Cabazitaxel-Induced Stabilization of Microtubules Enhances Radiosensitivity in Ovarian Cancer Cells

Abstract

Background: Up to 40% of women with ovarian cancer have short disease-free intervals due to molecular mechanisms of chemotherapy resistance. New therapeutic strategies are sought. Ovarian cancers are sensitive to radiochemotherapy. The taxane cabazitaxel (XRP6258, Jevtana) promotes tubulin assembly and stabilizes microtubules against depolymerization in cells, acting similarly in mechanism to paclitaxel. Here, sequences of cabazitaxel-radiation co-administration are tested for drug-alone cytotoxicity and optimal radiosensitization.Materials and Methods: SKOV3, OVCAR3, and TOV-112D ovarian cancer cells were administered cabazitaxel 24 h before (first), 18 h before (second), together (third), or 24 h after (fourth) a single radiation dose, and then, investigated by clonogenic assay and flow cytometric assays. Radiation dose-cell survival data were fitted by two-stage multivariate analyses of variance. High-content flow cytometry partitioned cabazitaxel effects into G2-phase versus M-phase events by DNA content, cyclin A2, and phospho-S10-histone H3 (PHH3). Paclitaxel served as a comparator.Findings: Cabazitaxel cytotoxicity and radiosensitization were dose dependent. Cabazitaxel added 24 h before radiation was the most lethal schedule. DNA content measurements by flow cytometry showed that cabazitaxel-treated cells accumulated in the radiosensitive G2/M 4C DNA complement compartment. Cytometry also showed that surviving cabazitaxel-induced cell cycle arrested cells resolve the arrest by entering 4C or by 8C DNA complement cell cycles.Interpretation: The radiosensitizing effect of cabazitaxel was schedule dependent, due to cell cycle redistribution, and best when cabazitaxel was given 24 h before radiation. Clinical trials of administering both cabazitaxel and radiation should be explored in women with chemoresistant ovarian cancer.

Cabazitaxel inhibits proliferation and potentiates the radiation response of U87MG glioblastoma cells

“…Therefore, the results showed that well‐tolerated doses of Cabazitaxel followed by radiation administration against U87MG cells will exert profound alteration of radiation response and bring about cell growth suppression. The result of the present study is in line with the study of Kunos et al (Kunos et al, ). These authors evaluated the radiosensitizing effect of Cabazitaxel in ovarian cancer cells.…”

<p>pH- and Ultrasound-Responsive Paclitaxel-Loaded Carboxymethyl Chitosan Nanodroplets for Combined Imaging and Synergistic Chemoradiotherapy</p>

“…30,31 PTX-mediated radiosensitization is caused mainly by the stabilization of microtubules as a result of enhanced tubulin polymerization that leads to an accumulation of cells in the G2/M phase of cell cycle, which are known to be radiosensitive. 32 Second, the NDs combined ultrasound irradiation can mechanically perturb cell membranes, dysregulate biochemical signaling pathways of cell apoptosis, and additionally initiate tumor cell injury and lysis directly. 33,34 Early studies have discovered that the interaction of ultrasound with tissue can induce mechanical effects, chemical effects and thermal effects.…”