Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway

Fuli Li,Fuli Li,Fuli Li,Cong Zhou,Cong Zhou,Cong Zhou,Qingli Li,Qingli Li,Qingli Li,Xiaojiao Cheng,Shuiping Tu,Shuiping Tu,Shuiping Tu,Yao Tang,Yao Tang,Yao Tang,Jianzheng Wang,Tinglei Huang,Tinglei Huang,Tinglei Huang,Baiwen Zhang,Baiwen Zhang,Baiwen Zhang,Wenhui Zhang

doi:10.1038/s41419-021-03619-6

Abstract

Utidelone (UTD1), a novel microtubule stabilizing agent, is an epothilone B analogue which was produced by genetic engineering. UTD1 has exhibited broad antitumor activity in multiple solid tumors. However, its activity and mechanism in colorectal cancer (CRC) remain to be studied. In this study, UTD1 dramatically inhibited CRC cell proliferation (with 0.38 µg/ml, 0.77 µg/ml IC50 in RKO and HCT116, respectively) in vitro. Immunofluorescence staining showed that UTD1 induced the formation of microtubule bundling and asters in RKO cells. Flow cytometry analysis demonstrated that UTD1 induced cell cycle to arrest in G2/M phase, subsequent apoptosis. Significantly, UTD1 exhibited stronger effect on inducing apoptosis than paclitaxel and 5-FU, especially in HCT15 cells which is ABCB1 high-expression. UTD1 exposure cleaved caspase-3 and poly ADP-ribose polymerase (PARP), decreased mitochondrial membrane potential, released cytochrome c, increased the production of active oxygen and activated c-Jun N-terminal kinase (JNK), suggesting ROS/JNK pathway was involved in this process. Moreover, UTD1 inhibited tumor growth and was more effective and safer compared with paclitaxel and 5-FU in RKO xenograft in nude mice. Taken together, our findings first indicate that UDT1 inhibits tumor growth in CRC xenograft model and may be a promising agent for CRC treatment.

Highlights

Colorectal cancer (CRC) is one of the most common tumors in the world
Epothilones are with high water solubility and more tolerable toxicity, and are proved to have fewer side effects compared with paclitaxel. These findings suggest that UTD1 might have antitumor activity for CRC
To determine the consequence of UTD1-induced cellcycle arrest, we evaluated annexin V-FITC/propidium iodide (PI) staining of treated cells. 48 h later, percentage of apoptosis was approximately 85% in RKO cells (Fig. 3A, C left)

Summary

Introduction

Colorectal cancer (CRC) is one of the most common tumors in the world. Treatments for CRC include chemotherapies, endoscopic and surgical excision, targeted therapies, local ablative therapies, and immunotherapies[3,4,5,6]. There are multiple treatments, CRC still is the leading cause of cancer-related deaths[7,8]. Chemotherapies occupy an important role in advanced colorectal cancer, but Antimitotic drugs, called microtubule targeted drugs, are classified as microtubule-stabilizing or microtubule-destabilizing agents according to their influence on microtubule dynamics. Vincristine, colchicine, and maytansine belong to microtubule-destabilizing agents[9,10,11,12]. Epothilones, which involve epothilone A, B, C, D, E, and F, have anticancer activities similar to paclitaxel, and competed with paclitaxel for binding sites on microtubules[15]

Methods

Results

Conclusion