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Small-Molecule Therapeutic Perspectives for the Treatment of Progeria.

ABSTRACT: Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in the nuclear lamina. This accumulation elicits several alterations at the nuclear, cellular, and tissue levels that are phenotypically reflected in a systemic disorder with important alterations, mainly in the cardiovascular system, bones, skin, and overall growth, which results in premature death at an average age of 14.5 years. In 2020, lonafarnib became the first (and only) FDA approved drug for treating progeria. In this context, the present review focuses on the different therapeutic strategies currently under development, with special attention to the new small molecules described in recent years, which may represent the upcoming first-in-class drugs with new mechanisms of action endowed with effectiveness not only to treat but also to cure progeria.

SUBMITTER: Macicior J

PROVIDER: S-EPMC8267806 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Small-Molecule Therapeutic Perspectives for the Treatment of Progeria.

Macicior Jon J Marcos-Ramiro Beatriz B Ortega-Gutiérrez Silvia S

International journal of molecular sciences 20210703 13

Hutchinson-Gilford progeria syndrome (HGPS), or progeria, is an extremely rare disorder that belongs to the class of laminopathies, diseases characterized by alterations in the genes that encode for the lamin proteins or for their associated interacting proteins. In particular, progeria is caused by a point mutation in the gene that codifies for the lamin A gene. This mutation ultimately leads to the biosynthesis of a mutated version of lamin A called progerin, which accumulates abnormally in th ...[more]

PMID: 34281245

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Project description:Despite the therapeutic advancement with chemotherapy and targeted therapy against non-small-cell lung cancer (NSCLC), most patients ultimately develop resistance to these drugs, exhibiting disease progression, metastasis, and worse prognosis. There is, therefore, a need for the development of novel multi-targeted therapies that can offer a high therapeutic index with lesser chances of drug resistance against NSCLC. In the present study, we evaluated the therapeutic potential of a novel multi-target small molecule NLOC-015A for targeted treatment of NSCLC. Our in vitro studies revealed that NLOC-015A exhibited a broad spectrum of anticancer activities against lung cancer cell line. NLOC-015A decreased the viability of H1975 and H1299 cells with respective IC50 values of 2.07±0.19 and 1.90±0.23 µm. In addition, NLOC-015A attenuated the oncogenic properties (colony formation, migratory ability, and spheroid formation) with concomitant downregulation of expression levels of epidermal growth factor receptor (EGFR)/mammalian target of rapamycin (mTOR)/AKT, nuclear factor (NF)-κB, signaling network. In addition, the stemness inhibitory effect of NLOC0-15A was accompanied by decreased expression levels of aldehyde dehydrogenase (ALDH), MYC Proto-Oncogene (C-Myc), and (sex-determining region Y)-box 2 (SOX2) in both H1975 and H1299 cell lines. Furthermore, NLOC-015A suppressed the tumor burden and increased the body weight and survival of H1975 xenograft-bearing mice. Treatment with NLOC-015A also attenuated biochemical and hematological alterations in the tumor bearing mice. Interestingly, NLOC-015A synergistically enhanced the in vitro efficacy, and therapeutic outcome of osimertinib in vivo. In addition, the toxicity of osimertinib was significantly attenuated by combination with NLOC-015A. Altogether, our findings suggested that combining osimertinib with NLOC-015 appears to be a promising way to improve osimertinib's efficacy and achieve better therapeutic results against NSCLC. We therefore suggest that NLOC-015A might represent a new candidate for treating NSCLC via acting as a multitarget inhibitor of EGFR/mTOR/NF-Κb signaling networks and efficiently compromising the oncogenic phenotype of NSCLC.

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Small-Molecule Therapeutic Perspectives for the Treatment of Progeria.

Publications

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria.

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