Abstract
Breast cancer (BC) is a heterogeneous disease with different molecular subtypes. The high conductance calcium-activated potassium channels (BK, Maxi-K channels) play an important role in the survival of some BC phenotypes, via membrane hyperpolarization and regulation of cell cycle. BK channels have been implicated in BC cell proliferation and invasion. Penitrems are indole diterpene alkaloids produced by various terrestrial and marine Penicillium species. Penitrem A (1) is a selective BK channel antagonist with reported antiproliferative and anti-invasive activities against multiple malignancies, including BC. This study reports the high expression of BK channel in different BC subtypes. In silico BK channel binding affinity correlates with the antiproliferative activities of selected penitrem analogs. 1 showed the best binding fitting at multiple BK channel crystal structures, targeting the calcium-sensing aspartic acid moieties at the calcium bowel and calcium binding sites. Further, 1 reduced the levels of BK channel expression and increased expression of TNF-α in different BC cell types. Penitrem A (1) induced G1 cell cycle arrest of BC cells, and induced upregulation of the arrest protein p27. Combination treatment of 1 with targeted anti-HER drugs resulted in synergistic antiproliferative activity, which was associated with reduced EGFR and HER2 receptor activation, as well as reduced active forms of AKT and STAT3. Collectively, the BK channel antagonists represented by penitrem A can be novel sensitizing, chemotherapeutics synergizing, and therapeutic agents for targeted BC therapy.
Highlights
Breast cancer (BC) is the most commonly diagnosed malignancy among women, globally contributing to high mortality rates [1]
Combination treatment of 1 with targeted anti-HER drugs resulted in synergistic antiproliferative activity, which was associated with reduced epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) receptor activation, as well as reduced active forms of AKT and STAT3
The BK channel antagonists represented by penitrem A can be novel sensitizing, chemotherapeutics synergizing, and therapeutic agents for targeted BC therapy
Summary
Breast cancer (BC) is the most commonly diagnosed malignancy among women, globally contributing to high mortality rates [1]. BC is highly heterogeneous at both molecular and clinical level, with various pathological and molecular subtypes [2]. (HER2)-positive, and basal-like subtypes [3,4,5]. Both luminal A and luminal B tumors are hormone receptor-positive, and have expression patterns reminiscent of the luminal epithelial component of the breast [6]. HER2-enriched tumors are characterized by overexpression/amplification of the ErbB2/HER2 gene, and are generally hormone receptor-negative [2,7]. Basal-like tumors are predominantly triple-negative, lacking the expression of hormone receptors and HER2 [7]. The subtypes are associated with distinct pathological features and clinical outcomes [2]
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