Working with a platform that employed a wide selection of human GBM lines, like clinically relevant patient derived key GBM lines, our screening uncovered 22 compounds from diverse classes with anti neoplastic activity in GBM. Amongst other people, the cardiovascular drugs statins showed high efficacy in lowering tumor growth both in vitro and in vivo, drawing our focus to these fairly non toxic cholesterol lowering drugs. The present study demonstrates the potency of pitavastatin relative to other statins. Importantly, our final results demon strated that co administration of pitavastatin with low dose chemotherapy, significantly elevated the potency of your latter, lowering the IC50 values for irinotecan by 40 to 70 fold, with couple of adverse effects.
Experimentally, we identified that statins independently induced autophagy in GBM and that statins could potentiate chemotherapeutic agents by inhibiting MDR 1 function. This was constant with in silico screening benefits utilizing our selelck kinase inhibitor virtual tumor cell technologies, which suggested that pitavastatin affects cell viability by inducing autophagy. Cholesterol has a important function in cell membranes, cell me tabolism, cell signaling and has been implicated in tumor improvement and progression. Therefore, as cholesterol lowering agents, questions concerning the anti tumor effects of statins happen to be already posed. Statins decrease cholesterol levels by inhibiting the enzyme HMG CoA reductase in the liver. Moreover, mevalonate, and isopren oid intermediates such as geranylgeranylpyrophosphate and farnesylpyrophosphate within the cholesterol synthesis pathway are also depleted following statin treatment.
A different intermediate, dolichol, an critical substrate for protein N glycosylation, can also be blocked NSC319726 concentration by statins. Thinking of that GBMs are hugely proliferative taking up substantial quantities of cholesterol, potentially they might be vulnerable to statin remedy. Nevertheless, the mechanism of sensitivity of GBM to statins has not been elucidated. Current research have shown that statins might have an anti GBM impact in xenograft mouse models, by targeting the low density lipoprotein receptor, inducing apoptosis by means of ERK AKT pathway. Other information hypothesize that statins might inhibit tumor development by inducing autophagy by way of the NF B pathway in human colon cancer cell line. Our data obtained in each steady cell lines and main patient samples clearly demonstrated that pitavastatin induced macro autophagy in GBM cells.
Additional experiments are now ongoing to investigate the signaling pathway involved within this effect. Importantly, we have shown that pitavastatin potentiated the anti tumor effects of low dose irinotecan, a topoisom erase inhibitor. Pitavastatin is know to become a substrate of your multi drug resistance protein, MDR 1, which can be over expressed in GBM upon drug remedy and is partly responsible for the resistance of GBM to chemotherapy.