A Novel Derivative of Curcumol, HCL-23, Inhibits the Malignant Phenotype of Triple-Negative Breast Cancer and Induces Apoptosis and HO-1-Dependent Ferroptosis
Peng Zhao,
Hui Song,
Futian Gao,
Liang Chen,
Jianfei Qiu,
Jun Jin,
Chaolan Pan,
Yunyan Tang,
Meijun Chen,
Yang Pan,
Yanmei Li,
Liejun Huang,
Jue Yang,
Xiaojiang Hao
Affiliations
Peng Zhao
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Hui Song
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Futian Gao
School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China
Liang Chen
School of Pharmaceutical Sciences, Guizhou University, Guiyang 550025, China
Jianfei Qiu
Key Laboratory of Modern Pathogen Biology and Characteristics, School of Basic Medicine, Guizhou Medical University, Guiyang 550025, China
Jun Jin
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Chaolan Pan
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Yunyan Tang
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Meijun Chen
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Yang Pan
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Yanmei Li
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Liejun Huang
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Jue Yang
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Xiaojiang Hao
State Key Laboratory of Functions and Applications of Medicinal Plants & Key Laboratory of Endemic and Ethnic Diseases & Ministry of Education & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang 550025, China
Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype of breast cancer. Curcumol, as a natural small molecule compound, has potential anti-breast cancer activity. In this study, we chemically synthesized a derivative of curcumol, named HCL-23, by structural modification and explored its effect on and underlying mechanism regarding TNBC progression. MTT and colony formation assays demonstrated that HCL-23 significantly inhibited TNBC cells proliferation. HCL-23 induced G2/M phase cell cycle arrest and repressed the capability of migration, invasion, and adhesion in MDA-MB-231 cells. RNA-seq results identified 990 differentially expressed genes including 366 upregulated and 624 downregulated genes. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) revealed that these differentially expressed genes were obviously enriched in adhesion, cell migration, apoptosis, and ferroptosis. Furthermore, HCL-23 induced apoptosis via the loss of mitochondrial membrane potential and the activation of the caspase family in TNBC cells. In addition, HCL-23 was verified to trigger ferroptosis through increasing cellular reactive oxygen species (ROS), labile iron pool (LIP), and lipid peroxidation levels. Mechanistically, HCL-23 markedly upregulated the expression of heme oxygenase 1 (HO-1), and the knockdown of HO-1 could attenuate ferroptosis induced by HCL-23. In animal experiments, we found that HCL-23 inhibited tumor growth and weight. Consistently, the upregulation of Cleaved Caspase-3, Cleaved PARP, and HO-1 expression was also observed in tumor tissues treated with HCL-23. In summary, the above results suggest that HCL-23 can promote cell death through activating caspases-mediated apoptosis and HO-1-dependent ferroptosis in TNBC. Therefore, our findings provide a new potential agent against TNBC.
