Abstract
This paper was to explore bullatacin-mediated multidrug-resistant cell apoptosis at extremely low concentration. To investigate its precise mechanisms, the pathway of cell apoptosis induced by bullatacin was examined. Bullatacin causes an upregulation of ROS and a downregulation of ΔΨm in a concentration-dependent manner in ABCB1-overexpressing KBv200 cells. In addition, cleavers of caspase-9, caspase-3, and PARP were observed following the release of cytochrome c from mitochondria after bullatacin treatment. However, neither cleavage of caspase-8 nor change of expression level of bcl-2, bax and Fas was observed by the same treatment. Pretreating KBv200 cells with N-acetylcysteine, an antioxidant modulator, resulted in a significant reduction of ROS generation and cell apoptosis induced by bullatacin. Bullatacin-induced apoptosis was antagonized by z-LEHD-fmk, a caspase-9 inhibitor, but not by z-IETD-fmk, a caspase-8 inhibitor. These implied that apoptosis of KBv200 cells induced by bullatacin was associated with the mitochondria-dependent pathway that was limited to activation of apical caspase-9.
Highlights
Multidrug resistance (MDR) is recognized as one of the most common causes of failure in cancer chemotherapy.The MDR phenotype renders cross-resistance to structurally and functionally unrelated antitumor agents
Cell apoptosis? Which pathway of cell apoptosis induced by bullatacin will be involved in? Further research on the functioning of mitochondria will hopefully lead to a better assessment for the applicability of bullatacin
To determine the resistant property of KBv200 cells, cytotoxicity of anticancer drugs for KBv200 was compared with their parental drug-sensitive KB cells
Summary
Multidrug resistance (MDR) is recognized as one of the most common causes of failure in cancer chemotherapy. The MDR phenotype renders cross-resistance to structurally and functionally unrelated antitumor agents. This phenomenon often causes overexpression of MDR1 gene that encodes a 170-KD transmembrane glycoprotein named as Pglycoprotein (P-gp, ABCB1) [1]. It has been postulated that MDR cells were sensitive to apoptosis induced by a mitochondria-dependent pathway. Bullatacin exhibits potent bioactivities via inhibiting the complex I of mitochondria and the NADH oxidase of plasma membrane in tumor cells and depletion of ATP levels [5]. (d) The apoptotic rates of KB and KBv200 cells was examined with Annexin V/PI after treated with bullatacin for 48 hours. (e) ROS levels detection in KBv200 cells after treatment with bullatacin for 12 hours. Could bullatacin induce MDR cell apoptosis? Which pathway of cell apoptosis induced by bullatacin will be involved in? Further research on the functioning of mitochondria will hopefully lead to a better assessment for the applicability of bullatacin
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