Journal Article Ppublish 1 citation
PubMed: 42003108 DOI: 10.1002/ddr.70286
Cryptocaryone Exhibits ROS/MAPK-Dependent Antiproliferative and Apoptosis-Inducing Effects on Triple-Negative Breast Cancer Cells and Proof-of-Concept Breast Cancer Mouse Model.
Drug Dev Res 87(3):e70286
Authors: Ya-Ting Chuang, Wangta Liu, Tsu-Ming Chien, Ammad Ahmad Farooqi, Hsun-Shuo Chang, Jun-Ping Shiau, Hsueh-Wei Chang
Affiliations
- Department of Biomedical Science and Environmental Biology, PhD Program in Life Sciences, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
- School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Department of Urology, Kaohsiung Gangshan Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Molecular Oncology, Institute of Biomedical and Genetic Engineering (IBGE), Islamabad, Pakistan.
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Surgery, Division of Breast Oncology and Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Center for Cancer Research, and Research Center for Molecular Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
Abstract
Omics' technologies have enabled clinicians to gain previously unprecedented insights into the molecular complexity and clinical heterogeneity of triple-negative breast cancer (TNBC). Increasingly it is being realized that TNBC does not respond well to current targeted therapies. This study aims to explore the antiproliferative effects and cancer regulatory mechanisms which underlie the drug resistance and aggressiveness of TNBC cells. Cryptocaryone (CPC) derived from Cryptocarya concinna demonstrated antiproliferative responses to TNBC cells (HCC1937 and MDA-MB-231), while normal breast cells (H184B5F5/M10) exhibited low cytotoxicity. In an in vivo assessment, CPC effectively reduced tumor growth in the MDA-MB-231 xenografted mouse model without significantly affecting body weight. Mechanistically, CPC triggered apoptosis, as indicated by an increase in sub-G1 and annexin V, as well as activated caspase 3 and 8. CPC also induced substantial oxidative stress by generating reactive oxygen species, mitochondrial superoxide, and membrane depolarization. CPC also induced oxidative DNA damage, as evidenced by the presence of γH2AX and 8-hydroxy-2-deoxyguanosine, in TNBC cells. All these CPC-induced changes were more pronounced in TNBC cells than normal cells. JNK and p38 MAPK inhibitors attenuate CPC-induced antiproliferation in TNBC cells. CPC upregulates phosphorylated JNK and p38 in TNBC cells. N-acetylcysteine pretreatment confirmed that oxidative stress plays a vital role in enhancing the antiproliferation, apoptosis, and DNA damage in TNBC cells. Moreover, the CPC-upregulated apoptosis and caspase 3/8 activations in TNBC cells were inhibited by JNK and p38 inhibitors. The impact of ERK activation on antiproliferation and apoptosis was evident in MDA-MB-231 cells, but not in HCC1937 cells. In conclusion, CPC demonstrated antiproliferative effects on TNBC cells through apoptosis and DNA damage induced by oxidative stress and MAPK activation, while showing drug safety in normal cells and breast cancer mouse model.
MeSH
Cells, Triple Negative Breast Neoplasms, Breast Neoplasms, Pharmaceutical Preparations, Acetylcysteine, Stress, Physiological, Neoplasms, Caspase 3, Oxidative Stress, Caspases, Deoxyguanosine, Breast, Apoptosis