Homoharringtonine stabilizes secondary structure of guanine-rich sequence existing in the 5′-untranslated region of Nrf2. Issue 16 (15th August 2019)

• Record Type: Journal Article
• Authors: Kang, Jong-Su; Lee, June; Nam, Le Ba; Yoo, Ok-Kyung; Pham, Kim-Thanh; Duong, Thi-Hoai-Men; Keum, Young-Sam
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 16(2019)
• Page Start: 2189
• Page End: 2196
• Publication Date: 2019-08-15
• Subjects: Homoharringtonine (HHT) -- NF-E2-related factor 2 (NRF2) -- Antioxidant response element (ARE) -- 5′-Untranslated region (5′-UTR); Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.06.049
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Homoharringtonine, known as omacetaxine mepesuccinate, is a pharmaceutical drug substance approved for treatment of chronic myeloid leukemia. Here, we report that homoharringtonine (HHT) is a novel chemical inhibitor of NRF2. HHT significantly suppressed NRF2 and ARE-dependent gene expression in human lung carcinoma A549 cells. HHT stabilized secondary structure of guanine-rich sequence existing in the 5′-untranslated region (5′-UTR) of Nrf2 and sensitized A549 cells to etoposide-induced apoptosis. To the best of our knowledge, HHT is the first type of transcriptional inhibitor of Nrf2 that stabilizes guanine-rich sequence existing in the 5′-UTR. Our study also provides a novel mechanism of action underlying how HHT exerts anti-carcinogenic effects in cancer cells.