 (BCL2) inhibitor venetoclax (ABT-199) in primary leukemia and lymphoma cells but not in normal human peripheral blood mononuclear cells. By blocking mevalonate production, HMGCR inhibition suppressed protein geranylgeranylation, resulting in up-regulation of proapoptotic protein p53 up-regulated modulator of apoptosis (PUMA). In support of these findings, dynamic BH3 profiling confirmed that statins primed cells for apoptosis. Furthermore, in retrospective analyses of three clinical studies of chronic lymphocytic leukemia, background statin use was associated with enhanced response to venetoclax, as demonstrated by more frequent complete responses. Together, this work provides mechanistic justification and clinical evidence to warrant prospective clinical investigation of this combination in hematologic malignancies.
Association between statins and prostate tumor inflammatory infiltrate in men undergoing radical prostatectomy. https://www.ncbi.nlm.nih.gov/pubmed/20160265/
Given previous reports that inflammation is associated with advanced prostate cancer, and statin use is associated with decreased prostate cancer progression risk, our findings suggest that inhibition of inflammation within tumors may be a potential mechanism for purported anti-prostate cancer properties of statins.
Statins and prostate cancer: role of cholesterol inhibition vs. prevention of small GTP-binding proteins https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186052/
Prostate cancer (PCa) is initially regulated by androgens, such as testosterone and dihydrotestosterone, which regulates cell proliferation and survival by activating the androgen receptor (AR), but later progresses to an aggressive, metastatic, androgen-independent stage for which, currently, there is no cure. Here, we argue that prevention of PCa progression is a better strategy compared to trying to cure the disease once it has already progressed. Statins inhibit the mevalonate pathway, thus preventing the synthesis of cholesterol, geranylgeranyl pyrophosphate and farnesyl pyrophosphate. Multiple clinical studies have shown an inverse relationship between statin use and PCa risk, especially the risk for developing advanced metastatic cancer. Biochemical investigations have largely corroborated the positive effect of statins on PCa risk, showing that statins inhibited cell proliferation, induced apoptosis, and decreased cell migration and invasion in PCa cells in vitro. However, investigations of the biochemical mechanism of statin action in preventing advanced/high risk PCa remains inconclusive, as statins can act through cholesterol, geranylgeranyl, or farnesyl mediated signals. This review discusses the current clinical and biochemical findings on the use of statins in preventing PCa. Evidence of statin action through cholesterol as well as geranylgeranylation and farnesylation has been discussed. As cholesterol is a precursor of androgen production, it can reduce PCa risk by decreasing the levels of circulating testosterone, which in turn reduces the levels of interprostatic dihydrotestosterone, a strong ligand for the AR. Cholesterol was also shown to accumulate in lipid rafts and regulate the activation of the phosphatidylinositol 3-kinase/Akt pathway. However, clinical evidence from multiple studies also point to the existence of cholesterol-independent pathways mediating statin action in PCa patients. In particular, ligand-activated AR activation is seen in early stage PCa and activation of the cholesterol pathway did not indicate an effect on metastasis. Cell migration and invasion, on the other hand, is regulated strongly by members of the Ras superfamily of small GTPases, especially the Rho family, which is geranylgeranylated. This review, therefore, also compares the effects of statins on both cholesterol and geranylgeranylated and farnesylated small GTPases regulating tumor progression and metastasis in biochemical and clinical studies.
Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis https://www.tandfonline.com/doi/full/10.1080/15384047.2016.1219817
The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]−17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells 4 d after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.
Dietary geranylgeraniol can limit the activity of pitavastatin as a potential treatment for drug-resistant ovarian cancer https://www.nature.com/articles/s41598-017-05595-4
Pre-clinical and retrospective studies of patients using statins to reduce plasma cholesterol have suggested that statins may be useful to treat cancer. However, prospective clinical trials have yet to demonstrate significant efficacy. We have previously shown that this is in part because a hydrophobic statin with a long half-life is necessary. Pitavastatin, the only statin with this profile, has not undergone clinical evaluation in oncology. The target of pitavastatin, hydroxymethylglutarate coenzyme-A reductase (HMGCR), was found to be over-expressed in all ovarian cancer cell lines examined and upregulated by mutated TP53, a gene commonly altered in ovarian cancer. Pitavastatin-induced apoptosis was blocked by geranylgeraniol and mevalonate, products of the HMGCR pathway, confirming that pitavastatin causes cell death through inhibition of HMGCR. Solvent extracts of human and mouse food were also able to block pitavastatin-induced apoptosis, suggesting diet might influence the outcome of clinical trials. When nude mice were maintained on a diet lacking geranylgeraniol, oral pitavastatin caused regression of Ovcar-4 tumour xenografts. However, when the animal diet was supplemented with geranylgeraniol, pitavastatin failed to prevent tumour growth. This suggests that a diet containing geranylgeraniol can limit the anti-tumour activity of pitavastatin and diet should be controlled in clinical trials of statins.
Ovarian cancer: Statins might be effective with diet control https://www.medicalnewstoday.com/articles/318453.php
Inhibition of the mevalonate pathway augments the activity of pitavastatin against ovarian cancer cells https://www.nature.com/articles/s41598-017-08649-9
Only 40% of patients with advanced ovarian cancer survive more than 5 years. We have previously shown that pitavastatin induces regression of ovarian cancer xenografts in mice. To evaluate whether the response of ovarian cancer cells to pitavastatin is potentiated by farnesyl diphosphate synthase inhibitors or geranylgeraniol transferase I inhibitors, we evaluated combinations of pitavastatin with zoledronic acid, risedronate and GGTI-2133 in a panel of ovarian cancer cells. Pitavastatin (IC50 = 0.6–14 μM), zoledronic acid (IC50 = 21–57 μM), risedronate (IC50 > 100 μM) or GGTI-2133 (IC50 > 25 μM) inhibited the growth of ovarian cancer cell cultures. Combinations of pitavastatin with zoledronic acid displayed additive or synergistic effects in cell growth assays in 10 of 11 cell lines evaluated as well as in trypan blue exclusion, cellular ATP or caspase 3/7, 8 and 9 assays. Pitavastatin reduced levels of GGT-IIβ and the membrane localization of several small GTPases and this was potentiated by zoledronic acid. siRNA to GGT-Iβ and GGT-IIβ used in combination, but not when used individually, significantly increased the sensitivity of cells to pitavastatin. These data suggest that zoledronic acid, a drug already in clinical use, may be usefully combined with pitavastatin in the treatment of ovarian cancer.
Statins could ease coughing in lung disease patients, study finds https://www.sciencedaily.com/releases/2014/03/140324111554.htm
Statins improve the anti-tumor effects of ACLY inhibition http://onlinelibrary.wiley.com/doi/10.1002/jcp.22895/abstract
Atorvastatin Decreases the Coenzyme Q10 Level in the Blood of Patients at Risk for Cardiovascular Disease and Stroke https://jamanetwork.com/journals/jamaneurology/fullarticle/786017
Background Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are widely used for the treatment of hypercholesterolemia and coronary heart disease and for the prevention of stroke. There have been various adverse effects, most commonly affecting muscle and ranging from myalgia to rhabdomyolysis. These adverse effects may be due to a coenzyme Q10 (CoQ10) deficiency because inhibition of cholesterol biosynthesis also inhibits the synthesis of CoQ10.
Objective To measure CoQ10 levels in blood from hypercholesterolemic subjects before and after exposure to atorvastatin calcium, 80 mg/d, for 14 and 30 days.
Design Prospective blinded study of the effects of short-term exposure to atorvastatin on blood levels of CoQ10.
Setting Stroke center at an academic tertiary care hospital.
Patients We examined a cohort of 34 subjects eligible for statin treatment according to National Cholesterol Education Program: Adult Treatment Panel III criteria.
Results The mean ± SD blood concentration of CoQ10 was 1.26 ± 0.47 µg/mL at baseline, and decreased to 0.62 ± 0.39 µg/mL after 30 days of atorvastatin therapy (P<.001). A significant decrease was already detectable after 14 days of treatment (P<.001).
Conclusions Even brief exposure to atorvastatin causes a marked decrease in blood CoQ10 concentration. Widespread inhibition of CoQ10 synthesis could explain the most commonly reported adverse effects of statins, especially exercise intolerance, myalgia, and myoglobinuria.
Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer https://www.ncbi.nlm.nih.gov/pubmed/10460692
Pure and mixed isoprenoid end products of plant mevalonate metabolism trigger actions that suppress 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. These actions modulate HMG CoA reductase mRNA translation and the proteolytic degradation of HMG CoA reductase. Such post-transcriptional events, we propose, are activated directly by acyclic isoprenoids and indirectly by cyclic isoprenoids. Isoprenoids, acting secondarily to the dominant transcriptional effector of sterologenesis, modestly lower cholesterol levels, if and only if, sterologenesis is not repressed by a saturating imput of dietary cholesterol. An anomaly associated with tumor growth-a sterol feedback-resistant HMG CoA reductase activity-ensures a pool of sterologenic pathway intermediates. Such intermediates provide lipophilic anchors essential for membrane attachment and biological activity of growth hormone receptors, nuclear lamins A and B, and oncogenic ras. Tumor HMG CoA reductase retains high sensitivity to the isoprenoid-mediated secondary regulation. Repression of mevalonate synthesis by plant-derived isoprenoids reduces ras and lamin B processing, arrests cells in G1, and initiates cellular apoptosis. This unique tumor cell-specific sensitivity allows isoprenoids to be used for tumor therapy, an application emulating that of the statins, but one free of adverse effects. When evaluated at levels provided by a typical diet, isoprenoids individually have no impact on cholesterol synthesis and tumor growth. Nonetheless, isoprenoid-mediated activities are additive, and, sometimes synergistic. Therefore, the combined actions of the estimated 23,000 isoprenoid constituents of plant materials, acting in concert with other chemopreventive phytochemicals, may explain the lowered cancer risk associated with a diet rich in plant products. In contrast, that lowering of cancer risk does not correspond to supplemental intake of other dietary factors associated with fruits, vegetables, and cereal grains, namely fiber, beta-carotene, vitamin C, and vitamin E, and only weakly to supplemental folate.
Studies of the isoprenoid-mediated inhibition of mevalonate synthesis applied to cancer chemotherapy and chemoprevention https://www.ncbi.nlm.nih.gov/pubmed/15229351/
Pools of farnesyl diphosphate and other phosphorylated products of the mevalonate pathway are essential to the post-translational processing and physiological function of small G proteins, nuclear lamins, and growth factor receptors. Inhibitors of enzyme activities providing those pools, namely, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and mevalonic acid-pyrophosphate decarboxylase, and of activities requiring substrates from the pools, the prenyl protein transferases, have potential for development as novel chemotherapeutic agents. Their potentials as suggested by the clinical responses recorded in Phase I and II investigations of inhibitors of HMG CoA reductase (the statins), of mevalonic acid-pyrophosphate decarboxylase (sodium phenylacetate and sodium phenylbutyrate), and of farnesyl protein transferase (R115777, SCH66336, BMS-214662, Tipifarnib, L-778,123, and, prematurely, perillyl alcohol) are dimmed by dose-limiting toxicities. These nondiscriminant growth-suppressive agents induce G1 arrest and initiate apoptosis and differentiation, effects attributed to modulation of cell signaling pathways either by modulating gene expression, suppressing the post-translational processing of signaling proteins and growth factor receptors, or altering diacylglycerol signaling. Diverse isoprenoids and the HMG CoA reductase inhibitor, lovastatin, modulate cell growth, induce cell cycle arrest, initiate apoptosis, and suppress cellular signaling activities. Perillyl alcohol, the isoprenoid of greatest clinical interest, initially was considered to inhibit farnesyl protein transferase; follow-up studies revealed that perillyl alcohol suppresses the synthesis of small G proteins and HMG CoA reductase. In sterologenic tissues, sterol feedback control, mediated by sterol regulatory element binding proteins (SREBPs) 1a and 2, exerts the primary regulation on HMG CoA reductase activity at the transcriptional level. Secondary regulation, a nonsterol isoprenoid-mediated fine-tuning of reductase activity, occurs at the levels of reductase translation and degradation. HMG CoA reductase activity in tumors is elevated and resistant to sterol feedback regulation, possibly as a consequence of aberrant SREBP activities. Nonetheless, tumor reductase remains sensitive to isoprenoid-mediated post-transcriptional downregulation. Farnesol, an acyclic sesquiterpene, and farnesyl homologs, gamma-tocotrienol and various farnesyl derivatives, inhibit reductase synthesis and accelerate reductase degradation. Cyclic monoterpenes, d-limonene, menthol and perillyl alcohol and beta-ionone, a carotenoid fragment, lower reductase mass; perillyl alcohol and d-limonene lower reductase mass by modulating translational efficiency. The elevated reductase expression and greater demand for nonsterol products to maintain growth amplify the susceptibility of tumor reductase to isoprenoids, therein rendering tumor cells more responsive than normal cells to isoprenoid-mediated growth suppression. Blends of lovastatin, a potent nondiscriminant inhibitor of HMG CoA reductase, and gamma-tocotrienol, a potent isoprenoid shown to post-transcription-ally attenuate reductase activity with specificity for tumors, synergistically affect the growth of human DU145 and LNCaP prostate carcinoma cells and pending extensive preclinical evaluation, potentially offer a novel chemotherapeutic strategy free of the dose-limiting toxicity associated with high-dose lovastatin and other nondiscriminant mevalonate pathway inhibitors.
Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop https://www.ncbi.nlm.nih.gov/pubmed/24994712
New therapies are urgently needed for hematologic malignancies, especially in patients with relapsed acute myelogenous leukemia (AML) and multiple myeloma. We and others have previously shown that FDA-approved statins, which are used to control hypercholesterolemia and target the mevalonate pathway (MVA), can trigger tumor-selective apoptosis. Our goal was to identify other FDA-approved drugs that synergize with statins to further enhance the anticancer activity of statins in vivo. Using a screen composed of other FDA approved drugs, we identified dipyridamole, used for the prevention of cerebral ischemia, as a potentiator of statin anticancer activity. The statin-dipyridamole combination was synergistic and induced apoptosis in multiple myeloma and AML cell lines and primary patient samples, whereas normal peripheral blood mononuclear cells were not affected. This novel combination also decreased tumor growth in vivo. Statins block HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the MVA pathway. Dipyridamole blunted the feedback response, which upregulates HMGCR and HMG-CoA synthase 1 (HMGCS1) following statin treatment. We further show that dipyridamole inhibited the cleavage of the transcription factor required for this feedback regulation, sterol regulatory element-binding transcription factor 2 (SREBF2, SREBP2). Simultaneously targeting the MVA pathway and its restorative feedback loop is preclinically effective against hematologic malignancies. This work provides strong evidence for the immediate evaluation of this novel combination of FDA-approved drugs in clinical trials.
Feedback Regulation of Cholesterol Synthesis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742364/
HMG CoA reductase produces mevalonate, an important intermediate in the synthesis of cholesterol and essential nonsterol isoprenoids. The reductase is subject to an exorbitant amount of feedback control through multiple mechanisms that are mediated by sterol and nonsterol end-products of mevalonate metabolism. Here, I will discuss recent advances that shed light on one mechanism for control of reductase, which involves rapid degradation of the enzyme. Accumulation of certain sterols triggers binding of reductase to endoplasmic reticulum (ER) membrane proteins called Insig-1 and Insig-2. Reductase-Insig binding results in recruitment of a membrane-associated ubiquitin ligase called gp78, which initiates ubiquitination of reductase. This ubiquitination is an obligatory reaction for recognition and degradation of reductase from ER membranes by cytosolic 26S proteasomes. Thus, sterol accelerated degradation of reductase represents an example of how a general cellular process (ER-associated degradation) is used to control an important metabolic pathway (cholesterol synthesis).
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