Biological evaluation of new diarylpentanoid analogues for antitumor activity

Abstract

Background: Cancer is associated with high mortality rates and its incidence worldwide is increasing significantly [1]. Several therapeutic strategies have been used in cancer therapy such as microtu-bule-targeting agents [2]. However, these drugs are highly toxic and are associated with high tumor resistance, making their long-term use unfeasible [3,4]. Therefore, new small molecules that can overcome the disadvantages associated with the drugs currently in use in the clinic are needed. We previously reported the in vitro growth inhibitory effect of the diarylpentanoid BP-M345 on human cancer cells, as well as its cellular mechanism of action [5]. Here, BP-M345 analogues have been syn-thetized in a goal to improve the antimitotic/antitumor efficacy of the original BP-M345. Objective: The present study aimed to characterize BP-M345 analogues regarding their cytotoxic activity and mechanism of action, focusing on their potential as antimitotic agent. Methods: A sulforhodamine B assay was used to determine the GI₅₀ of BP-M345 analogues in different cancer cell lines. To evaluate the antimitotic activity, the mitotic index was determined. In addition, lung cancer cells were exposed to compounds, A sulforhodamine B assay was used to determine the GI₅₀ of BP-M345 analogues in different cancer cell lines. To evaluate the antimitotic activity, the mitotic index was determined. In addition, lung cancer cells were exposed to compounds, for twenty-four or forty- eight hours, and the consequence on spindle morphology, cellular proliferation and cell death were evaluated using the following assays: immunofluorescence, colony-formation assay, and flow cytometry, respectively. Time-lapse microscopy imaging was also performed to follow in real time the cell fate of the compound-treated cells. Results: BP-M345 analogues showed potent growth inhibition activity on cancer cells and exhibited a potent antimitotic activity. Mechanistically, BP-M345 analogues induced perturbation of the mitotic spindles through microtubule instability. Consequently, treated cells exhibit defects in chromosome congression during mitosis, which induced a prolonged spindle assembly checkpoint-dependent mitotic arrest, followed by apoptosis. Conclusions: BP-M345 analogues have been shown to be highly potent antimitotic agents, more effective than the original BP-M345 leading to massive cancer cell death.