New uses for old drugs

Chong, Curtis R.; Sullivan, David J.

doi:10.1038/448645a

Cited by 929 publications

(669 citation statements)

References 12 publications

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“…18 However, evidence from hematological malignancies demonstrates that already available drugs can have substantial impact. Examples include the use of retinoic acid 19 and arsenic trioxide 20 in acute promyelocytic leukemia and thalidomide in multiple myeloma.…”

Section: Discussionmentioning

confidence: 99%

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

et al. 2008

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B-cell chronic lymphocytic leukemia (CLL), the most common leukemia in older adults, remains largely incurable and novel treatments are urgently required. We previously reported powerful pro-apoptotic actions of bezafibrate (BEZ) and medroxyprogesterone acetate (MPA) against Burkitts lymphoma cells. Here, we demonstrate that BEZ and MPA individually, and more potently when combined (BEZ þ MPA), induce apoptosis of unsorted and CD19 þ ve -selected CLL cells and abrogate the pro-proliferative activity of CD40 L . This action was tumor cell specific, as the drugs had little impact on normal donor cells. The antiproliferative actions of BEZ þ MPA were associated with the generation of reactive oxygen species (ROS), and the proapoptotic actions were associated with the generation of both ROS and mitochondrial superoxide (MSO). BEZ increased prostaglandin D 2 (PGD 2 ) synthesis by CLL cells, and treatment with PGD 2 and its antineoplastic derivative 15dD 12,14, PGJ 2 recapitulated BEZ-induced antiproliferative and proapoptotic actions. The PGD 2 receptor antagonist, BW868C, did not block BEZ or PGD 2 activity against CLL cells. The potency of BEZ þ MPA against CLL cells mirrored that of chlorambucil, and BEZ þ MPA combined with chlorambucil was more potent than either treatment alone. Given the known safety profiles of BEZ and MPA, our data warrant further investigation of their potential as novel therapy for CLL.

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Section: Discussionmentioning

confidence: 99%

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

et al. 2008

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“…However, a repurposed drug already comes with the systemic toxicity knowledge, reducing cytotoxicity problems. 19 Indeed, repurposed drugs contain 30% of FDA approved drugs in the last years. 20 Therefore, we selected an already-approved drug library as our starting point for identifying TRAIL-sensitizing agents.…”

Section: Discussionmentioning

confidence: 99%

Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

Senbabaoglu

Cingöz

Kaya

et al. 2016

Cancer Biology & Therapy

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Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has tremendous promise in treating various forms of cancers. However, many cancer cells exhibit or develop resistance to TRAIL. Interestingly, many studies have identified several secondary agents that can overcome TRAIL resistance. To expand on these studies, we conducted an extensive drug-re-profiling screen to identify FDA-approved compounds that can be used clinically as TRAIL-sensitizing agents in a very malignant type of brain cancer, Glioblastoma Multiforme (GBM). Using selected isogenic GBM cell pairs with differential levels of TRAIL sensitivity, we revealed 26 TRAIL-sensitizing compounds, 13 of which were effective as single agents. Cardiac glycosides constituted a large group of TRAIL-sensitizing compounds, and they were also effective on GBM cells as single agents. We then explored a second class of TRAIL-sensitizing drugs, which were enhancers of TRAIL response without any effect on their own. One such drug, Mitoxantrone, a DNAdamaging agent, did not cause toxicity to non-malignant cells at the doses that synergized with TRAIL on tumor cells. We investigated the downstream changes in apoptosis pathway components upon Mitoxantrone treatment, and observed that Death Receptors (DR4 and DR5) expression was upregulated, and pro-apoptotic and anti-apoptotic gene expression patterns were altered in favor of apoptosis. Together, our results suggest that combination of Mitoxantrone and TRAIL can be a promising therapeutic approach for GBM patients.

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“…Historically, conventional drug discovery takes one of two routes [44] , either the target-centered or compound-centered approach, and each route may take around 15 years. Consequently, there is growing interest in an approach that focuses on investigating new indications for drugs that have already been approved by the FDA (ie, "drug rediscovery") [24][25][26] . Aside from their well-characterized pharmacology, such drugs would have a safety profile that has been well defined through many years of clinical experience.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, despite all efforts, only 20-30 drugs receive approval by the Food and Drug Administration (FDA) in the USA in any given year [23] . One solution to these limitations is to discover new uses for currently prescribed drugs; the "repurposing old drugs for new uses" approach [24][25][26] . Based on these considerations, we elected to undertake a similar approach in our pursuit of a TPR antagonist.…”

Section: Introductionmentioning

confidence: 99%

Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane A2 receptor

2010

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Aim: To investigate the potential antagonistic activity of the antidiabetic agent glybenclamide for the human platelet thromboxane A 2 receptor (abbreviated as TPR). Methods: Platelets were obtained from healthy donors. Aggregation studies were performed in a model 700 aggregometry system. Radioactivity was counted in a Beckman LS 6000 liquid scintillation counter and calcium imaging was performed using an LS50B PerkinElmer Fluorescence Spectrometer. Results: It was found that glybenclamide: 1) inhibited aggregation induced by the TPR agonist U46619 (IC 50 =2.3±0.31 µmol/L) and by the thromboxane A 2 precursor arachidonic acid (IC 50 =2.6±0.24 µmol/L); 2) displaced SQ29,548 from its binding sites on platelets; 3) lacked any detectable effects on aggregation stimulated by ADP, or the thrombin receptor activating-peptide 4; 4) blocked calcium mobilization induced by U46619, but not by ADP; and 5) failed to raise cAMP levels. Conclusion:The findings indicate that glybenclamide exerts inhibitory effects on platelets by interacting with TPR. Thus, glybenclamide or a rationally designed derivative has the potential to serve as an antithrombotic agent.

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New uses for old drugs

Cited by 929 publications

References 12 publications

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

Treatment of primary CLL cells with bezafibrate and medroxyprogesterone acetate induces apoptosis and represses the pro-proliferative signal of CD40-ligand, in part through increased 15dΔ12,14,PGJ2

Identification of Mitoxantrone as a TRAIL-sensitizing agent for Glioblastoma Multiforme

Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane A2 receptor

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