Abstract
Due to a lack of hormone receptors, current treatment strategies for triple-negative breast cancer (TNBC) are limited with frequent disease recurrence and metastasis. Recent findings have suggested that aberrant methylation of histone H3 lysine 79 residue (H3K79me) by the histone methyltransferase disruptor of telomeric silencing 1-like (DOT1L) is a potential therapeutic target for TNBC clinical management. Therefore, we developed DOT1L inhibitors as potential antitumor agents against TNBC cells. We reveal that a synthetic half-selenopsammaplin A analog 9l (subsequently known as 9l) exhibited inhibitory activity against DOT1L-mediated H3K79 methylation, and showed antitumor activity in TNBC cells. The analog 9l also significantly inhibited TNBC invasion and migration via the modulation of epithelial-mesenchymal transition (EMT) markers, including N-cadherin and vimentin downregulation and E-cadherin upregulation. In an MDA-MB-231/Luc-implanted orthotopic mouse metastasis model, treatment with 9l effectively inhibited tumor growth and lung metastasis via DOT1L regulatory activity and EMT processes. Taken together, these findings highlight the potential of 9l as a novel therapeutic candidate for treating metastatic TNBC via DOT1L modulation.
Highlights
Cancer is a major cause of human death worldwide, and the incidence is gradually increasing triggered by environmental and dietary factors
The synthesis of heteromonomeric psammaplin A analogs was prepared from the analogs of dimeric psammaplin A or selenopsammaplin A that was previously reported (Figure 1)
Before we prepared a series of half monomer analogs, we assessed the molecular stability of four possible analogs (Figure 2)
Summary
Cancer is a major cause of human death worldwide, and the incidence is gradually increasing triggered by environmental and dietary factors. Most deaths attributed to BC are associated with recurrent and/or metastatic disease. Recurrent BCs are often highly metastatic, and tend to acquire resistance to previously used conventional therapies, including chemotherapy (i.e., anthracyclines, taxanes, carboplatin, and capecitabine), or targeted bio-drugs (i.e., trastuzumab) [5,6]. BCs are typically categorized into subtypes based on the existence of three surface receptors; i.e., the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2). These receptors are promising therapeutic targets for BC patients.
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