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Review
. 2014 Jun 10;10(7):654-63.
doi: 10.7150/ijbs.9224. eCollection 2014.

Recent advances in drug repositioning for the discovery of new anticancer drugs

Joong Sup Shim  1 , Jun O Liu  2
Affiliations
Review

Recent advances in drug repositioning for the discovery of new anticancer drugs

Joong Sup Shim et al. Int J Biol Sci. .

Abstract

Drug repositioning (also referred to as drug repurposing), the process of finding new uses of existing drugs, has been gaining popularity in recent years. The availability of several established clinical drug libraries and rapid advances in disease biology, genomics and bioinformatics has accelerated the pace of both activity-based and in silico drug repositioning. Drug repositioning has attracted particular attention from the communities engaged in anticancer drug discovery due to the combination of great demand for new anticancer drugs and the availability of a wide variety of cell- and target-based screening assays. With the successful clinical introduction of a number of non-cancer drugs for cancer treatment, drug repositioning now became a powerful alternative strategy to discover and develop novel anticancer drug candidates from the existing drug space. In this review, recent successful examples of drug repositioning for anticancer drug discovery from non-cancer drugs will be discussed.

Keywords: angiogenesis; cancer; drug discovery; drug library.; drug repositioning; drug screening.

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Conflict of interest statement

Conflict of Interests: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1
Proposed mechanisms of anticancer activity of itraconazole. Extracellular cholesterols are transported into cells in the form of low-density lipoprotein (LDL) through binding to LDL receptor. Cholesterol esters are then hydrolyzed in the late endosome/lysosomes and transported to various cellular destinations through cholesterol trafficking system. Itraconazole is known to block the cholesterol release from the late endosome/lysosomes causing hyper-accumulation of cholesterols in the organelle (so-called Niemann-Pick C phenotype). This leads to the inhibition of mTOR activity and VEGFR2 glycosylation in endothelial cells. Itraconazole is also known to inhibit Smoothened (SMO) activation in Hedgehog signaling by a mechanism distinct from that of cyclopamine and other known SMO antagonists. Itraconazole suppresses Sonic hedgehog (SHH)-induced accumulation of SMO in the primary cilium.
Figure 2
Figure 2
Proposed mechanisms of anticancer activity of nelfinavir. Nelfinavir is known to have a strong anticancer activity through multiple pathways including induction of ER stress, apoptosis and autophagy, and inhibition of AKT pathway and hypoxia-inducible factor 1α (HIF-1α)-dependent angiogenesis. Nelfinavir was shown to inhibit the chymotrypsin- and trypsin-like activities of 20S human proteasome. However, whether anti-proteasome effect is the primary mechanism of nelfinavir for anticancer activity remains elusive since nelfinavir causes proteasome-dependent degradation of several proteins. HSP90 is another proposed molecular target of nelfinavir, of which the inhibition leads to a decrease in the levels of its client proteins including HER2, AKT and CDKs through proteasome-dependent degradation.
Figure 3
Figure 3
Proposed mechanisms of anticancer activity of digoxin. Digoxin is a phytoestrogen which inhibits AR signaling pathway by preventing AR binding to AR-responsive element (ARE), leading to decrease in AR target genes such as PSA in prostate cancer cells. Digoxin is also known to inhibit HIF-1α synthesis, thereby reducing HIF-1α binding to its cognate element, hypoxia-responsive element (HRE), and suppressing the expression of HIF-1α target genes such as VEGF in cancer cells. Binding of cardiac glycosides to Na+/K+-ATPase is known to activate Src, epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation, which leads to an accumulation of p21/CIP1 and induction of cell cycle arrest in cancer cells.
Figure 4
Figure 4
Proposed mechanisms of anticancer activity of nitroxoline. Nitroxoline was shown to inhibit both MetAP2 and sirtuins (SIRT1 and 2) in human endothelial cells. Inhibition of MetAP2 by nitroxoline induced hypo-phosphorylation of retinoblastoma protein (pRb) and increased the level of p53. Inhibition of SIRT1 and 2 caused an increase in acetylation of p53 (K382) and α-tubulin (in the presence of histone deacetylase inhibitor), leading to an induction of endothelial cell senescence. A synergy in increasing the acetylation level of p53 (K382) and inducing senescence was observed when MetAP2 and SIRT1 were inhibited simultaneously, representing a mechanism of nitroxoline for its anti-angiogenic activity. Nitroxoline was also shown to bind and inhibit cathepsin B, an enzyme responsible for extracellular matrix (ECM) protein degradation in cancer cells, thereby blocking cell migration and invasion.
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