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

Yang，Heng1; Zhang，Tiantian1; Chen，Chunlan1; Chiang，Chengyao2; Chen，Kai3; Wu，Yan1; Liu，Zhengxin1; Zhou，Yajun1; Zhu，Lizhi1; Zheng，Duo1

2023-09-25

10.1016/j.cbi.2023.110681

Chemico-Biological Interactions   Impact Factor & Quartile

0009-2797

1872-7786

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.

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

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Natural Science Foundation of Guangdong Province[2021A1515010996];Natural Science Foundation of Guangdong Province[2021A1515011046];China Postdoctoral Science Foundation[2022M722209];Natural Science Foundation of Guangdong Province[2023A1515011669];Shenzhen Graduate School, Peking University[JCYJ20210324093408024];Shenzhen Graduate School, Peking University[SZXK060];

Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Toxicology

Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Toxicology

WOS:001075242500001

ELSEVIER IRELAND LTD

PHARMACOLOGY & TOXICOLOGY

2-s2.0-85170435324

Scopus

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,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,Guangdong,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

Yang，Heng,Zhang，Tiantian,Chen，Chunlan,et al. Laxiflorin B covalently binds the tubulin colchicine-binding site to inhibit triple negative breast cancer proliferation and induce apoptosis[J]. Chemico-Biological Interactions,2023,383.

Yang，Heng.,Zhang，Tiantian.,Chen，Chunlan.,Chiang，Chengyao.,Chen，Kai.,...&Zheng，Duo.(2023).Laxiflorin B covalently binds the tubulin colchicine-binding site to inhibit triple negative breast cancer proliferation and induce apoptosis.Chemico-Biological Interactions,383.

Yang，Heng,et al."Laxiflorin B covalently binds the tubulin colchicine-binding site to inhibit triple negative breast cancer proliferation and induce apoptosis".Chemico-Biological Interactions 383(2023).