BackgroundGlioblastoma (GBM) is a therapeutic challenge, associated with high mortality. More effective GBM therapeutic options are urgently needed. Hence, we screened a large multi-class drug panel comprising the NIH clinical collection (NCC) that includes 446 FDA-approved drugs, with the goal of identifying new GBM therapeutics for rapid entry into clinical trials for GBM.MethodsScreens using human GBM cell lines revealed 22 drugs with potent anti-GBM activity, including serotonergic blockers, cholesterol-lowering agents (statins), antineoplastics, anti-infective, anti-inflammatories, and hormonal modulators. We tested the 8 most potent drugs using patient-derived GBM cancer stem cell-like lines. Notably, the statins were active in vitro; they inhibited GBM cell proliferation and induced cellular autophagy. Moreover, the statins enhanced, by 40-70 fold, the pro-apoptotic activity of irinotecan, a topoisomerase 1 inhibitor currently used to treat a variety of cancers including GBM. Our data suggest that the mechanism of action of statins was prevention of multi-drug resistance protein MDR-1 glycosylation. This drug combination was synergistic in inhibiting tumor growth in vivo. Compared to animals treated with high dose irinotecan, the drug combination showed significantly less toxicity.ResultsOur data identifies a novel combination from among FDA-approved drugs. In addition, this combination is safer and well tolerated compared to single agent irinotecan.ConclusionsOur study newly identifies several FDA-approved compounds that may potentially be useful in GBM treatment. Our findings provide the basis for the rational combination of statins and topoisomerase inhibitors in GBM.
Statins are a class of drug that inhibits 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase that is the rate-limiting enzyme of cholesterols synthesis. Now, statins are among the most prescribed drug used for treatment of hypercholesterolemia by lower down the serum cholesterol concentration and it is also a major means to preventing and reducing the risk for cardiovascular diseases. In addition to prevent and treat cardiovascular diseases, the emerging evidences indicated the statins usage has a number of beneficial effect such as anti-inflammation and lowering down the risk of cancer. To investigate the anti-cancer effect statins drugs that have been approved to clinical usage we evaluated the inhibition of breast cancer and GBM cell line growth. Statins are also potent inhibitors to stem cell-like primary GBM cells freshly isolated from patients. Unexpected, statins treatment induces strong cell autophagy death signals as weak if not at all cellular apoptosis. Tumor cells can be rescued after statin treatment by adding intermediated product of cholesterol synthesis (mevalonate and GGPP), it indicates that the target of the statins is specifically related the cholesterols synthesis pathway. Knock-down the expression of geranylgeranyl pyrophosphate synthetase-1 (GGPS-1), another key enzyme in cholesterol synthesis pathway, also stimulated strong cell autophagy and cell death in vitro, also dramatically reduced U87 tumor growth in vivo. In vivo data also showed that directly injection of statin is better than oral administrate to delay GBM tumor growth. This study showed statins are potent anti-cancer drug in vitro and in animal model. These safe and well-tolerate drugs are good candidates for clinical test as cancer chemotherapy reagents. Citation Format: Pengfei Jiang, Rajesh Mukthavavam, Ying Chao, Natsuko Nomura, Valentina Fogal, Sandra Pastorino, Ila Summit, Santosh Kesari. Preclinical study for statins as anticancer drug. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1856. doi:10.1158/1538-7445.AM2013-1856 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Zoledronic Acid (ZA) is a potent nitrogen-containing bisphosphonates (NBP) has been extensively used to limit bone turnover in a various diseases including tumors. Recently, clinical trails of Zoledronic Acid demonstrated direct anti-cancer effects as well as the known skeletal-related events. We investigated the effect of 4 NBPs on human tumor cells proliferation and found ZA is most potent for GBM cell, breast cell and GBM patients' stem-cell-like cells. ZA also effectively inhibited GBM tumor growth in mouse model. ZA stimulated strong autophagy but not apoptotic signals in all tested cells. One intermediate product of cholesterols synthesis pathway—-geranylgeranyl diphosphate (GGPP) rescued cell from the cytotoxicity of ZA. Knock-down RABGGTA, which encoded a subunit of the Rab geranylgeranyltransferase proteins, induced a similar effect as Zoledronic Acid in cancer cell lines. These data suggested great potential for Zoledronic Acid against human cancer. Note: This abstract was not presented at the meeting. Citation Format: Pengfei Jiang, Rajesh Mukthavavam, Natsuko Nomura, Sandeep C. Pingle, Santosh Kesari. Direct anti-cancer effects of zoledronic acid on human cancer cell. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1628. doi:10.1158/1538-7445.AM2014-1628
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