Journal
JOURNAL OF HEMATOLOGY & ONCOLOGY
Volume 14, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13045-020-01015-9
Keywords
SERCA; T cell acute lymphoblastic leukemia; Thapsigargin; Notch signaling; NOTCH1; CAD204520; T-ALL
Categories
Funding
- AIRC Start-up Investigator Grant [17107]
- Fondazione Cariparma [3576/2017, 0180/2018]
- Fondazione Grande Ale Onlus
- Leukemia Research Foundation
- Feliciani Ferretti Fellowship
- Associazione Italiana contro le Leucemie-Linfomi e Mieloma ONLUS (AIL) Parma chapter
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P-type ATPase inhibitors are widely used in modern pharmacology, but clinical translation of Ca2+ -ATPase modulators remains challenging. Recent evidence suggests that SERCA inhibitors can exert anti-leukemia effects by inhibiting Notch1 signaling.
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 gamma -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.
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