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Antifungal Drug Itraconazole Targets VDAC1 to Modulate the AMPK/Mtor Signaling Axis in Endothelial Cells

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Antifungal Drug Itraconazole Targets VDAC1 to Modulate the AMPK/Mtor Signaling Axis in Endothelial Cells Antifungal drug itraconazole targets VDAC1 to PNAS PLUS modulate the AMPK/mTOR signaling axis in endothelial cells Sarah A. Heada, Wei Shia,b, Liang Zhaoc, Kirill Gorshkova, Kalyan Pasunootia,d, Yue Chene, Zhiyou Denge, Ruo-jing Lia, Joong Sup Shima,f, Wenzhi Tang, Thomas Hartungc, Jin Zhanga, Yingming Zhaoe, Marco Colombinig, and Jun O. Liua,h,1 aDepartment of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Baltimore, MD 21205; bDepartment of Chemistry and Biochemistry, University of Arkansas, Fayetteville, AR 72701; cDepartment of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205; dDivision of Structural Biology and Biochemistry, School of Biological Sciences, Nanyang Technological University, Singapore 637551; eBen May Department of Cancer Research, The University of Chicago, Chicago, IL 60637; fFaculty of Health Sciences, University of Macau, Taipa, Macau Special Administrative Region, China; gDepartment of Biology, University of Maryland, College Park, MD 20742; and hDepartment of Oncology, Johns Hopkins School of Medicine, Baltimore, MD 21205 Edited by Michael N. Hall, University of Basel, Basel, Switzerland, and approved November 12, 2015 (received for review July 7, 2015) Itraconazole, a clinically used antifungal drug, was found to possess and Drug Administration (FDA) of a few antiangiogenic drugs. potent antiangiogenic and anticancer activity that is unique among Bevacizumab (Avastin), a monoclonal antibody targeting VEGF, the azole antifungals. Previous mechanistic studies have shown that gained FDA approval for the treatment of metastatic colorectal itraconazole inhibits the mechanistic target of rapamycin (mTOR) cancer (4, 5). Pegaptanib (Macugen), a polynucleotide-based signaling pathway, which is known to be a critical regulator of en- aptamer targeting VEGF (6), also has been approved by the FDA dothelial cell function and angiogenesis. However, the molecular for the treatment of age-dependent macular degeneration. More target of itraconazole that mediates this activity has remained recently, several kinase inhibitors, including sorafenib, sunitinib, unknown. Here we identify the major target of itraconazole in en- pazopanib, and everolimus, that have a major, albeit nonspecific, dothelial cells as the mitochondrial protein voltage-dependent anion effect on angiogenesis also have entered the clinic (7). channel 1 (VDAC1), which regulates mitochondrial metabolism by Drug discovery and development is a time-consuming and costly PHARMACOLOGY controlling the passage of ions and small metabolites through the process. The discovery and development of antiangiogenic drugs is outer mitochondrial membrane. VDAC1 knockdown profoundly in- no exception. To accelerate the process, we began a new initiative hibits mTOR activity and cell proliferation in human umbilical vein to collect known drugs and assemble them into what is now known cells (HUVEC), uncovering a previously unknown connection as the “Johns Hopkins Drug Library” (JHDL). Screening of JHDL between VDAC1 and mTOR. Inhibition of VDAC1 by itraconazole using an endothelial cell proliferation assay led to the identifi- disrupts mitochondrial metabolism, leading to an increase in the cation of a number of hits. Among the most interesting hits is the cellular AMP:ATP ratio and activation of the AMP-activated protein antifungal drug itraconazole (8). Itraconazole potently inhibits kinase (AMPK), an upstream regulator of mTOR. VDAC1-knockout cells are resistant to AMPK activation and mTOR inhibition by Significance itraconazole, demonstrating that VDAC1 is the mediator of this activity. In addition, another known VDAC-targeting compound, Tumors promote angiogenesis to facilitate their growth and erastin, also activates AMPK and inhibits mTOR and proliferation in metastasis; thus, inhibition of angiogenesis is a promising HUVEC. VDAC1 thus represents a novel upstream regulator of mTOR strategy for treating cancer. During angiogenesis, endothelial signaling in endothelial cells and a promising target for the devel- cells (EC) are stimulated by proangiogenic factors to proliferate opment of angiogenesis inhibitors. and migrate, leading to the formation of new blood vessels. Understanding the mechanisms regulating EC function there- angiogenesis | mitochondria | metabolism | itraconazole | VDAC1 fore is essential for the development of new antiangiogenic interventions. Here, we identify a novel mechanism of EC regu- ngiogenesis, or the formation of new blood vessels from lation by the recently discovered angiogenesis inhibitor itraco- Apreexisting vasculature, is a critical process both in normal nazole, mediated by direct binding to the mitochondrial protein development and in the pathogenesis of a myriad of diseases. In voltage-dependent anion channel 1 (VDAC1). VDAC1 inhibition particular, it has long been recognized that angiogenesis is re- perturbs mitochondrial ATP production, leading to activation of quired for tumor growth and metastasis and that growing tu- the AMP-activated protein kinase pathway and subsequent in- mors can promote angiogenesis by secreting proangiogenic hibition of mechanistic target of rapamycin, a regulator of EC factors, such as VEGF, basic FGF, EGF, and others (1, 2). proliferation. This study suggests VDAC1 may serve as a new These proangiogenic factors stimulate the proliferation, migra- therapeutic target for angiogenesis inhibition. tion, and differentiation of the endothelial cells that make up the inner layer of all blood vessels, causing them to form new vessels Author contributions: S.A.H., J.S.S., and J.O.L. designed research; S.A.H., W.S., L.Z., K.G., K.P., Z.D., R.-j.L., and W.T. performed research; T.H., J.Z., Y.Z., and M.C. contributed new reagents/ that grow toward the source of these factors. This process, termed analytic tools; S.A.H., W.S., L.Z., K.G., K.P., Y.C., Z.D., R.-j.L., J.S.S., Y.Z., M.C., and J.O.L. “tumor angiogenesis,” allows the tumor to keep up with an in- analyzed data; and S.A.H., W.S., and J.O.L. wrote the paper. creasing demand for oxygen and nutrients as it grows, eliminate Conflict of interest statement: The intellectual properties covering the use of itraconazole accumulating waste products, and shed cancerous cells into cir- and its stereoisomers as angiogenesis inhibitors have been patented by the Johns Hopkins culation leading to metastasis. Without angiogenesis, a tumor University and licensed to Accelas Pharmaceuticals, Inc., of which J.O.L. is a cofounder and – equity holder. The potential conflict of interest has been managed by the Office of Policy cannot grow larger than about 1 2 mm in diameter, the largest Coordination of the Johns Hopkins School of Medicine. The results disclosed in this article size at which nutrients can permeate by diffusion alone, and thus is are not directly related to those intellectual properties. rendered essentially harmless to the host (3). Inhibition of an- This article is a PNAS Direct Submission. giogenesis is emerging as a useful strategy for treating cancer. The 1To whom correspondence should be addressed. Email: [email protected]. discovery and development of angiogenesis inhibitors as ther- This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. apeutics for cancer has culminated in the approval by the Food 1073/pnas.1512867112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1512867112 PNAS Early Edition | 1of10 Downloaded by guest on September 23, 2021 endothelial cell proliferation with an IC50 value (ca. 200 nM) that is Results significantly below its peak plasma levels (>2 μM) (9), suggesting Design and Synthesis of a Photoaffinity Probe of Itraconazole That that it is likely to have antiangiogenic activity under existing drug- Retains Full Cellular Activity. To identify molecular target(s) of itra- administration regimens. It also displays high cell-type selectivity, conazole, we turned to a live-cell photoaffinity labeling approach, being most potent against primary human endothelial cells in which allows capture of drug-binding proteins in their native en- comparison with human foreskin fibroblasts and most human vironment and unbiased target identification by mass spectrometry. cancer cell lines. Moreover, it is more than 30-fold more potent For this approach to be successful, a probe must be designed that than other members of the azole family of antifungal drugs, in- can bind to the same target proteins and induce the same effects as cluding ketoconazole and terconazole (8). the parent drug with a similar potency. Our previous studies on all Itraconazole was developed originally as an antifungal drug and eight individual stereoisomers of itraconazole revealed that the has been used clinically for more than 30 years with a well-established stereochemistry in the sec-butyl side chain is least important for the safety record. Upon validation of its antiangiogenic and antitumor growth inhibition of human umbilical vein endothelial cells activity in a number of models both in vitro and in vivo (8, 10, 11), it (HUVEC) (21). Therefore, we speculated that the alkyl group entered multiple phase 2 clinical trials for treating cancer. To date, attached to the triazolone ring may be a suitable position for de- the pilot trials in nonsmall cell lung cancer, prostate cancer, and basal rivatization to make a chemical probe for target identification. cell carcinoma have been completed; itraconazole has been shown Further elaborated structure–activity
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