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

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.

Bioactive Compounds from Marine-Derived Aspergillus, Penicillium, Talaromyces and Trichoderma Species

“…The assays carried out on several human tumor cell lines were indicative of general antiproliferative effects [ 8 , 10 , 12 , 13 , 14 ]. In the case of penitrem A, a previously known mycotoxin, a potential for its use in cancer therapy was disclosed, based on the BK channel affinity and other side effects, which characterize this product as a possible novel sensitizing and chemotherapeutic synergizing agent [ 16 ].…”

Tremorgenic and neurotoxic paspaline-derived indole-diterpenes: biosynthetic diversity, threats and applications

“…Penitrem A induces G1 cell cycle arrest and up-regulates the arrest protein p27 (Goda et al 2018). The documented synergistic effects of penitrem A treatment with anti-HER drugs may have a significant impact on future development of breast cancer chemotherapies (Goda et al 2018).…”

“…Penitrem A induces G1 cell cycle arrest and up-regulates the arrest protein p27 (Goda et al 2018). The documented synergistic effects of penitrem A treatment with anti-HER drugs may have a significant impact on future development of breast cancer chemotherapies (Goda et al 2018). Interestingly, the early biosynthetic intermediates paspaline and emindole SB also show noticeable antiproliferative and antimigratory activities, with the anti-haptotactic activity of paspaline almost equipotent to that of the more elaborate congener penitrem A (Sallam et al 2013a; Sallam et al 2013b).…”

“…Intriguingly, some paspaline-derived IDTs such as penitrem A may also be regarded as Janus-faced compounds with potential applications in anticancer chemotherapies, either as monotherapies or in combination with other antiproliferative drugs (Sallam et al 2013a; Sallam et al 2013b; Goda et al 2018). Therefore, future metabolic engineering and fermentation optimization studies may need to target the improvement of the yields of these compounds under industrial fermentation conditions (Motoyama et al 2012; Kalinina et al 2017).…”

Emerging roles for multifunctional ion channel auxiliary subunits in cancer

“…BK channels are expressed in most tissues and are involved in a range of functions, such as learning and memory [ 183 ], pain modulation [ 184 ] and blood pressure regulation [ 185 ]. BK channels are upregulated in glioblastoma primary cells and promote proliferation and invasion [ 117 , 186 ]. BK channel function is modulated by two groups of auxiliary subunits- BKβ 1-4 and BKγ 1-4 , both double-pass membrane proteins.…”