Of all the life-threatening diseases in this world, the ones we worry about the most are cancer and cardiovascular disease (CVD) (1). This duo has been the leading causes of death in the U.S. for nearly a century (2,3).
During this time, it has been an everlasting goal for scientists and doctors to find better ways to prevent and treat both CVD and cancer. Preventative measures have always been the best way to reduce mortality; in the case of heart disease, lowering low-density lipoprotein cholesterol (LDL) or "bad" cholesterol (especially Very Low-Density Lipoprotein) reduces the risk of heart attack and heart disease (4). Statins are a commonly enlisted drug to lower LDL; Lovastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitor, was the first approved in 1987 for human therapy. Since then, statins have become the most widely prescribed lipid-lowering drugs (5).
Something interesting happens when a drug is around for as long as statins; namely, new clinical applications begin to uncloak themselves. The reason for this goes to the heart of pharmacology; primarily small molecule drugs like statins affect an average of six relevant cellular pathways. It’s not hard to imagine why this is: If you were to throw a handful of ball bearings into a running engine, they would bounce around until they eventually settled into the right-sized nooks and crannies within the engine gears, valves, hoses, etc., thus "inhibiting" multiple systems within the engine. The same concept holds for statins; they strongly inhibit the enzyme responsible for cholesterol synthesis but settle into other "nooks and crannies" within cellular proteins, thus affecting other relevant cellular pathways. This "dirty" component of small molecule drugs sometimes results in unwanted side effects, but other times, it can positively impact other disease states. In the case of statins, decades of observation have led to some fascinating data on cancer prevention and treatment.
An analysis of seven observational studies was presented at the American Society of Clinical Oncology in 2017 by Dr. Binliang Liu of the National Cancer Center in Beijing; it found that patients who took statins after a breast cancer diagnosis for less than four years had a 38% reduction in mortality from cancer and all other causes of death (6). In his analysis, Dr. Liu highlighted that not all statins are created equal for the observed reduction in mortality. These therapeutic effects heavily depended on the duration of time the patient was taking the drug and the type of statin used.
The "type" Dr Liu is referring to is lipophilic statins. Statins are either hydrophilic or lipophilic depending on what media they dissolve in; as the name implies, lipophilic drugs dissolve more readily in lipid-containing fatty or oily solutions, while hydrophilic drugs dissolve in water (5). Because of this quality, lipophilic drugs absorb faster and can enter cells much easier than hydrophilic statins, which excel in other areas such as renal excretion. It is this cell entering quality that Dr Liu believed gave lipophilic statins their anticancer abilities.
In another remarkable observational study, researchers examined the data from 383,784 people in the U.K. Biobank who met strict exclusion criteria for the study, including 114,451 new users of lipid-lowering drugs, over an average of 12.8 years. The results show that new users of statins had a lower risk of 20 different types of cancer, with risk reductions for the cancer types ranging from 38% to 66%.(7)
What's going on here? How is lowering cholesterol also fighting cancer? In a 2023 review of clinical trials involving statins, Dr. Chengyu Liu and colleagues offered a hypothesis for this phenomenon: statins work to lower cholesterol by inhibiting the HMG-CoA reductase from blocking the mevalonate pathway, a pathway leading to the production of cholesterol. This reduction in LDL cholesterol essentially starves the cancer cells of the cholesterol they need for membrane synthesis. In a normal healthy cell, cholesterol is essential for sterol hormone production, cell membranes, and regulating tumor-related pathways. The difference between your normal cells and a cancer cell is that a healthy cell strictly regulates the amount of intracellular cholesterol and has pathways to mediate its biosynthesis; cancer cells do not do this. Cholesterol production and uptake continue unchecked, fueling tumor growth, so it makes sense that targeting cholesterol metabolism could be an effective cancer treatment. They also found that inhibition of protein prenylation caused a disruption in cell signaling, which led to the repression of tumor growth, migration, and drug resistance when other anticancer drugs were employed (8).
A new study published in August of 2024 by Giovanni Buccioli at the Department of Chemistry, Materials, and Chemical Engineering in Milan, Italy, suggests that statins may also leverage the concept of Synthetic Lethality (S.L.). In this therapeutic approach, two gene-related events, although harmless on their own, cause cancer cell death when combined. These SL-based therapies will selectively target cancer cells with specific mutations, sparing healthy cells – a very targeted and precise strategy that diminishes the side effects of cancer treatments (9).
In this study, a computational analysis of 37,000 SL gene pairs identified potential drug candidates, and surprise, surprise; lipophilic statins were a viable treatment for metastatic cancers with two mutations: KRAS and BRCA1. In a retrospective meta-analysis and previous experiments, Simvastatin and Lovastatin showed the most promising anticancer activity. These two targeted the genes HDAC2 and HMGCR, which form S.L. pairs with BRCA1 and KRAS - BRCA1 mutations commonly associated with breast and ovarian cancer and KRAS with colon and triple-negative breast cancer. The computational analysis laboratory tests done on cell lines with and without KRAS and BRCA1 mutations showed that breast cancer cells with the mutations showed significant sensitivity with low concentrations of the statins, 2.108 μM of Simvastatin and 9.5 nM of Lovastatin. The same was not valid for the cancer cell lines, which lacked the relevant mutations for the S.L. mechanism to take place. This principle confirmed precisely what the scientists suspected: by inhibiting the synthetically lethal gene pairs, the statins were able to exploit the breast cancer cells' genetic weakness, effectively causing cell death in cancer cells with KRAS and BRCA1 mutations (9).
Additionally, the researchers explored how statins could be paired with traditional chemotherapy to enhance treatment outcomes. From a pool of nearly 5,000 possible drug combinations, 565 promising pairs were identified, including statins combined with Temozolomide, a standard chemotherapy drug. This combination and statins' unique ability to target cancer mutations through S.L. hold potential for accelerated clinical applications and personalized cancer treatments (9).
This study highlighted that out of approximately 2,500 drugs approved by the FDA, only three have been repurposed for cancer treatment (9). You'd think this number would be higher. Still, unfortunately, once an approved drug loses its patent protection, there's no financial incentive for these large drug corporations to win a new indication from the FDA and then advertise the drug for this new purpose. So, the doctors prescribing "off-label" take career risks and are rarely even familiar with the data. This fact is the unfortunate reality of U.S. healthcare; it leaves it up to us to research and take charge of our health.
This study emphasizes the potential for drug repurposing to offer an innovative and cost-effective approach to cancer therapies that exploit synthetic lethality.
For us at Meakin Metabolic Care, this approach is incredibly exciting, and we will report further on these SL opportunities.
Chuck Meakin MD
Disclaimer: This information is not meant as direct medical advice. Readers should always review options with their local medical team. This is the sole opinion of Dr. Meakin based on a literature review at the time of the blog and may change as new evidence evolves.
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References
Centers for Disease Control and Prevention. (2024, May 2). FASTSTATS - deaths and mortality. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/fastats/deaths.htm
More than half of U.S. adults don't know heart disease is the leading cause of death, despite a 100-year reign. American Heart Association. (n.d.). https://newsroom.heart.org/news/more-than-half-of-u-s-adults-dont-know-heart-disease-is-leading-cause-of-death-despite-100-year-reign#:~:text=“Heart%20disease%20has%20now%20been,Wu%2C%20M.D.%2C%20Ph.
Centers for Disease Control and Prevention. (2024b, August 2). Cancer deaths - health, United States. Centers for Disease Control and Prevention. https://www.cdc.gov/nchs/hus/topics/cancer-deaths.htm#:~:text=Cancer%20has%20been%20one%20of,years%20(1%2C2).
Cholesterol. www.heart.org. (n.d.). https://www.heart.org/en/health-topics/cholesterol
Climent E, Benaiges D, Pedro-Botet J. Hydrophilic or Lipophilic Statins? Front Cardiovasc Med. 2021 May 20;8:687585. doi: 10.3389/fcvm.2021.687585. PMID: 34095267; PMCID: PMC8172607.
Guardian News and Media. (2017, June 2). Statins could reduce risk of breast cancer death by 38%, research shows. The Guardian. https://www.theguardian.com/society/2017/jun/02/statins-breast-cancer-death-research
Longitudinal cohort study highlights cancer-preventive benefits of lipid-lowering drugs. Yuan, Zinuo et al. iScience, Volume 27, Issue 9, 110680
Buccioli, G., Testa, C., Jacchetti, E. et al. The molecular basis of the anticancer effect of statins. Sci Rep 14, 20298 (2024). https://doi.org/10.1038/s41598-024-71240-6
Liu C, Chen H, Hu B, Shi J, Chen Y, Huang K. New insights into the therapeutic potentials of statins in cancer. Front Pharmacol. 2023 July 7;14:1188926. doi: 10.3389/fphar.2023.1188926. PMID: 37484027; PMCID: PMC10359995.
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