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4, 9-dihydroxy-α-lapachone as a potent antiproliferation agent for triple-negative breast cancer via ferroptosis
Zhong He1, Hui Long2, Hongyue Ma2
1Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, China; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Sciences, China Three Gorges University, Yichang 443002, China; State Key Laboratory of Drug Research, Molecular Imaging Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Abstract:
Triple-negative breast cancer (TNBC) is the most aggressive and malignant breast cancer. Ferroptosis is an oxidative, iron-dependent form of regulated cell death. Ferroptosis-targeted therapies is a promising approach to improving treatment outcomes of TNBC. Combining death pathway inhibitors with relevant indices for ferroptosis and LipROS, this study uncovered that a natural product of 4, 9-dihydroxy-α-lapachone (DLN) from Catalpa bungei "jinsi" exhibited in vitro and in vivo inhibitory activity against TNBC via ferroptosis. The molecular mechanism is an activation of the FTH1 led to iron overload, and then inhibition of cysteine-glutamate antiporter (system Xc-) and GPX4, which further sensitized TNBC cells to ferroptosis. This study clarified the pathway of DLN-induced cell death in TNBC treatment and exhibited its potential as therapeutic agent for TNBC.
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