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

Marine Drugs
Amira A GodaKhalid A El Sayed

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 ...Continue Reading

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Citations

Jun 21, 2020·World Journal of Microbiology & Biotechnology·R BharadwajS Ramalingam
Jan 8, 2019·Applied Microbiology and Biotechnology·László KozákIstván Molnár
May 30, 2019·Toxins·Priyanka ReddySimone Rochfort
Aug 28, 2021·International Journal of Molecular Sciences·Loretta FerreraMichael Pusch
Dec 22, 2021·Natural Product Reports·Devon J SchatzSergey V Pronin

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