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Mar. Drugs 2018, 16(5), 157;

The Maxi-K (BK) Channel Antagonist Penitrem A as a Novel Breast Cancer-Targeted Therapeutic

Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, LA 71201, USA
Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid 22110, Jordan
Department of Pharmacognosy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt
Author to whom correspondence should be addressed.
Received: 6 April 2018 / Revised: 6 May 2018 / Accepted: 9 May 2018 / Published: 11 May 2018
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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. View Full-Text
Keywords: breast cancer; BK (Maxi-K) channel; EGFR; HER2; penitrem A; gefitinib; lapatinib; TNF-α breast cancer; BK (Maxi-K) channel; EGFR; HER2; penitrem A; gefitinib; lapatinib; TNF-α

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Goda, A.A.; Siddique, A.B.; Mohyeldin, M.; Ayoub, N.M.; El Sayed, K.A. The Maxi-K (BK) Channel Antagonist Penitrem A as a Novel Breast Cancer-Targeted Therapeutic. Mar. Drugs 2018, 16, 157.

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