Selective targeting of breast cancer cells through ROS-mediated mechanisms potentiates the lethality of paclitaxel by a novel diterpene, gelomulide K |
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Authors: | Yang Juan-Cheng Lu Mei-Chin Lee Chia-Lin Chen Guan-Yu Lin Yan-Yu Chang Fang-Rong Wu Yang-Chang |
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Affiliation: | a Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwanb Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 944, Taiwanc Taiwan National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwand Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwane Natural Medicinal Products Research Center, China Medical University Hospital, Taichung 404, Taiwanf Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwang Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan |
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Abstract: | Defects in apoptotic pathways confer resistance to tubulin-binding agents via downregulation of caspases or overexpression of antiapoptotic factors, urging the need for novel agents acting on an alternative pathway. The purpose of this study was to investigate whether induction of ROS can induce caspase-independent cell death in breast cancer cells and thereby enhance the activity of paclitaxel. Here, we report that gelomulide K acts as a caspase-independent cell death-inducing agent that synergizes with paclitaxel in breast cancer cells and has low toxicity in normal cells. Treatment with gelomulide K induced PARP-1 hyperactivation, AIF nuclear translocation, and cytoprotective autophagy. These effects were associated with increased ROS production and a decrease in cellular GSH levels in cancer cells. Furthermore, pretreatment with NAC, a precursor of intracellular GSH, effectively abrogated gelomulide K-induced caspase-independent cell death and autophagy, suggesting that ROS-mediated downstream signaling is essential to the anticancer effects of gelomulide K. Additionally, in a xenograft model, gelomulide K induced PARP-1 activation and reduced tumor growth. In terms of structure-activity relationships, analysis not only showed a correlation between ROS levels and drug activity but also highlighted the importance of the 8,14-epoxy group. Taken together, our results show that enhancement of paclitaxel activity can be achieved with gelomulide K and that the structurally relevant pharmacophore provides important insight into the development of new caspase-independent cell death-inducing agents. |
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Keywords: | ROS, reactive oxygen species PEG-SOD, polyethylene glycol-superoxide dismutase PEG-CAT, polyethylene glycol-catalase NAC, N-acetyl- smallcaps" >l-cysteine hGST, human glutathione S-transferase tSBO, trans-stilbene oxide AIF, apoptosis-inducing factor PARP-1, poly(ADP-ribose) polymerase-1 MDC, monodansylcadaverine AVO, acidic vacuoles MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide ANI, 4-amino-1,8-naphthalimide 3-AB, 3-aminobenzamide |
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