Budlein A methylacrylate demonstrates potent activity against triple-negative breast cancer by targeting IκBα kinase and exportin-1

• Published in: Toxicology and applied pharmacology 2020-12, Vol.408, p.115263, Article 115263
• Main Authors: Wang, Xin-zhi, Feng, Yin, Han, Ye-fan, Bian, Yong, Liang, Jie, Wen, Hong-mei, Wu, Hao
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; budlein A methylacrylate; Cell Line, Tumor; Cell Survival - drug effects; Female; Humans; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - genetics; IKKβ; Karyopherins - antagonists & inhibitors; Karyopherins - genetics; Lactones - pharmacology; Lactones - therapeutic use; Methacrylates - pharmacology; Methacrylates - therapeutic use; Mice, Inbred BALB C; Mice, Nude; NF-kappa B - metabolism; NF-κB pathway; RNA, Small Interfering - genetics; Sesquiterpenes - pharmacology; Sesquiterpenes - therapeutic use; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - metabolism; Triple-negative breast cancer; XPO-1
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2020.115263

Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat because there are no targeted therapies. Currently, chemotherapy is the only clinical option for TNBC despite development of resistance. New therapeutic agents with unique mechanisms of action are urgently needed; therefore, this study investigated the potential anti-TNBC effects of budlein A methylacrylate (BAM), a natural sesquiterpene lactone isolated from plants of the Helianthus genus. We discovered that BAM selectively suppressed and induced apoptosis TNBC cell growth versus other breast cancer or normal mammary epithelial cells. Mechanistically, BAM co-inhibited inhibitor of nuclear factor κBα (IκBα) kinase subunit β (IKKβ) and exportin-1 (XPO-1; chromosome region maintenance 1, CRM1), which are two dysregulated onco-related proteins in TNBC cells, by covalently modifying key functional cysteine residues (Cys179 of IKKβ, Cys528 of XPO-1). Dual inhibition led to the stabilization and nuclear retention of IκBα, impairment of NF-κB transcriptional activity, and consequent induction of TNBC cell apoptosis. In conclusion, this study provides evidence that co-inhibition of IKKβ and XPO-1 by BAM was effective against TNBC, demonstrating it as a representative new generation inhibitor with potential for TNBC treatment. •Budlein A methylacrylate (BAM) suppressed TNBC cell and in vivo tumor growth.•BAM co-inhibited onco-related proteins IKKβ and XPO-1 in TNBC cells.•BAM covalently modified key functional Cys residues of IKKβ (179) and XPO-1 (528).•Co-inhibition of IKKβ and XPO-1 by BAM stabilized and retained nuclear IκBα.•BAM-mediated impairment of NF-κB transcription, leading to apoptosis of TNBC cells.