T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with poor response to conventional therapy, derived from hematopoietic progenitors committed to T-cell lineage. Relapsed/Refractory patients account for nearly 20% of childhood and 45% of adult cases. Aberrant Notch signaling plays a critical role in T-ALL pathogenesis and therapy resistance. Notch inhibition is a promising therapeutic target for personalized medicine, and a variety of strategies to prevent Notch activation, including γ-secretase (GS) inhibitors (GSIs) and antibodies neutralizing Notch receptors or ligands, have been developed. Disruption of apoptosis is pivotal in cancer development and progression. Different reports evidenced the interplay between Notch and the anti-apoptotic Bcl-2 family proteins in T-ALL. Although based on early research data, this review discusses recent advances in directly targeting Notch receptors and the use of validated BH3 mimetics for the treatment of T-ALL and their combined action in light of current evidence of their use.

Spermidine (SPD) and related polyamines are small polycationic molecules typically elevated in cancer cells, where their depletion suppresses tumor growth both in vitro and in vivo. Paradoxically, SPD has also been proposed as a dietary supplement for its potential health benefits, including cancer prevention, prompting considerable interest in elucidating its mechanisms of action. In vitro studies using cultured cancer cell lines treated with exogenous SPD have yielded conflicting results, with reports of enhanced proliferation, cytotoxicity, or modulation of autophagy. To address these discrepancies, we used polyamine-depleted colorectal cancer (CRC) cells to systematically evaluate SPD's effects across a range of concentrations. Following depletion with difluoromethylornithine, SPD exhibited a biphasic response: at low concentrations (100 µM) induced DHPS-independent cytotoxicity mediated by bovine serum amine oxidase (BSAO) activity in fetal bovine serum. High SPD doses transiently inhibited the autophagic flux, while low doses did not display any effect at all time points tested. The DHPS inhibitor GC7 (N1-guanyl-1,7-diaminoheptane) suppressed SPD-induced proliferation at low concentrations and unexpectedly prevented cytotoxicity at high concentrations. Kinetic assays revealed that GC7 also inhibits BSAO in a non-competitive manner (Ki ≈ 300 nM), independent of DHPS. In silico docking analysis indicated that GC7 binds BSAO via non-covalent interactions, outside the topaquinone organic cofactor site. These findings clarify the concentration-dependent effects of SPD in CRC cells, reconcile conflicting in vitro data, and identify BSAO as a previously unrecognized target of GC7, providing new mechanistic insights into polyamine-driven cancer biology.

T-cell acute lymphoblastic leukemia is an aggressive neoplasia due to hyper-proliferation of lymphoid progenitors and lacking a definitive cure to date. Notch-activating mutations are the most common in driving disease onset and progression, often in combination with sustained activity of NF-κB. Myeloid-derived suppressor cells represent a mixed population of immature progenitors exerting suppression of anti-cancer immune responses in the tumor microenvironment of many malignancies. We recently reported that in a transgenic murine model of Notch3-dependent T-cell acute lymphoblastic leukemia there is an accumulation of myeloid-derived suppressor cells, dependent on both Notch signaling deregulation and IL-6 production inside tumor T-cells. However, possible interaction between NF-κB and Notch in this context remains unexplored. Interestingly, we also reported that Notch3 transgenic and NF-κB1/p50 deleted double mutant mice display massive myeloproliferation. Here, we demonstrated that the absence of the p50 subunit in these mice dramatically enhances the induction and suppressive function of myeloid-derived suppressor cells. This runs in parallel with an impressive increase in IL-6 concentration in the peripheral blood serum, depending on IL-6 hyper-production by tumor T-cells from double mutant mice. Mechanistically, IL-6 increase relies on loss of the negative control exerted by the p50 subunit on the IL-6 promoter. Our results reveal the Notch/NF-κB cross-talk in regulating myeloid-derived suppressor cell biology in T-cell leukemia, highlighting the need to consider carefully the pleiotropic effects of NF-κB-based therapy on the tumor microenvironment.