reducing tumor growth both in vitro and in vivo, drawing our attention to these relatively non to ic cholesterol lowering drugs. The present study demonstrates the potency of pitavastatin relative to other statins. Importantly, our results demon strated that co administration of pitavastatin with low dose chemotherapy, greatly increased the potency of the latter, lowering the IC50 values for irinotecan by 40 to 70 fold, with few adverse effects. E perimentally, we found that statins independently induced autophagy in GBM and that statins may potentiate chemotherapeutic agents by inhibiting MDR 1 function. This was consistent with in silico screening results using our virtual tumor cell technology, which suggested that pitavastatin affects cell viability by inducing autophagy.

Cholesterol has a key role in cell membranes, cell me tabolism, cell signaling and has been implicated in tumor development and progression. Therefore, as cholesterol lowering agents, questions about the anti tumor effects of statins have been already posed. Statins decrease cholesterol levels by inhibiting the enzyme HMG CoA reductase in the liver. In addition, mevalonate, and isopren oid intermediates such as geranylgeranylpyrophosphate and farnesylpyrophosphate in the cholesterol synthesis pathway are Carfilzomib also depleted after statin treatment. Another intermediate, dolichol, an essential substrate for protein N glycosylation, is also blocked by statins. Considering that GBMs are highly proliferative taking up large quantities of cholesterol, potentially they may be vulnerable to statin treatment.

However, the mechanism of sensitivity of GBM to statins has not been elucidated. Recent studies have shown that statins may have an anti GBM effect in enograft mouse models, by targeting the low density lipoprotein receptor, inducing apoptosis via ERK AKT pathway. Other data hypothesize that statins may inhibit tumor growth by inducing autophagy via the NF ��B pathway in human colon cancer cell line. Our data obtained in both stable cell lines and primary patient samples clearly demonstrated that pitavastatin induced macro autophagy in GBM cells. Further e periments are now ongoing to investigate the signaling pathway involved in 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 be a substrate of the multi drug resistance protein, MDR 1, which is over e pressed in GBM upon drug treatment and is partly responsible for the resistance of GBM to chemotherapy. Our data indicate that, in combination with irinotecan, pitavastatin suppressed glycosylation of MDR 1, thereby inhibiting its function and allowing irinotecan to accumu late intracellularly. Accumulation of irinotecan is likely responsible for the increased apoptosis in the presence of pitavastatin. The MDR 1 e pression in cancer cells can be a significant obstacle to the success of chemo therapy. Many MDR 1 inhibito