Meichen Wang1,2, Changwei Wang3,4, Chao Feng1, Wanrong Guo4, Huan Chen5, Bing Liu5, Enxiao Li2, Wei Liu6, Adam Taouil7, Iwao Ojima8,9, Peng Hou10. 1. Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China. 2. Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. 3. Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, 11794-3400, USA. 4. Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 510530, Guangzhou, China. 5. BioBank, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China. 6. Ultrasound Diagnosis Center, Shaanxi Provincial People's Hospital, 710068, Xi'an, China. 7. Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400, USA. 8. Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, 11794-3400, USA. iwao.ojima@stonybrook.edu. 9. Department of Chemistry, Stony Brook University, Stony Brook, NY, 11794-3400, USA. iwao.ojima@stonybrook.edu. 10. Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, China. phou@xjtu.edu.cn.
Abstract
PURPOSE: Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancers and it is rapidly fatal without any effective therapeutic regimens. There are some clinical trials showing that paclitaxel-based chemotherapy for ATC can achieve a relatively high response rate and low incidence of adverse reaction. The aim of this study was to evaluate potential therapeutic activity of novel taxoids in ATC cells. METHODS: We evaluated antitumor activity of five novel 3'-difluorovinyltaxoids (DFV-taxoids) in anaplastic thyroid cancer cells by a series of in vitro and in vivo experiments. Besides, we also explored the potential mechanism underlying the difference among the taxoids and paclitaxel by molecular docking and tubulin polymerization assays. RESULTS: Our data showed that these novel DFV-taxoids were more effective than paclitaxel in ATC cell lines and xenografts, as reflected by the inhibition of cell proliferation, colony formation and tumorigenic potential in nude mice, and the induction of G2/M phase arrest and cell apoptosis. Using tubulin polymerization assays and molecular docking analysis, we found that these DFV-taxoids promoted more rapid polymerization of β-tubulin than paclitaxel. CONCLUSIONS: Our data demonstrate that these novel taxoids exhibit stronger antitumor activity in ATC cells than paclitaxel, thereby providing a promising therapeutic strategy for the patients with ATC.
PURPOSE: Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancers and it is rapidly fatal without any effective therapeutic regimens. There are some clinical trials showing that paclitaxel-based chemotherapy for ATC can achieve a relatively high response rate and low incidence of adverse reaction. The aim of this study was to evaluate potential therapeutic activity of novel taxoids in ATC cells. METHODS: We evaluated antitumor activity of five novel 3'-difluorovinyltaxoids (DFV-taxoids) in anaplastic thyroid cancer cells by a series of in vitro and in vivo experiments. Besides, we also explored the potential mechanism underlying the difference among the taxoids and paclitaxel by molecular docking and tubulin polymerization assays. RESULTS: Our data showed that these novel DFV-taxoids were more effective than paclitaxel in ATC cell lines and xenografts, as reflected by the inhibition of cell proliferation, colony formation and tumorigenic potential in nude mice, and the induction of G2/M phase arrest and cell apoptosis. Using tubulin polymerization assays and molecular docking analysis, we found that these DFV-taxoids promoted more rapid polymerization of β-tubulin than paclitaxel. CONCLUSIONS: Our data demonstrate that these novel taxoids exhibit stronger antitumor activity in ATC cells than paclitaxel, thereby providing a promising therapeutic strategy for the patients with ATC.
Authors: M I Nicoletti; T Colombo; C Rossi; C Monardo; S Stura; M Zucchetti; A Riva; P Morazzoni; M B Donati; E Bombardelli; M D'Incalci; R Giavazzi Journal: Cancer Res Date: 2000-02-15 Impact factor: 12.701
Authors: I Ojima; J C Slater; S D Kuduk; C S Takeuchi; R H Gimi; C M Sun; Y H Park; P Pera; J M Veith; R J Bernacki Journal: J Med Chem Date: 1997-01-31 Impact factor: 7.446
Authors: I Ojima; J C Slater; E Michaud; S D Kuduk; P Y Bounaud; P Vrignaud; M C Bissery; J M Veith; P Pera; R J Bernacki Journal: J Med Chem Date: 1996-09-27 Impact factor: 7.446
Authors: Iwao Ojima; Jin Chen; Liang Sun; Christopher P Borella; Tao Wang; Michael L Miller; Songnian Lin; Xudong Geng; Larisa Kuznetsova; Chuanxing Qu; David Gallager; Xianrui Zhao; Ilaria Zanardi; Shujun Xia; Susan B Horwitz; Jon Mallen-St Clair; Jennifer L Guerriero; Dafna Bar-Sagi; Jean M Veith; Paula Pera; Ralph J Bernacki Journal: J Med Chem Date: 2008-05-09 Impact factor: 7.446