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Caractérisation d'un nouveau composé pharmacologique qui potentialise la réponse des cellules au paclitaxel (Taxol®)

Abstract : Microtubules (MTs) targeting agents are a powerful weapon in the war against aggressive cancers. Paclitaxel (PTX) has been used successfully for the treatment of solid tumors for decades. Several features, including side-effects and resistance of some cancers make this drug not always effective. With the aim to identify new chemical compounds that sensitize cells to paclitaxel we screened a library of 8,000 compounds, to select those not toxic for cell cultures when applied alone, that become toxic when applied in combination with a non-toxic dose of paclitaxel. This lead to the selection of a carbazole derivative: carba1. In cells, the carba1/PTX combination has a greater cytotoxic effect than the addition of the effects of each drug assayed separately, indicating a synergistic effect. In addition, in-depth phenotypic analyzes indicate that the administration of carba1 amplify the effects of PTX.High doses of carba1 induce a cell blockade in prometaphase, but do not alter the MT network in interphase or mitosis. In contrast, in vitro, carba1 targets the tubulin colchicine binding site, causing a delay and a decrease in MT polymerization. Genetic studies conducted on yeast indicated other potential additional targets including CENP-E, an essential kinesin for chromosome alignment during mitosis.Studies conducted on a preclinical mouse model of aggressive breast cancer (orthotopic grafts) revealed that carba1 alone and carba1/PTX showed no toxicity. In addition, the anti-tumor and anti-metastatic effects of the carba1/PTX combination on these models have been encouraging, but an optimization of the posology is still needed. Carba1 is a new molecule, with previously unknown applications. This is why a declaration of invention, with a view to filing a patent, has been submitted to the CNRS.
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Submitted on : Tuesday, May 26, 2020 - 11:14:51 PM
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Lauralie Peronne. Caractérisation d'un nouveau composé pharmacologique qui potentialise la réponse des cellules au paclitaxel (Taxol®). Biologie du développement. Université Grenoble Alpes, 2019. Français. ⟨NNT : 2019GREAV003⟩. ⟨tel-02628502⟩

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