ADEPTUS: A discovery tool for disease prediction, enrichment and network analysis based on profiles from many diseases.

Bioinformatics. 2018 Jan 19;:

Authors: Amar D, Vizel A, Levy C, Shamir R

Abstract
Motivation: Large-scale publicly available genomic data on many disease phenotypes could improve our understanding of the molecular basis of disease. Tools that undertake this challenge by jointly analyzing multiple phenotypes are needed.
Results: ADEPTUS is a web-tool that enables various functional genomics analyses based on a high quality curated database spanning >38,000 gene expression profiles and >100 diseases. It offers four types of analysis. (1) For a gene list provided by the user it computes disease ontology (DO), pathway, and gene ontology (GO) enrichment and displays the genes as a network. (2) For a given disease, it enables exploration of drug repurposing by creating a gene network summarizing the genomic events in it. (3) For a gene of interest, it generates a report summarizing its behavior across several studies. (4) It can predict the tissue of origin and the disease of a sample based on its gene expression or its somatic mutation profile. Such analyses open novel ways to understand new datasets and to predict primary site of cancer.
Availability and implementation: data and tool: http://adeptus.cs.tau.ac.il/home Analyses: Supplementary Text.
Contact: rshamir@tau.ac.il.
Supplementary information: Supplementary Text is available at Bioinformatics online.

PMID: 29360930 [PubMed - as supplied by publisher]

Screening of drug library identifies inhibitors of cell intoxication by CNF1.

ChemMedChem. 2018 Jan 23;:

Authors: Mahtal N, Brewee C, Pichard S, Visvikis O, Cintrat JC, Barbier J, Lemichez E, Gillet D

Abstract
The Cytotoxic Necrotizing Factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra-intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation, and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work, we developed a fluorescent, cell-based immunoassay to screen for inhibitors of CNF1-induced Rac1 degradation among 1,120 mostly approved drugs. Eleven compounds prevented CNF1-induced Rac1 degradation and five showed also a protective effect on CNF1-induced multinucleation. At last, lasalocid, monensin, bepridil and amodiaquine protect cells from both diphtheria toxin and CNF1 challenges. These data highlight potential drug repositioning to fight several bacterial toxi-infections and Rac1-based diseases.

PMID: 29359495 [PubMed - as supplied by publisher]

Repurposing atovaquone: targeting mitochondrial complex III and OXPHOS to eradicate cancer stem cells.

Oncotarget. 2016 Jun 07;7(23):34084-99

Authors: Fiorillo M, Lamb R, Tanowitz HB, Mutti L, Krstic-Demonacos M, Cappello AR, Martinez-Outschoorn UE, Sotgia F, Lisanti MP

Abstract
Atovaquone is an FDA-approved anti-malarial drug, which first became clinically available in the year 2000. Currently, its main usage is for the treatment of pneumocystis pneumonia (PCP) and/or toxoplasmosis in immune-compromised patients. Atovaquone is a hydroxy-1,4-naphthoquinone analogue of ubiquinone, also known as Co-enzyme Q10 (CoQ10). It is a well-tolerated drug that does not cause myelo-suppression. Mechanistically, it is thought to act as a potent and selective OXPHOS inhibitor, by targeting the CoQ10-dependence of mitochondrial complex III. Here, we show for the first time that atovaquone also has anti-cancer activity, directed against Cancer Stem-like Cells (CSCs). More specifically, we demonstrate that atovaquone treatment of MCF7 breast cancer cells inhibits oxygen-consumption and metabolically induces aerobic glycolysis (the Warburg effect), as well as oxidative stress. Remarkably, atovaquone potently inhibits the propagation of MCF7-derived CSCs, with an IC-50 of 1 μM, as measured using the mammosphere assay. Atovaquone also maintains this selectivity and potency in mixed populations of CSCs and non-CSCs. Importantly, these results indicate that glycolysis itself is not sufficient to maintain the proliferation of CSCs, which is instead strictly dependent on mitochondrial function. In addition to targeting the proliferation of CSCs, atovaquone also induces apoptosis in both CD44+/CD24low/- CSC and ALDH+ CSC populations, during exposure to anchorage-independent conditions for 12 hours. However, it has no effect on oxygen consumption in normal human fibroblasts and, in this cellular context, behaves as an anti-inflammatory, consistent with the fact that it is well-tolerated in patients treated for infections. Future studies in xenograft models and human clinical trials may be warranted, as the IC-50 of atovaquone's action on CSCs (1 μM) is >50 times less than its average serum concentration in humans.

PMID: 27136895 [PubMed - indexed for MEDLINE]

The promise and challenges of drug repurposing in psychiatry.

World Psychiatry. 2018 Feb;17(1):28-29

Authors: Fava M

PMID: 29352538 [PubMed]

Drug repurposing screening identifies bortezomib and panobinostat as drugs targeting cancer associated fibroblasts (CAFs) by synergistic induction of apoptosis.

Invest New Drugs. 2018 Jan 18;:

Authors: Lee HM, Lee E, Yeo SY, Shin S, Park HK, Nam DH, Kim SH

Abstract
Cancer associated fibroblasts (CAFs) are the most abundant components of cancer-microenvironment. They play important roles in cancer initiation, progression, and metastasis. In addition, CAFs can confer drug-resistance to cancer cells. Considering their pro-tumorigenic roles, it is recommended to remove CAFs to prevent cancer recurrence after chemotherapy. Despite their clinical significance, few anti-CAF drugs have been developed. The objective of this study was to find a drug that could suppress the viability of patient-derived CAFs through repurposed screening of 51 drugs that were in clinical trials or received FDA approval. As a result, bortezomib (BTZ), carfilzomib (CFZ), and panobinostat (PST) were identified as anti-CAF drug candidates. It was confirmed that BTZ and PST could decrease the viability of various patients derived CAFs through inducing of caspase-3 mediated apoptosis. Interestingly, combination therapy with BTZ and PST showed better efficacy of inhibiting CAFs than single treatment. The synergistic effect between BTZ and PST on viability of CAFs was observed both in vitro CAF culture and in vivo mouse model. Furthermore, combination therapy with BTZ/PST and conventional anticancer compound docetaxel strongly inhibited tumor growth in xenografts of mouse breast cancer cells with mouse CAFs. In conclusion, our present study revealed that BTZ and PST could significantly reduce the viability of CAFs. Therefore, a combination therapy with BTZ/PST and anticancer drugs might be considered as a new rational for the development of anticancer therapy.

PMID: 29349597 [PubMed - as supplied by publisher]

Drug Repurposing Screening Identifies Tioconazole as an ATG4 Inhibitor that Suppresses Autophagy and Sensitizes Cancer Cells to Chemotherapy.

Theranostics. 2018;8(3):830-845

Authors: Liu PF, Tsai KL, Hsu CJ, Tsai WL, Cheng JS, Chang HW, Shiau CW, Goan YG, Tseng HH, Wu CH, Reed JC, Yang LW, Shu CW

Abstract
Background: Tumor cells require proficient autophagy to meet high metabolic demands and resist chemotherapy, which suggests that reducing autophagic flux might be an attractive route for cancer therapy. However, this theory in clinical cancer research remains controversial due to the limited number of drugs that specifically inhibit autophagy-related (ATG) proteins. Methods: We screened FDA-approved drugs using a novel platform that integrates computational docking and simulations as well as biochemical and cellular reporter assays to identify potential drugs that inhibit autophagy-required cysteine proteases of the ATG4 family. The effects of ATG4 inhibitors on autophagy and tumor suppression were examined using cell culture and a tumor xenograft mouse model. Results: Tioconazole was found to inhibit activities of ATG4A and ATG4B with an IC50 of 1.3 µM and 1.8 µM, respectively. Further studies based on docking and molecular dynamics (MD) simulations supported that tioconazole can stably occupy the active site of ATG4 in its open form and transiently interact with the allosteric regulation site in LC3, which explained the experimentally observed obstruction of substrate binding and reduced autophagic flux in cells in the presence of tioconazole. Moreover, tioconazole diminished tumor cell viability and sensitized cancer cells to autophagy-inducing conditions, including starvation and treatment with chemotherapeutic agents. Conclusion: Tioconazole inhibited ATG4 and autophagy to enhance chemotherapeutic drug-induced cytotoxicity in cancer cell culture and tumor xenografts. These results suggest that the antifungal drug tioconazole might be repositioned as an anticancer drug or chemosensitizer.

PMID: 29344310 [PubMed - in process]

Repurposing the anti-malarial drug, quinacrine: new anti-colitis properties.

Oncotarget. 2016 Aug 16;7(33):52928-52939

Authors: Chumanevich AA, Witalison EE, Chaparala A, Chumanevich A, Nagarkatti P, Nagarkatti M, Hofseth LJ

Abstract
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is associated with an increased risk of colorectal cancer in 8-10 years after disease onset. Current colitis treatment strategies do not offer a cure for the disease, but only treat the symptoms with limited success and dangerous side-effects. Also, there is no preventive treatment for either UC or colorectal cancer. Quinacrine is an anti-malarial drug with versatile use in the treatment of diseases involving inflammatory response such as rheumatoid arthritis and lupus erythematosus. It also has putative anti-cancer effect. Quinacrine's anti-inflammatory, anti-oxidant properties, and anti-tumorigenic properties make it a potential small molecule preventive agent for both UC and associated colorectal cancer.
RESULTS: There were obvious changes in the CDI, histology, and inflammatory load in quinacrine-treated groups in a dose and time dependent manner in both models of UC, induced by chemical or haptenating agent.
MATERIALS AND METHODS: We tested quinacrine at two different doses as a colitis treatment agent in two mouse models of UC - the dextran sulfate sodium and oxazolone. The clinical disease index (CDI), histological changes of the colon, levels of inflammatory markers (Cox-2, iNOS, p53) and overall health vitals were evaluated.
CONCLUSIONS: We demonstrate that quinacrine successfully suppresses colitis without any indication of toxicity or side-effects in two mouse models of UC.

PMID: 27447967 [PubMed - indexed for MEDLINE]

The prescribable drugs with efficacy in experimental epilepsies (PDE3) database for drug repurposing research in epilepsy.

Epilepsia. 2018 Jan 17;:

Authors: Sivapalarajah S, Krishnakumar M, Bickerstaffe H, Chan Y, Clarkson J, Hampden-Martin A, Mirza A, Tanti M, Marson A, Pirmohamed M, Mirza N

Abstract
OBJECTIVE: Current antiepileptic drugs (AEDs) have several shortcomings. For example, they fail to control seizures in 30% of patients. Hence, there is a need to identify new AEDs. Drug repurposing is the discovery of new indications for approved drugs. This drug "recycling" offers the potential of significant savings in the time and cost of drug development. Many drugs licensed for other indications exhibit antiepileptic efficacy in animal models. Our aim was to create a database of "prescribable" drugs, approved for other conditions, with published evidence of efficacy in animal models of epilepsy, and to collate data that would assist in choosing the most promising candidates for drug repurposing.
METHODS: The database was created by the following: (1) computational literature-mining using novel software that identifies Medline abstracts containing the name of a prescribable drug, a rodent model of epilepsy, and a phrase indicating seizure reduction; then (2) crowdsourced manual curation of the identified abstracts.
RESULTS: The final database includes 173 drugs and 500 abstracts. It is made freely available at www.liverpool.ac.uk/D3RE/PDE3. The database is reliable: 94% of the included drugs have corroborative evidence of efficacy in animal models (for example, evidence from multiple independent studies). The database includes many drugs that are appealing candidates for repurposing, as they are widely accepted by prescribers and patients-the database includes half of the 20 most commonly prescribed drugs in England-and they target many proteins involved in epilepsy but not targeted by current AEDs. It is important to note that the drugs are of potential relevance to human epilepsy-the database is highly enriched with drugs that target proteins of known causal human epilepsy genes (Fisher's exact test P-value < 3 × 10-5 ). We present data to help prioritize the most promising candidates for repurposing from the database.
SIGNIFICANCE: The PDE3 database is an important new resource for drug repurposing research in epilepsy.

PMID: 29341109 [PubMed - as supplied by publisher]

Design of a tripartite network for the prediction of drug targets.

J Comput Aided Mol Des. 2018 Jan 16;:

Authors: Kunimoto R, Bajorath J

Abstract
Drug-target networks have aided in many target prediction studies aiming at drug repurposing or the analysis of side effects. Conventional drug-target networks are bipartite. They contain two different types of nodes representing drugs and targets, respectively, and edges indicating pairwise drug-target interactions. In this work, we introduce a tripartite network consisting of drugs, other bioactive compounds, and targets from different sources. On the basis of analog relationships captured in the network and so-called neighbor targets of drugs, new drug targets can be inferred. The tripartite network was found to have a stable structure and simulated network growth was accompanied by a steady increase in assortativity, reflecting increasing correlation between degrees of connected nodes leading to even network connectivity. Local drug environments in the tripartite network typically contained neighbor targets and revealed interesting drug-compound-target relationships for further analysis. Candidate targets were prioritized. The tripartite network design extends standard drug-target networks and provides additional opportunities for drug target prediction.

PMID: 29340865 [PubMed - as supplied by publisher]

Identification of antipsychotic drug fluspirilene as a potential anti-glioma stem cell drug.

Oncotarget. 2017 Dec 19;8(67):111728-111741

Authors: Dong Y, Furuta T, Sabit H, Kitabayashi T, Jiapaer S, Kobayashi M, Ino Y, Todo T, Teng L, Hirao A, Zhao SG, Nakada M

Abstract
Glioma stem cell (GSC)-targeted therapy is expected to be one of the most innovative approaches to treat patients with glioblastoma (GBM). A number of the drugs that restrain the signaling pathway essential for GSC maintenance have been under clinical trials. Here, we identified fluspirilene, a traditional antipsychotic drug, as a GSC-targeting agent, selected from thousands of existing drugs, and investigated its therapeutic effects against GBM with the purpose of drug repositioning. To develop novel therapeutics targeting GSCs, we initially screened drug libraries for small-molecule compounds showing a greater efficacy, compared to that of controls, in inhibiting the proliferation and survival of different GSC lines using cell proliferation assay. Drugs already reported to show therapeutic effects against GBM or those under clinical trials were excluded from subsequent screening. Finally, we found three drugs showing remarkable antiproliferative effects on GSCs at low concentrations and investigated their therapeutic effects on GSCs, glioma cell lines, and in a GBM mouse model. Of the three compounds, fluspirilene demonstrated a significant inhibitory effect on the proliferation and invasion of glioma cells as well as in the model mice treated with the drug. These effects were associated with the inactivation of the signal transducer and activator of transcription 3 (STAT3). Redeveloping of fluspirilene is a promising approach for the treatment of GBM.

PMID: 29340087 [PubMed]

Repurposing existing drugs for new AMPK activators as a strategy to extend lifespan: a computer-aided drug discovery study.

Biogerontology. 2018 Jan 15;:

Authors: Mofidifar S, Sohraby F, Bagheri M, Aryapour H

Abstract
Dietary restriction is one of the several ways which could putatively extend organisms' lifespan, ranging from Saccharomyces cerevisiae to rodents, by activating the AMP-activated protein kinase (AMPK), an ATP/AMP sensor. Extensive researches have shown that aging reduces sensibility of AMPK and eventually causes energy imbalance in cells. Research in mammals' AMPK depicts that this signaling molecule could control autophagy, improve cellular stress resistance and suppress inflammatory responses. Hence, in this study we performed a drug repurposing of 1908 FDA-approved drugs in order to discover putative safe activators of AMPK and to find new applications for existing drugs. For this purpose, FDA-approved drugs were screened by virtual screening and the ligand-protein interactions were carefully inspected. Moreover, through MM/PBSA analysis, the binding affinity of hit compounds in γ and αβ binding sites were investigated. As Cangrelor, Nacitentan, Levoleucovorin and Glisoxepide had lower binding affinities; we predicted that they would probably prove to be more potential activators than C2. However, hit-compounds in αβ binding site, exhibited higher unfavorable binding affinity. Hence, present findings can prove to be valuable for discovering new activators for AMPK.

PMID: 29335817 [PubMed - as supplied by publisher]

Reprofiling using a zebrafish melanoma model reveals drugs cooperating with targeted therapeutics.

Oncotarget. 2016 Jun 28;7(26):40348-40361

Authors: Fernandez Del Ama L, Jones M, Walker P, Chapman A, Braun JA, Mohr J, Hurlstone AF

Abstract
Phenotype-guided re-profiling of approved drug molecules presents an accelerated route to developing anticancer therapeutics by bypassing the target-identification bottleneck of target-based approaches and by sampling drugs already in the clinic. Further, combinations incorporating targeted therapies can be screened for both efficacy and toxicity. Previously we have developed an oncogenic-RAS-driven zebrafish melanoma model that we now describe display melanocyte hyperplasia while still embryos. Having devised a rapid method for quantifying melanocyte burden, we show that this phenotype can be chemically suppressed by incubating V12RAS transgenic embryos with potent and selective small molecule inhibitors of either MEK or PI3K/mTOR. Moreover, we demonstrate that combining MEK inhibitors (MEKi) with dual PI3K/mTOR inhibitors (PI3K/mTORi) resulted in a super-additive suppression of melanocyte hyperplasia. The robustness and simplicity of our novel screening assay inspired us to perform a modest screen of FDA approved compounds for their ability to potentiate MEKi PD184352 or PI3K/mTORi NVPBEZ235 suppression of V12RAS-driven melanocyte hyperplasia. Through this route, we confirmed Rapamycin as a compound that could synergize with MEKi and even more so with PI3K/mTORi to suppress melanoma development, including suppressing the growth of cultured human melanoma cells. Further, we discovered two additional compounds-Disulfiram and Tanshinone-that also co-operate with MEKi to suppress the growth of transformed zebrafish melanocytes and showed activity toward cultured human melanoma cells. In conclusion, we provide proof-of-concept that our phenotype-guided screen could be used to identify compounds that affect melanoma development and prompt further evaluation of Disulfiram and Tanshinone as possible partners for combination therapy.

PMID: 27248171 [PubMed - indexed for MEDLINE]

What do the genetic association data say about the high risk of suicide in people with depression? A novel network-based approach to find common molecular basis for depression and suicidal behavior and related therapeutic targets.

J Affect Disord. 2018 Jan 08;229:463-468

Authors: Bozorgmehr A, Alizadeh F, Ofogh SN, Hamzekalayi MRA, Herati S, Moradkhani A, Shahbazi A, Ghadirivasfi M

Abstract
BACKGROUND: Available sources indicate that the risk of suicide in people with major depression is higher than other psychiatric disorders. Although it seems that these two conditions may have a shared cause in some cases, no studies have been conducted to identify a common basis for them.
METHODS: In this study, following an extensive review of literature, we found almost all the genes that are involved in major depression and suicidal behavior, and we isolated genes shared between the two conditions. Then, we found all physical or functional interactions within three mentioned gene sets and reconstructed three genetic interactive networks. All networks were analyzed topologically and enriched functionally. Finally, using a drug repurposing approach, we found the main available drugs that interacted with the most central genes shared between suicidal behavior and depression.
RESULTS: The results demonstrated that BDNF, SLC6A4, CREB1, and TNF are the most fundamental shared genes; and generally, disordered dopaminergic, serotonergic, and immunologic pathways in neuronal projections are the main shared deficient pathways. In addition, we found two genes, SLC6A4 and SLC6A2, to be the main therapeutic targets, and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) and Tricyclic Antidepressants (TCA) to be the most effective drugs for individuals with depression at risk for suicide.
CONCLUSIONS: Our results, in addition to shedding light on the integrated molecular basis of depression-suicide, offer new therapeutic targets for individuals with depression at high risk for suicide and could pave the way for future preclinical and clinical studies. However, integrative systems biology-based studies highly depend on existing data and related databases, as well as the arrival of new experimental data sources in the future, possibly affecting the current results.

PMID: 29331709 [PubMed - as supplied by publisher]

A bibliometric review of drug repurposing.

Drug Discov Today. 2018 Jan 09;:

Authors: Baker NC, Ekins S, Williams AJ, Tropsha A

Abstract
We have conducted a bibliometric review of drug repurposing by scanning >25 million papers in PubMed and using text-mining methods to gather, count and analyze chemical-disease therapeutic relationships. We find that >60% of the ∼35 000 drugs or drug candidates identified in our study have been tried in more than one disease, including 189 drugs that have been tried in >300 diseases each. Whereas in the majority of cases these drugs were applied in therapeutic areas close to their original use, there have been striking, and perhaps instructive, successful attempts of drug repurposing for unexpected, novel therapeutic areas.

PMID: 29330123 [PubMed - as supplied by publisher]

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Classifying cancer genome aberrations by their mutually exclusive effects on transcription.

BMC Med Genomics. 2017 Dec 21;10(Suppl 4):66

Authors: Dayton JB, Piccolo SR

Abstract
BACKGROUND: Malignant tumors are typically caused by a conglomeration of genomic aberrations-including point mutations, small insertions, small deletions, and large copy-number variations. In some cases, specific chemotherapies and targeted drug treatments are effective against tumors that harbor certain genomic aberrations. However, predictive aberrations (biomarkers) have not been identified for many tumor types and treatments. One way to address this problem is to examine the downstream, transcriptional effects of genomic aberrations and to identify characteristic patterns. Even though two tumors harbor different genomic aberrations, the transcriptional effects of those aberrations may be similar. These patterns could be used to inform treatment choices.
METHODS: We used data from 9300 tumors across 25 cancer types from The Cancer Genome Atlas. We used supervised machine learning to evaluate our ability to distinguish between tumors that had mutually exclusive genomic aberrations in specific genes. An ability to accurately distinguish between tumors with aberrations in these genes suggested that the genes have a relatively different downstream effect on transcription, and vice versa. We compared these findings against prior knowledge about signaling networks and drug responses.
RESULTS: Our analysis recapitulates known relationships in cancer pathways and identifies gene pairs known to predict responses to the same treatments. For example, in lung adenocarcinomas, gene-expression profiles from tumors with somatic aberrations in EGFR or MET were negatively correlated with each other, in line with prior knowledge that MET amplification causes resistance to EGFR inhibition. In breast carcinomas, we observed high similarity between PTEN and PIK3CA, which play complementary roles in regulating cellular proliferation. In a pan-cancer analysis, we found that genomic aberrations in BRAF and VHL exhibit downstream effects that are clearly distinct from other genes.
CONCLUSION: We show that transcriptional data offer promise as a way to group genomic aberrations according to their downstream effects, and these groupings recapitulate known relationships. Our approach shows potential to help pharmacologists and clinical trialists narrow the search space for candidate gene/drug associations, including for rare mutations, and for identifying potential drug-repurposing opportunities.

PMID: 29322935 [PubMed - in process]

Meta-analysis of human gene expression in response to Mycobacterium tuberculosis infection reveals potential therapeutic targets.

BMC Syst Biol. 2018 Jan 10;12(1):3

Authors: Wang Z, Arat S, Magid-Slav M, Brown JR

Abstract
BACKGROUND: With the global emergence of multi-drug resistant strains of Mycobacterium tuberculosis, new strategies to treat tuberculosis are urgently needed such as therapeutics targeting potential human host factors.
RESULTS: Here we performed a statistical meta-analysis of human gene expression in response to both latent and active pulmonary tuberculosis infections from nine published datasets. We found 1655 genes that were significantly differentially expressed during active tuberculosis infection. In contrast, no gene was significant for latent tuberculosis. Pathway enrichment analysis identified 90 significant canonical human pathways, including several pathways more commonly related to non-infectious diseases such as the LRRK2 pathway in Parkinson's disease, and PD-1/PD-L1 signaling pathway important for new immuno-oncology therapies. The analysis of human genome-wide association studies datasets revealed tuberculosis-associated genetic variants proximal to several genes in major histocompatibility complex for antigen presentation. We propose several new targets and drug-repurposing opportunities including intravenous immunoglobulin, ion-channel blockers and cancer immuno-therapeutics for development as combination therapeutics with anti-mycobacterial agents.
CONCLUSIONS: Our meta-analysis provides novel insights into host genes and pathways important for tuberculosis and brings forth potential drug repurposing opportunities for host-directed therapies.

PMID: 29321020 [PubMed - in process]

Towards repositioning of quinacrine for treatment of acute myeloid leukemia - Promising synergies and in vivo effects.

Leuk Res. 2017 Dec;63:41-46

Authors: Eriksson A, Chantzi E, Fryknäs M, Gullbo J, Nygren P, Gustafsson M, Höglund M, Larsson R

Abstract
We previously reported that the anti-malarial drug quinacrine has potential to be repositioned for treatment of acute myeloid leukemia (AML). As a next step towards clinical use, we assessed the efficacy of quinacrine in an AML-PS mouse model and investigated possible synergistic effects when combining quinacrine with nine other antileukemic compounds in two AML cell lines. Furthermore, we explored the in vivo activity of quinacrine in combination with the widely used AML agent cytarabine. The in vivo use of quinacrine (100mg/kg three times per week for two consecutive weeks) significantly suppressed circulating blast cells at days 30/31 and increased the median survival time (MST). The in vitro drug combination analysis yielded promising synergistic interactions when combining quinacrine with cytarabine, azacitidine and geldanamycin. Finally, combining quinacrine with cytarabine in vivo showed a significant decrease in circulating leukemic blast cells and increased MST compared to the effect of either drug used alone, thus supporting the findings from the in vitro combination experiments. Taken together, the repositioning potential of quinacrine for treatment of AML is reinforced by demonstrating significant in vivo activity and promising synergies when quinacrine is combined with different agents, including cytarabine, the hypomethylating agent azacitidine and HSP-90 inhibitor geldanamycin.

PMID: 29100024 [PubMed - indexed for MEDLINE]

Repurposing Tecfidera for cancer.

Aging (Albany NY). 2016 07;8(7):1289-90

Authors: Booth L, Malkin M, Dent P

PMID: 27429364 [PubMed - indexed for MEDLINE]

Repurposing of FDA-approved drugs against cancer - focus on metastasis.

Aging (Albany NY). 2016 04;8(4):567-8

Authors: Ozsvári B, Lamb R, Lisanti MP

PMID: 27038638 [PubMed - indexed for MEDLINE]