Synergistic Antiproliferative Effects of All-Trans Retinoic Acid and Paclitaxel on Autosomal Dominant Polycystic Kidney Disease Epithelial Cells

Nguyen, Que Thanh Thanh; Hoang, Thi Xoan; Ryu, Hyunjin; Oh, Kook Hwan; Kim, Jae Young

doi:10.1155/2021/1242916

Cited by 6 publications

(5 citation statements)

References 46 publications

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“…Additionally, paclitaxel has been studied as a potential repurposing candidate for ADPKD given its ability to arrest the cell cycle, and we identified multiple targets of paclitaxel upregulated in both cystic data sets ( KIF1A and TUBB , Fig. 4 D) (Nguyen et al 2021 ).…”

Section: Discussionmentioning

confidence: 95%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Wilk

Howton

Fisher

et al. 2023

Mol Med

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Background Autosomal dominant polycystic kidney disease (ADPKD) is one of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. Methods As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available Pkd2 kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates’ target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. Results With this in-silico approach, we prioritized 29 unique drug targets differentially expressed in Pkd2 ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine, which can be further tested in-vitro and in-vivo. Conclusion Collectively, these results indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD. Graphical Abstract

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Section: Discussionmentioning

confidence: 95%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Wilk

Howton

Fisher

et al. 2023

Mol Med

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“…(84) Additionally, paclitaxel has been studied as a potential repurposing candidate for ADPKD given its ability to arrest the cell cycle, and we identified multiple targets of paclitaxel upregulated in both cystic data sets ( KIF1A and TUBB , Figure 5D). (85)…”

Section: Discussionmentioning

confidence: 99%

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mousePkd2model gene expression reversion

Wilk

Howton

Fisher

et al. 2022

Preprint

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Autosomal dominant polycystic kidney disease (ADPKD) isone of the most prevalent monogenic human diseases. It is mostly caused by pathogenic variants in PKD1 or PKD2 genes that encode interacting transmembrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). Among many pathogenic processes described in ADPKD, those associated with cAMP signaling, inflammation, and metabolic reprogramming appear to regulate the disease manifestations. Tolvaptan, a vasopressin receptor-2 antagonist that regulates cAMP pathway, is the only FDA-approved ADPKD therapeutic. Tolvaptan reduces renal cyst growth and kidney function loss, but it is not tolerated by many patients and is associated with idiosyncratic liver toxicity. Therefore, additional therapeutic options for ADPKD treatment are needed. As drug repurposing of FDA-approved drug candidates can significantly decrease the time and cost associated with traditional drug discovery, we used the computational approach signature reversion to detect inversely related drug response gene expression signatures from the Library of Integrated Network-Based Cellular Signatures (LINCS) database and identified compounds predicted to reverse disease-associated transcriptomic signatures in three publicly available kidney transcriptomic data sets of mouse ADPKD models. We focused on a pre-cystic model for signature reversion, as it was less impacted by confounding secondary disease mechanisms in ADPKD, and then compared the resulting candidates' target differential expression in the two cystic mouse models. We further prioritized these drug candidates based on their known mechanism of action, FDA status, targets, and by functional enrichment analysis. With this approach, we prioritized 29 unique drug targets differentially expressed in ADPKD cystic models and 16 prioritized drug repurposing candidates that target them, including bromocriptine and mirtazapine. Collectively, these indicate drug targets and repurposing candidates that may effectively treat pre-cystic as well as cystic ADPKD.

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“…Su indicación debe acompañarse del conjunto de medidas no específicas dirigidas a enlentecer la progresión de la ERC (20) . Junto con la búsqueda de estrategias para minimizar los efectos adversos del tratamiento con tolvaptán (21) , un conjunto de nuevos fármacos se encuentran en desarrollo y evaluación con el fin de constituirse en tratamientos específicos dirigidos a enlentecer la progresión de la ERC en pacientes con PQRAD (22)(23)(24)(25)(26)(27) .…”

Section: Conclusiones Y Perspectivasunclassified

Poliquistosis renal autosómica dominante: ¿quiénes se benefician del tratamiento con tolvaptán? Estado del arte

2022

RMU

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Synergistic Antiproliferative Effects of All-Trans Retinoic Acid and Paclitaxel on Autosomal Dominant Polycystic Kidney Disease Epithelial Cells

Cited by 6 publications

References 46 publications

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mouse Pkd2 model gene expression reversion

Prioritized polycystic kidney disease drug targets and repurposing candidates from pre-cystic and cystic mousePkd2model gene expression reversion

Poliquistosis renal autosómica dominante: ¿quiénes se benefician del tratamiento con tolvaptán? Estado del arte

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