BP-M345, a New Diarylpentanoid with Promising Antimitotic Activity.

Pedro Novais,Joana Moreira,Patrícia M A Silva,Honorina Cidade,Isabel Amorim,Hassan Bousbaa,Madalena Pinto,Andreia Palmeira

doi:10.3390/molecules26237139

Abstract

Previously, we reported the in vitro growth inhibitory effect of diarylpentanoid BP-M345 on human cancer cells. Nevertheless, at that time, the cellular mechanism through which BP-M345 exerts its growth inhibitory effect remained to be explored. In the present work, we report its mechanism of action on cancer cells. The compound exhibits a potent tumor growth inhibitory activity with high selectivity index. Mechanistically, it induces perturbation of the spindles through microtubule instability. As a consequence, treated cells exhibit irreversible defects in chromosome congression during mitosis, which induce a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by massive apoptosis, as revealed by live cell imaging. Collectively, the results indicate that the diarylpentanoid BP-M345 exerts its antiproliferative activity by inhibiting mitosis through microtubule perturbation and causing cancer cell death, thereby highlighting its potential as antitumor agent.

Highlights

Microtubule-targeting agents (MTAs) remain one of the best characterized therapeutic drugs for the treatment of a wide range of tumor types, including ovarian, lung, breast, head, and neck [1]
In order to evaluate the potential of BP-M345 to inhibit tumor cell growth, a Sulforhodamine B (SRB) assay was performed to determine the concentration of a compound that induces 50% cell growth inhibition (GI50 ) in three human cancer cell lines from melanoma (A375-C5), breast adenocarcinoma (MCF-7), and non-small cell lung cancer (NCI-H460)
We investigated whether BP-M345 was promoting the activation of the spindle assembly checkpoint (SAC) to sustain the observed mitotic arrest

Summary

Introduction

Microtubule-targeting agents (MTAs) remain one of the best characterized therapeutic drugs for the treatment of a wide range of tumor types, including ovarian, lung, breast, head, and neck [1]. MTAs are typically divided into two groups based on their action mechanism: microtubule destabilizers and stabilizers [2,3]. Microtubule destabilizers consist of vinca alkaloids, such as vinblastine and vincristine, that bind to β-tubulin subunits, inducing microtubule depolymerization. Microtubule stabilizers include epothilones and taxanes, such as paclitaxel and docetaxel, and bind to β-tubulin subunits, resulting in the stabilization of microtubules and increased polymerization [3,4]. By perturbing the mitotic spindle, MTAs activate the spindle assembly checkpoint (SAC), which delays cancer cells in mitosis. The SAC is a highly sensitive mechanism (SAC), which delays cancer cells in mitosis. The SAC is a highly sensitive mechanism that controls chromosome attachment at kinetochores to spindle microtubules [5]. In the that controls chromosome attachment atkinetochores, kinetochoresthe to spindle microtubules [5].

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