Cabazitaxel antiproliferative mechanism of action in U87MG human glioblastoma cells: a promising cell-cycle phase-specific radiosensitizer

Abstract

<strong>Introduction</strong>: One mechanism of cell cycle manipulation and mitotic catastrophe is arrest at G2/M phase of cell cycle. Cabazitaxel, a mitotic inhibitor agent, is a second-generation semisynthetic taxane. An expected anti-neoplastic effect of Cabazitaxel is cell cycle perturbation and alteration of microtubule dynamics. In contrast to other taxane compounds, Cabazitaxel is a poor substrate for P-gp efflux transporters, hence, penetrates easily across the blood brain barrier (BBB). In the present study, we investigate its distinct antiproliferative mechanism of action and radiosensitizing potential against U87MG glioblastoma cells. <strong>Materials and Methods:</strong> In order to evaluate the effect of Cabazitaxel, cells were treated with different concentrations of the drug at different time points and then cytotoxicity and cell cycle were assessed using MTT and flow cytometry assays, respectively. Comparison of induced apoptosis and necrosis in population of cells was depicted by Annexin/PI assay. In order to investigate the expression of genes involved in apoptosis real-time polymerase chain reaction (PCR) method was used. <strong>Results:</strong> A consistent G2/M arrest was exerted by Cabazitaxel. The drug resulted in a concentration- and time-dependent toxicity and a shap decline in cell viabiliity. EC50 and IC50 in cells treated with Cabazitaxel for 24 hours exactly approved each other. The cytotoxicity response of U87MG cells increased following Cabazitaxel-IR administration. On the other hand, IC50 of Cabazitaxel-IR in comparison with 24 or 48 hours treated cells showed a significant decrease. Concurrently, these observations were further supported by up regulation of pro- apoptotic genes and down regulation of anti-apoptotic genes. <strong>Conclusion:</strong> To our Knowledge, no straightforward explanation thus far has addressed the effect of Cabazitaxel applied before radiation on U87MG cells. This report provides the first preclinical evidence supporting that Cabazitaxel can render cells more susceptible to the cytotoxicity of radiation and potentiates the effect of RT. In the near future, Cabazitaxel could potentially be administered in combination modalities as a potential therapeutic compound and also promising cell cycle-specific radiosensitizer to stall tumor growth.