Overcoming Cancer With Statins 2016

Abstract-

 

One of the main obstacles to success of chemotherapy agents is the development of cancer resistance.

 

Cancer multi-drug resistance (MDR) is thought to arise from over-expression of efflux transporters on cancer cells’ plasma membranes.

 

 

Recently, microparticles (MP) were found to play a major role in mediating the resistance to antineoplastic agents.

 

Microparticles can confer MDR phenotype to cancer cells though 3 complimentary pathways:

 

1) Intercellular transfer of P-gp and MRP1;

 

2) Intercellular transfer of regulatory nucleic acids that ensure acquisition of MDR phenotype; and

 

3) Internal sequestration of anticancer drugs to reduce the amount of free active drug.

 

 

Compounds that inhibit MP formation

that are currently under investigation include

 

calpain inhibitors,

RhoA inhibitors, ROCK inhibitors,

calcium channel blockers,

pantethine, glutaminase inhibitors,

some anti-platelet drugs and some lipid-lowering agents.

 

This area of research requires further development to select,

improve and test those compounds that show the most promise in providing safe and effective treatment against MDR

 

 

F. Anti-platelet drugs –

Ticlopidine and Clopidogrel Ticlopidine and clopidogrel are anti-platelet agents used for prevention of thrombosis after a heart attack, stroke, stent placement or other similar conditions. These disease states are associated with high MP levels [111]. Ticlopidine (200mg/day) was shown to reduce MP levels in diabetic patients by 20 to 30%. Nevertheless, even after use of ticlopidine the numbers of MPs were still elevated compared to healthy individuals [111, 75]. The effect of clopidogrel on MP formation was assessed in 26 subjects with stable coronary artery disease. Amount of circulating MPs was inversely correlated with clopidogrel C-max and AUC [112]. In addition, in another recent study clopidogrel was found to decrease accumulation of MPs at the site of thrombosis and reduce tumor growth and metastasis in mice with pancreatic cancer [113].

 

 

G. Lipid-lowering agents –

Statins and EPA/DHA Statins are drugs of choice for prevention of cardiovascular events. Statins inhibit cholesterol biosynthesis in the liver, and they also have many pleiotropic effects on vascular function including anti-inflammatory and anti-thrombotic effects [114].

 

Recently, rosuvastatin was reported to influence the number of circulating microparticles. One week after rosuvastatin discontinuation, microparticle levels significantly increased suggesting its role in suppression of microparticle formation [115]. However, evidence regarding the effect of other statins on MP production is mixed. Atorvastatin decreased platelet derived MPs but increased endothelial MPs [116], while simvastatin had no effect on any microparticles in one study [117], but was found to increase endothelial MPs in another study [118].

 

 

EPA/DHA is also used as a lipid-lowering agent and prophylaxis against cardiovascular events.

 

In a 12-week study, EPA/DHA daily use was associated with significantly reduced levels of platelet-derived MPs [119].

 

Furthermore, when EPA was combined with pitavastatin for a 6 month period in diabetic patients; reduction in platelet-derived MPs was significantly greater than EPA alone (50% vs 20%) [120].

 

 

H. Glutaminase inhibitors -

BPTES and 968 compounds Metabolism in cancer cells is slightly different from metabolism in healthy human cells. Healthy human cells usually convert pyruvate into citrate in mitochondria to make ATP. Cancer cells, on the other hand, primarily convert pyruvate into lactic acid, and increase glutamine metabolism to produce alpha-ketoglutarate for entrance into citric acid cycle [121]. Inhibition of glutaminase, an enzyme that catalyzes glutamine transformation into glutamate, was found to inhibit microparticle formation.

 

In an experiment showing that glutaminase activity is linked with microparticle biogenesis, MDAMB23 breast cancer cells were treated with glutaminase allosteric inhibitors,

 

BPTES (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethylsulfide) and 968 (bromo- dibenzophenathridine). After a two day period, immunofluorescence analysis showed that untreated cells had 5 times more MP budding than BPTES and 968 treated cells [72].

 

Thus, BPTES and 968 compounds warrant further research as potential clinically useful inhibitors of microparticle formation.

 

IV. CONCLUSION

Overcoming cancer MDR is not an easy task.

Microparticle’s ability to confer MDR by sequestering chemotherapeutic agents and transferring P-gp, MRP1 and miRNA from one cell to another make MPs an excellent target for circumvention of acquired cancer resistance.

 

Many compounds that inhibit MP formation have been identified and are currently under investigation. This area of research requires further development to select, improve and test those compounds that show the most promise in providing safe and effective treatment against MDR.