1. Academic Validation
  2. Utidelone inhibits growth of colorectal cancer cells through ROS/JNK signaling pathway

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

  • Cell Death Dis. 2021 Apr 1;12(4):338. doi: 10.1038/s41419-021-03619-6.
Fuli Li  # 1 Tinglei Huang  # 1 Yao Tang 1 Qingli Li 1 Jianzheng Wang 2 Xiaojiao Cheng 1 Wenhui Zhang 3 Baiwen Zhang 1 Cong Zhou 1 Shuiping Tu 4
Affiliations

Affiliations

  • 1 State Key Laboratory of Oncogenes and related Genes, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 2 Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, NO.127, Dongming Road, Zhengzhou, 450008, China.
  • 3 Shanghai Institute of Precision Medicine, Shanghai, 200125, China.
  • 4 State Key Laboratory of Oncogenes and related Genes, Department of Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. tushuiping@yahoo.com.
  • # Contributed equally.
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.

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