The apoptotic and anti‐proliferative effects of Neosetophomone B in T‐cell acute lymphoblastic leukaemia via PI3K/AKT/mTOR pathway inhibition

<p dir="ltr">The phosphatidylinositol 3‐kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is pivotal in various cancers, including T‐cell acute lymphoblastic leukaemia (T‐ALL), a particularly aggressive type of leukaemia. This study investigates the effects of Neosetophomone B (NSP‐B), a meroterpenoid fungal metabolite, on T‐ALL cell lines, focusing on its anti‐cancer mechanisms and therapeutic potential. NSP‐B significantly inhibited the proliferation of T‐ALL cells by inducing G0/G1 cell cycle arrest and promoting caspase‐dependent apoptosis. Additionally, NSP‐B led to the dephosphorylation and subsequent inactivation of the PI3K/AKT/mTOR signalling pathway, a critical pathway in cell survival and growth. Molecular docking studies revealed a strong binding affinity of NSP‐B to the active site of AKT, primarily involving key residues crucial for its activity. Interestingly, NSP‐B treatment also induced apoptosis and significantly reduced proliferation in phytohemagglutinin‐activated primary human CD3+ T cells, accompanied by a G0/G1 cell cycle arrest. Importantly, NSP‐B did not affect normal primary T cells, indicating a degree of selectivity in its action, targeting only T‐ALL cells and activated T cells. In conclusion, our findings highlight the potential of NSP‐B as a novel therapeutic agent for T‐ALL, specifically targeting the aberrantly activated PI3K/AKT/mTOR pathway and being selective in action. These results provide a strong basis for further investigation into NSP‐B's anti‐cancer properties and potential application in T‐ALL clinical therapies.</p><h2>Other Information</h2><p dir="ltr">Published in: Cell Proliferation<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1111/cpr.13773" target="_blank">https://dx.doi.org/10.1111/cpr.13773</a></p><p dir="ltr">Other Institutions affiliated with: Hamad Bin Khalifa University, College of Health and Life Sciences, Weill Cornell Medicine-Qatar</p>