2. Academic Validation
  3. Laxiflorin B covalently binds the tubulin colchicine-binding site to inhibit triple negative breast cancer proliferation and induce apoptosis

Laxiflorin B covalently binds the tubulin colchicine-binding site to inhibit triple negative breast cancer proliferation and induce apoptosis

  • Chem Biol Interact. 2023 Sep 25:383:110681. doi: 10.1016/j.cbi.2023.110681.
Heng Yang 1,  Tiantian Zhang 1,  Chunlan Chen 1,  Chengyao Chiang 2,  Kai Chen 3,  Yan Wu 1,  Zhengxin Liu 1,  Yajun Zhou 1,  Lizhi Zhu 4,  Duo Zheng 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, School of Basic Medical Sciences; School of Pharmacy; Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine); Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China.
  • 2 Southern University of Science and Technology, Yantian Hospital, Shenzhen, China.
  • 3 School of Materials Science and Engineering, Central South University of Forestry and Technology, Changsha, 410004, China.
  • 4 Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, School of Basic Medical Sciences; School of Pharmacy; Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine); Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China. Electronic address: [email protected].
  • 5 Guangdong Provincial Key Laboratory of Genome Stability and Disease Prevention, International Cancer Center, Department of Cell Biology and Genetics, School of Basic Medical Sciences; School of Pharmacy; Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine); Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Shenzhen University Medical School, Shenzhen 518060, China. Electronic address: [email protected].
PMID: 37648048 DOI: 10.1016/j.cbi.2023.110681
Abstract

Laxiflorin B is a natural ent-kaurane diterpenoid that can be isolated from the leaves of the Isodon eriocalyx var. laxiflora, a perennial shrub native to parts of China. While this compound has potent cytotoxic activity against various tumor cells, the anti-tumor targets and molecular mechanisms of Laxiflorin B are unclear. Here, we show that Laxiflorin B exhibits strong antiproliferative and proapoptotic effects on triple-negative breast Cancer (TNBC) cells. At the mechanistic level, we show that β-tubulin (TUBB) is a cellular target of Laxiflorin B. By covalently binding the Cys239 and C354 residues of the TUBB colchicine-binding site, Laxiflorin B disturbs microtubule integrity and structure in vitro and in vivo. Cytotoxicity analyses also showed that the α, β-unsaturated carbonyl in the D ring of Laxiflorin B is responsible for mediating its covalent binding and anti-tumor activity. To assess the therapeutic effects of Laxiflorin B, we synthesized a Laxiflorin B-ALA pro-drug and delivered it by intraperitoneal injection (10 mg/kg) into a 4T1 orthotopic tumor mouse model. Drug treatment had anti-tumor effects without inducing notable weight loss or organ dysfunction. We conclude that Laxiflorin B is a promising colchicine binding site inhibitor that might be exploited in the context of TNBC treatment in the future.

Keywords

Colchicine-binding site inhibitors; Laxiflorin B; Proapoptotic; TUBB; Triple negative breast cancer.

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