Potent antitumor activity of novel taxoids in anaplastic thyroid cancer.

Wanrong Guo,Huan Chen,Bing Liu,Wei Liu,Chao Feng,Peng Hou,Iwao Ojima,Adam Taouil,Meichen Wang,Changwei Wang,Enxiao Li

doi:10.1007/s12020-021-02880-1

Abstract

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. 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. 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. 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.

Highlights

From 2000 to 2011, the incidence rate of thyroid cancers has risen the fastest, and it is the fourth most common cancer in China based on the latest statistics [1]
The results showed that these taxoids and paclitaxel significantly inhibited the proliferation of Anaplastic thyroid cancer (ATC) cells in a dose-dependent manner, and the taxoids were more effective than paclitaxel with a 2-9-fold increase in sensitivity (Fig. 1b)
The results showed that these taxoids exhibited more potent inhibitory effect on colony formation of ATC cells than paclitaxel (Fig. 3)

Summary

Introduction

From 2000 to 2011, the incidence rate of thyroid cancers has risen the fastest, and it is the fourth most common cancer in China based on the latest statistics [1]. Anaplastic thyroid cancer (ATC) accounts for 1–2 % of all thyroid cancers Rare, it is a major cause of death in thyroid cancer patients due to its aggressive behavior and resistance to treatment [2]. Paclitaxel promotes tubulin polymerization, causing cell cycle arrest and apoptotic death by disrupting normal microtubule dynamics required for cell division and vital interphase processes [4]. Despite their potent antitumor activity, paclitaxel can cause undesirable side effects and drug resistance [5]. It was apparent in the early 1990s that it would be essential to develop new taxoids with fewer side effects, enhanced activity, improved solubility and superior pharmacological properties [6]

Objectives

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Results

Conclusion