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Targeting oncogenic Notch signaling with SERCA inhibitors.

ABSTRACT: P-type ATPase inhibitors are among the most successful and widely prescribed therapeutics in modern pharmacology. Clinical transition has been safely achieved for H⁺/K⁺ ATPase inhibitors such as omeprazole and Na⁺/K⁺-ATPase inhibitors like digoxin. However, this is more challenging for Ca²⁺-ATPase modulators due to the physiological role of Ca²⁺ in cardiac dynamics. Over the past two decades, sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA) modulators have been studied as potential chemotherapy agents because of their Ca²⁺-mediated pan-cancer lethal effects. Instead, recent evidence suggests that SERCA inhibition suppresses oncogenic Notch1 signaling emerging as an alternative to ?-secretase modulators that showed limited clinical activity due to severe side effects. In this review, we focus on how SERCA inhibitors alter Notch1 signaling and show that Notch on-target-mediated antileukemia properties of these molecules can be achieved without causing overt Ca²⁺ cellular overload.

SUBMITTER: Pagliaro L

PROVIDER: S-EPMC7789735 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Targeting oncogenic Notch signaling with SERCA inhibitors.

Pagliaro Luca L Marchesini Matteo M Roti Giovanni G

Journal of hematology & oncology 20210106 1

P-type ATPase inhibitors are among the most successful and widely prescribed therapeutics in modern pharmacology. Clinical transition has been safely achieved for H+/K+ ATPase inhibitors such as omeprazole and Na+/K+-ATPase inhibitors like digoxin. However, this is more challenging for Ca2+-ATPase modulators due to the physiological role of Ca2+ in cardiac dynamics. Over the past two decades, sarco-endoplasmic reticulum Ca2+< ...[more]

PMID: 33407740

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