Involvement of Mitochondrial Permeability Transition Pore Opening in 7-Xylosyl-10-Deacetylpaclitaxel-Induced Apoptosis

Abstract

7-Xylosyl-10-deacetylpaclitaxel is a natural hydrophilic paclitaxel derivative. It has long been used in Chinese clinics to treat cancer. In order to further explore the underlying intracellular target of 7-xylosyl-10-deacetylpaclitaxel towards the PC-3 cell line, the ultra-structural morphology of mitochondria, the intracellular Ca²⁺, the intracellular ATP, the intracellular hydrogen peroxide and pro-apoptotic Bax and Bcl-2 protein expression were measured. Additionally, the changes of mitochondrial morphology and membrane potential (ΔΨm) were analyzed by atomic force microscopy (AFM) and flow cytometry, respectively. Our results suggest that the intracellular target of 7-xylosyl-10-deacetylpaclitaxel may be the mitochondrial permeability transition pore (mPTP). To further evaluate this hypothesis, we assessed the effect of a specific mPTP inhibitor (cyclosporine A) on the toxic action of 7-xylosyl-10-deacetylpaclitaxel. The 7-xylosyl-10-deacetylpaclitaxel-induced decrease in mitochondrial inner transmembrane potential (ΔΨm) was abolished by the addition of cyclosporine A (CsA) in PC-3 cells, indicating that 7-xylosyl-10-deacetylpaclitaxel may target mPTP. Furthermore, treatment with 7-xylosyl-10-deacetylpaclitaxel increased ROS levels in PC-3 cells. This effect was counteracted by 10 µM cyclosporine A. These data indicate that oxidative damage is involved in mPTP.

Key words

7‐xylosyl‐10deacetylpaclitaxel - mitochondrial permeability transition pores - apoptosis - ROS

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