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HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat.

ABSTRACT: Histone deacetylase inhibitors (HDACi) and panobinostat in particular are currently in the focus of intensive investigation as latency reversing agents against the human immunodeficiency virus (HIV). Regretfully, HDACi have dose limiting side-effects making controlled, optimized methods for delivery of panobinostat highly warranted. This has proven to be highly challenging, predominantly because panobinostat has no readily available classic sites for bioconjugation. In this work, we address this challenge and present the first macromolecular prodrugs of panobinostat engineered using self immolative linkers (SIL) and a disulfide trigger for drug release upon cell entry. Synthetic methodology involved the development of a novel monomer with functionalities of SIL and activated ester for one-step polymer-analogous conjugation to drugs. In agreement with the design set forward, copolymers were stable in buffered solutions and released panobinostat at reducing conditions. Synthesized polymers were highly efficacious as latency reversing agents as monitored in three cell lines harboring latent HIV, at no expense to the cytotoxicity of treatment. The data presented herein provide broad pre-in vivo characterization of a promising prodrug system developed to address a global healthcare challenge, safe and efficient reversal of HIV latency.

SUBMITTER: Zuwala K

PROVIDER: S-EPMC6003675 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat.

Zuwala Kaja K Smith Anton A A AAA Tolstrup Martin M Zelikin Alexander N AN

Chemical science 20160105 3

Histone deacetylase inhibitors (HDACi) and panobinostat in particular are currently in the focus of intensive investigation as latency reversing agents against the human immunodeficiency virus (HIV). Regretfully, HDACi have dose limiting side-effects making controlled, optimized methods for delivery of panobinostat highly warranted. This has proven to be highly challenging, predominantly because panobinostat has no readily available classic sites for bioconjugation. In this work, we address this ...[more]

PMID: 29997778

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Project description:IntroductionOf the more than one million global cases of breast cancer diagnosed each year, approximately fifteen percent are characterized as triple-negative, lacking the estrogen, progesterone, and Her2/neu receptors. Lack of effective therapies, younger age at onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with these malignancies. Here, we investigate the ability of the histone deacetylase inhibitor panobinostat (LBH589) to selectively target triple-negative breast cancer (TNBC) cell proliferation and survival in vitro and tumorigenesis in vivo.MethodsTNBC cell lines MDA-MB-157, MDA-MB-231, MDA-MB-468, and BT-549 were treated with nanomolar (nM) quantities of panobinostat. Relevant histone acetylation was verified by flow cytometry and immunofluorescent imaging. Assays for trypan blue viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation, and DNA fragmentation were used to evaluate overall cellular toxicity. Changes in cell cycle progression were assessed with propidium iodide flow cytometry. Additionally, qPCR arrays were used to probe MDA-MB-231 cells for panobinostat-induced changes in cancer biomarkers and signaling pathways. Orthotopic MDA-MB-231 and BT-549 mouse xenograft models were used to assess the effects of panobinostat on tumorigenesis. Lastly, flow cytometry, ELISA, and immunohistochemical staining were applied to detect changes in cadherin-1, E-cadherin (CDH1) protein expression and the results paired with confocal microscopy in order to examine changes in cell morphology.ResultsPanobinostat treatment increased histone acetylation, decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in all TNBC cell lines. Treatment also resulted in apoptosis induction at 24 hours in all lines except the MDA-MB-468 cell line. MDA-MB-231 and BT-549 tumor formation was significantly inhibited by panobinostat (10 mg/kg/day) in mice. Additionally, panobinostat up-regulated CDH1 protein in vitro and in vivo and induced cell morphology changes in MDA-MB-231 cells consistent with reversal of the mesenchymal phenotype.ConclusionsThis study revealed that panobinostat is overtly toxic to TNBC cells in vitro and decreases tumorigenesis in vivo. Additionally, treatment up-regulated anti-proliferative, tumor suppressor, and epithelial marker genes in MDA-MB-231 cells and initiated a partial reversal of the epithelial-to-mesenchymal transition. Our results demonstrate a potential therapeutic role of panobinostat in targeting aggressive triple-negative breast cancer cell types.

Dataset Information

HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat.

Publications

HIV anti-latency treatment mediated by macromolecular prodrugs of histone deacetylase inhibitor, panobinostat.

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