Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing

Melo, Sónia A.; Villanueva, Alberto; Moutinho, Cátia; Dávalos, Verónica; Spizzo, Riccardo; Ivan, Cristina; Rossi, Simona; Setién, Fernando; Casanovas, Oriol; Simó-Riudalbas, Laia; Carmona, Javier; Carrere, Jordi; Vidal, August; Aytés, Álvaro; Puertas, Sara; Ropero, Santiago; Kalluri, Raghu; Croce, Carlo M.; Calin, George A.; Esteller, Manel

doi:10.1073/pnas.1014720108

Cited by 228 publications

(260 citation statements)

References 46 publications

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“…These results are consistent with our proposal (Toro et al, 2012b) that, by blocking V-ATPase-microfilament-binding, enoxacin perturbs the specialized vesicular trafficking that is required for osteoclast differentiation and bone-resorptive activity. Enoxacin has also been reported to have anti-cancer activity, due its ability to enhance microRNA activity (Melo et al, 2011;Sousa et al, 2013). Further testing is required to determine whether BE stimulates microRNAs and/or has anti-cancer activity.…”

Section: Discussionmentioning

confidence: 99%

Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

et al. 2013

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Enoxacin inhibits binding between the B-subunit of vacuolar H + -ATPase (V-ATPase) and microfilaments, and also between osteoclast formation and bone resorption in vitro. We hypothesized that a bisphosphonate derivative of enoxacin, bis-enoxacin (BE), which was previously studied as a bone-directed antibiotic, might have similar activities. BE shared a number of characteristics with enoxacin: It blocked binding between the recombinant B-subunit and microfilaments and inhibited osteoclastogenesis in cell culture with IC 50 s of about 10 µM in each case. BE did not alter the relative expression levels of various osteoclast-specific proteins. Even though tartrate-resistant acid phosphatase 5b was expressed, proteolytic activation of the latent pro-enzyme was inhibited. However, unlike enoxacin, BE stimulated caspase-3 activity. BE bound to bone slices and inhibited bone resorption by osteoclasts on BE-coated bone slices in cell culture. BE reduced the amount of orthodontic tooth movement achieved in rats after 28 days. Analysis of these data suggests that BE is a novel anti-resorptive molecule that is active both in vitro and in vivo and may have clinical uses. Abbreviations: BE, bis-enoxacin; V-ATPase, vacuolar H + -ATPase; TRAP, tartrate-resistant acid phosphatase; αMEM D10, minimal essential media, alpha modification with 10% fetal bovine serum; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; RANKL, receptor activator of nuclear factor kappa B-ligand; NFATc1, nuclear factor of activated T-cells; ADAM, a disintegrin and metalloprotease domain; OTM, orthodontic tooth movement.

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Section: Discussionmentioning

confidence: 99%

Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

et al. 2013

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“…Here, we show that these orthotopic-based preclinical ovarian tumor models, which reproduce primary tumor properties, are outstanding resources for the development of new drug therapies. They would also be very valuable for exploring new therapeutic applications for drugs that are currently approved for use in humans, as we recently reported in microsatellite instability (MSI) þ colorectal tumors with enoxacin (46). Thus, assessed chemotherapy responses in cisplatin-sensitive and cisplatin-resistant tumor models that maintain the morphologic, histologic, and genetic characteristics of patients' tumors, including the behavior of the stromal component and the tissue architecture, may improve preclinical drug translation to patients.…”

Section: Discussionmentioning

confidence: 99%

Lurbinectedin (PM01183), a New DNA Minor Groove Binder, Inhibits Growth of Orthotopic Primary Graft of Cisplatin-Resistant Epithelial Ovarian Cancer

Vidal

Muñoz

Guillén

et al. 2012

Clinical Cancer Research

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Purpose: Epithelial ovarian cancer (EOC) is the fifth leading cause of death in women diagnosed with gynecologic malignancies. The low survival rate is because of its advanced-stage diagnosis and either intrinsic or acquired resistance to standard platinum-based chemotherapy. So, the development of effective innovative therapeutic strategies to overcome cisplatin resistance remains a high priority.Experimental Design: To investigate new treatments in in vivo models reproducing EOCs tumor growth, we generated a preclinical model of ovarian cancer after orthotopic implantation of a primary serous tumor in nude mice. Further, matched model of acquired cisplatin-resistant tumor version was successfully derived in mice. Effectiveness of lurbinectedin (PM01183) treatment, a novel marinederived DNA minor groove covalent binder, was assessed in both preclinical models as a single and a combined-cisplatin agent.Results: Orthotopically perpetuated tumor grafts mimic the histopathological characteristics of primary patients' tumors and they also recapitulate in mice characteristic features of tumor response to cisplatin treatments. We showed that single lurbinectedin or cisplatin-combined therapies were effective in treating cisplatin-sensitive and cisplatin-resistant preclinical ovarian tumor models. Furthermore, the strongest in vivo synergistic effect was observed for combined treatments, especially in cisplatin-resistant tumors. Lurbinectedin tumor growth inhibition was associated with reduced proliferation, increased rate of aberrant mitosis, and subsequent induced apoptosis.Conclusions: Taken together, preclinical orthotopic ovarian tumor grafts are useful tools for drug development, providing hard evidence that lurbinectedin might be a useful therapy in the treatment of EOC by overcoming cisplatin resistance.

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“…As such, small molecule libraries have been screened in order to identify compounds that modulate the biogenesis of particular miRNAs [122][123][124]. For example, the antibiotic enoxacin has been found to enhance miRNA biogenesis by binding to the RISC component TARRBP2 (TAR RNA-binding protein 2) which leads to increased levels of tumor suppressor miRNAs [125] and miRNAs involved in neural development [126].…”

Section: Microrna Therapymentioning

confidence: 99%

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

2013

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The most fundamental roles of non-coding RNAs (ncRNAs) and epigenetic mechanisms are the guidance of cellular differentiation in development and the regulation of gene expression in adult tissues. In brain, both ncRNAs and the various epigenetic gene regulatory mechanisms play a fundamental role in neurogenesis and normal neuronal function. Thus, epigenetic chromatin remodelling can render coding sites transcriptionally inactive by DNA methylation, histone modifications or antisense RNA interactions. On the other hand, microRNAs (miRNAs) are ncRNA molecules that can regulate the expression of hundreds of genes post-transcriptionally, typically recognising binding sites in the 3′ untranslated region (UTR) of mRNA transcripts. Furthermore, there are a myriad of interactions in the interface of miRNAs and epigenetics. For example, epigenetic mechanisms can silence miRNA coding sites, and miRNAs can be the effectors of transcriptional gene silencing, targeting complementary promoters or silencing the expression of epigenetic modifier genes like MECP2 and EZH2 leading to global changes in the epigenome. Alterations in this regulatory machinery play a key role in the pathology of complex disorders including cancer and neurological diseases. For example, miRNA genes are frequently inactivated by epimutations in gliomas. Here we describe the interactions between epigenetic and ncRNA regulatory systems and discuss therapeutic potential, with an emphasis on tumors, cognitive disorders and neurodegenerative diseases.

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Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing

Cited by 228 publications

References 46 publications

Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

Bis-enoxacin Inhibits Bone Resorption and Orthodontic Tooth Movement

Lurbinectedin (PM01183), a New DNA Minor Groove Binder, Inhibits Growth of Orthotopic Primary Graft of Cisplatin-Resistant Epithelial Ovarian Cancer

Epigenetics and ncRNAs in Brain Function and Disease: Mechanisms and Prospects for Therapy

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