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A Computational Framework to Characterize the Cancer Drug Induced Effect on Aging Using Transcriptomic Data

ABSTRACT: Cancer treatments such as chemotherapies may change or accelerate aging trajectories in cancer patients. Emerging evidence has shown that “omics” data can be used to study molecular changes of the aging process. Here, we integrated the drug-induced and normal aging transcriptomic data to computationally characterize the potential cancer drug-induced aging process in patients. Our analyses demonstrated that the aging-associated gene expression in the GTEx dataset can recapitulate the well-established aging hallmarks. We next characterized the drug-induced transcriptomic changes of 28 FDA approved cancer drugs in brain, kidney, muscle, and adipose tissues. Further drug-aging interaction analysis identified 34 potential drug regulated aging events. Those events include aging accelerating effects of vandetanib (Caprelsa®) and dasatinib (Sprycel®) in brain and muscle, respectively. Our result also demonstrated aging protective effect of vorinostat (Zolinza®), everolimus (Afinitor®), and bosutinib (Bosulif®) in brain.

SUBMITTER: Zhao Y

PROVIDER: S-EPMC9277350 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Paracoccidioidomycosis (PCM) is the most prevalent endemic mycosis in Latin America. The disease is caused by fungi of the genus Paracoccidioides and mainly affects low-income rural workers after inhalation of fungal conidia suspended in the air. The current arsenal of chemotherapeutic agents requires long-term administration protocols. In addition, chemotherapy is related to a significantly increased frequency of disease relapse, high toxicity, and incomplete elimination of the fungus. Due to the limitations of current anti-PCM drugs, we developed a computational drug repurposing-chemogenomics approach to identify approved drugs or drug candidates in clinical trials with anti-PCM activity. In contrast to the one-drug-one-target paradigm, our chemogenomics approach attempts to predict interactions between drugs, and Paracoccidioides protein targets. To achieve this goal, we designed a workflow with the following steps: (a) compilation and preparation of Paracoccidioides spp. genome data; (b) identification of orthologous proteins among the isolates; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Paracoccidioides essential targets using validated genes from Saccharomyces cerevisiae; (e) homology modeling and molecular docking studies; and (f) experimental validation of selected candidates. We prioritized 14 compounds. Two antineoplastic drug candidates (vistusertib and BGT-226) predicted to be inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at low micromolar concentrations (<10 μM). Four antifungal azole drugs (bifonazole, luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low nanomolar concentrations, validating our methodology. The results suggest our strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend hit-to-lead optimization studies to improve potency and selectivity, as well as pharmaceutical formulations to improve oral bioavailability of the antifungal azoles identified.

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A Computational Framework to Characterize the Cancer Drug Induced Effect on Aging Using Transcriptomic Data

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