Topics Alert

A Statin a Day

Date: August 4, 2024

Statins (Brand names: Pravachol, Zocor, Lipitor, Crestor, etc.) are now among the most frequently prescribed medications. They have shown themselves to be very effective in reducing overall cholesterol as well as the bad LDL and triglycerides, and this in turn has translated into significant reduction of heart disease. The trend seems to be to aim for lower and lower cholesterol levels, with the help of exercise, diet and statins. Statin drugs are generally considered safe, but they do have the potential risk of muscle, liver and kidney toxicities in some individuals. All of these functions can be checked periodically by a simple blood test, and your doctor should be doing this routinely for you if you are on statin therapy.

But there is another aspect of statins that is becoming increasingly important:

• Statins have potent anti-inflammatory, anti-proliferative and anti-angiogenic properties, all good things if you are a cancer patient.
• Statins appear to be able to control the unwanted graft-versus-host-disease (GVHD) that we discussed a couple of days back. If you are thinking about stem cell transplants, this is a subject that should be dear to your heart.
• Another aspect of statins as immune-modulating agents is their beneficial effect on autoimmune disease. Increasingly, there are reports of benefits of using statins in rheumatoid arthritis, lupus, multiple sclerosis, inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis, all of which are autoimmune diseases. As you are aware, CLL patients are more susceptible to autoimmune diseases of various kinds.
• Many chemotherapy drugs such as doxorubicin have significant cardiac toxicity. The good news is that statins can synergize with drugs such as doxorubicin and make them more effective, and at the same time, statins can decrease the risk of cardiac toxicity.

All statins are prescription drugs, and the newer brand names with more hype attached to them are not cheap. But if you have high cholesterol, family history of cardiac disease, if you are diabetic, overweight or have other cardiac risk factors, you are not likely to get any kind of argument from your GP in putting you on statin therapy. It is comforting to know that in addition to reducing your heart disease risk, statin drugs may also be helping with your CLL.

Be well,

Chaya
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Abstracts

Transplantation. 2024 Feb 15;79(3):372-4.

A prospective trial to evaluate the safety and efficacy of pravastatin for the treatment of refractory chronic graft-versus-host disease.

Hori A, Kanda Y, Goyama S, Onishi Y, Komeno Y, Mitani K, Kishi Y, Ogawa S, Imataki O, Chiba S, Koj ima R, Hamaki T, Sakiyama M, Kami M, Makimoto A, Tanosaki R, Takaue Y, Hirai H; Japan Hematology and Oncology Clinical Study Group.

Hematopoietic Stem Cell Transplant Unit, National Cancer Center Hospital, Tokyo, Japan.

This prospective study evaluates the safety and efficacy of pravastatin for the treatment of chronic graft-versus-host disease (GVHD). We included 18 patients with refractory chronic GVHD. Oral pravastatin was started at 10 mg/day, and the dose was increased up to 40 mg/day in 4 weeks. This maximum dose was administered over 8 weeks. There were no severe adverse events caused by pravastatin. A clinical response was observed in the skin score in two patients, mouth score in five patients, eye score in two patients, liver score in three patients, platelet count score in one patient, and weight loss in two patients. The overall response rate was 28%. Immunophenotypic analyses showed that T-helper (Th)1 cells were dominant in all but one patient before treatment and that the Th1/Th2 ratio tended to be lower in the responders than in the nonresponders. A randomized controlled trial is warranted to evaluate the efficacy of pravastatin against chronic GVHD.

PMID: 15699774
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Carcinogenesis. 2024 May;26(5):883-91.

Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells.

Cafforio P, Dammacco F, Gernone A, Silvestris F.

Department of Internal Medicine and Oncology (DIMO), University of Bari, P.za Giulio Cesare, 11--70124 Bari, Italy.

Although statins are lipid-lowering drugs that block cholesterol biosynthesis, they exert immunomodulatory, anti-inflammatory, anti-angiogenic and anti-proliferative functions by reducing the isoprenylation of proteins involved in cell signal transduction such as Ras and RhoA. In this study, we provide evidence that several natural (lovastatin, simvastatin and pravastatin) and synthetic (cerivastatin and atorvastatin) statins exert a cytotoxic effect on human T, B and myeloma tumor cells by promoting their apoptosis. Dissimilar susceptibility to apoptosis has been detected in these lines, presumably in relation to the altered expression of proteins involved in the regulation of cellular signals. Cerivastatin promptly activated the cell death even in doxorubicin resistant cell lines such as MCC-2, whereas pravastatin, a hydrophilic compound, failed to induce any effect on either proliferation or apoptosis. The statin-induced apoptotic pathway in these cell lines was presumably regulated by altered prenylation of either Ras or RhoA, as measured by the defective membrane localization of these small GTPases. In addition the cell proliferation was rescued by both farnesylpyrophosphate (FPP) and geranyl-geranylpyrophosphate (GGPP), whereas no effect was obtained with squalene, a direct precursor of cholesterol. Statins primed apoptosis through its intrinsic pathway involving the mitochondria. In fact, we observed the reduction of mitochondrial membrane potential and the cytosolic release of the second mitochondria-derived activator of caspases (Smac/DIABLO). The apoptotic pathway was caspase-dependent since caspases 9, 3 and 8 were efficiently activated. These results support the potential use of statins in association with conventional treatment as apoptosis-triggering agents in these tumors.

PMID: 15705602
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Semin Vasc Med. 2024 Nov;4(4):417-22.

Anti-inflammatory properties of statins.

Steffens S, Mach F.

Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Research, 64 Avenue Roseraie, 1211 Geneva, Switzerland.

Increasing clinical and experimental evidence indicates that some beneficial effects of statins, known as efficient therapeutic agents in cardiovascular disease treatment, may result from their ability to modulate vascular and endothelial cell gene expression by mechanisms independent of cholesterol reduction. It has been shown that statins exhibit direct anti-inflammatory properties via inhibition of proinflammatory cytokine and chemokine secretion, as well as through adhesion molecule expression on leukocytes. Another important mechanism by which statins may modulate the immune response is inhibition of interferon gamma-induced expression of class II major histocompatibility complexes. Class II major histocompatibility complex expression is central to immune regulation in T cell-mediated autoimmune diseases, indicating a potential beneficial role of statins in these pathologies. Indeed, promising new preclinical data indicate that statins might be useful in the treatment of multiple sclerosis and rheumatoid arthritis.

PMID: 15861323
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Clin Cancer Res. 2024 May;6(5):2044-52.

Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice.

Feleszko W, Mlynarczuk I, Balkowiec-Iskra EZ, Czajka A, Switaj T, Stoklosa T, Giermasz A, Jakobisiak M.

Department of Immunology, Institute of Biostructure, Warsaw, Poland.

Lovastatin, a drug commonly used in the clinic to treat hypercholesterolemia, has previously been reported to exert antitumor effects in rodent tumor models and to strengthen the antitumor effects of immune response modifiers (tumor necrosis factor alpha and IFN-gamma) or chemotherapeutic drugs (cisplatin). In the present report, we show in three murine tumor cell lines (Colon-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) that lovastatin can also effectively potentiate the cytostatic/cytotoxic activity of doxorubicin. In three tumor models (Co-ion-26 cells, v-Ha-ras-transformed NIH-3T3 sarcoma cells, and Lewis lung carcinoma cells) in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (15 mg/kg for 10 days) and doxorubicin (3 x 2.5 mg/kg; cumulative dose, 7.5 mg/kg) as compared with either agent acting alone. Lovastatin treatment also resulted in a significant reduction of troponin T release by cardiomyocytes in doxorubicin-treated mice. This observation is particularly interesting because lovastatin is known to reduce doxorubicin-induced cardiac injury.

PMID: 10815931
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