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Repurposing of the Drug Tezosentan for Cancer Therapy.

ABSTRACT: Tezosentan is a vasodilator drug that was originally developed to treat pulmonary arterial hypertension. It acts by inhibiting endothelin (ET) receptors, which are overexpressed in many types of cancer cells. Endothelin-1 (ET1) is a substance produced by the body that causes blood vessels to narrow. Tezosentan has affinity for both ET_A and ET_B receptors. By blocking the effects of ET1, tezosentan can help to dilate blood vessels, improve the blood flow, and reduce the workload on the heart. Tezosentan has been found to have anticancer properties due to its ability to target the ET receptors, which are involved in promoting cellular processes such as proliferation, survival, neovascularization, immune cell response, and drug resistance. This review intends to demonstrate the potential of this drug in the field of oncology. Drug repurposing can be an excellent way to improve the known profiles of first-line drugs and to solve several resistance problems of these same antineoplastic drugs.

SUBMITTER: Ribeiro E

PROVIDER: S-EPMC10297528 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Repurposing of the Drug Tezosentan for Cancer Therapy.

Ribeiro Eduarda E Vale Nuno N

Current issues in molecular biology 20230611 6

Tezosentan is a vasodilator drug that was originally developed to treat pulmonary arterial hypertension. It acts by inhibiting endothelin (ET) receptors, which are overexpressed in many types of cancer cells. Endothelin-1 (ET1) is a substance produced by the body that causes blood vessels to narrow. Tezosentan has affinity for both ET<sub>A</sub> and ET<sub>B</sub> receptors. By blocking the effects of ET1, tezosentan can help to dilate blood vessels, improve the blood flow, and reduce the workl ...[more]

PMID: 37367074

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Project description:Cancer remains a major cause of morbidity and mortality worldwide, and while current therapies, such as chemotherapy, immunotherapy, and cell therapy, have been effective in many patients, the development of novel therapeutic options remains an urgent priority. Mouse double minute 2 (MDM2) is a key regulator of the tumor suppressor protein p53, which plays a critical role in regulating cellular growth, apoptosis, and DNA repair. Consequently, MDM2 has been the subject of extensive research aimed at developing novel cancer therapies. In this study, we employed a machine learning-based approach to establish a quantitative structure-activity relationship model capable of predicting the potential in vitro efficacy of small molecules as MDM2 inhibitors. Our model was used to screen 5883 FDA-approved drugs, resulting in the identification of promising hits that were subsequently evaluated using molecular docking and molecular dynamics simulations. Two antihistamine drugs, cetirizine (CZ) and rupatadine (RP), exhibited particularly favorable results in the initial in silico analyses. To further assess their potential use as the activators of the p53 pathway, we investigated the antiproliferative capability of the abovementioned drugs on human glioblastoma and neuroblastoma cell lines. Both the compounds exhibited significant antiproliferative effects on the abovementioned cell lines in a dose-dependent manner. The half-maximal inhibitory concentration (IC50) of CZ was found to be 697.87 and 941.37 μM on U87 and SH-SY5Y cell lines, respectively, while the IC50 of RP was found to be 524.28 and 617.07 μM on the same cell lines, respectively. Further investigation by quantitative reverse transcriptase polymerase chain reaction analysis revealed that the CZ-treated cell lines upregulate the expression of the p53-regulated genes involved in cell cycle arrest, apoptosis, and DNA damage response compared to their respective vehicle controls. These findings suggest that CZ activates the p53 pathway by inhibiting MDM2. Our results provide compelling preclinical evidence supporting the potential use of CZ as a modulator of the MDM2-p53 axis and its plausible repurposing for cancer treatment.

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Repurposing of the Drug Tezosentan for Cancer Therapy.

Publications

Repurposing of the Drug Tezosentan for Cancer Therapy.

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