APO866 activity in hematologic malignancies: a preclinical in vitro study

The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

“…Moreover, we found 2-and 3-fold reductions in the proportion of BrdU + proliferating NB4 and HL60 cells, respectively, after treatment with AC93253, as compared to control DMSO treated cells ( Figure 3B). In line with previously published reports, 33,34 we found that neither NAMPT nor SIRT2 inhibitors diminished the proliferation ( Figure 2D …”

“…24 Active nuclear β-catenin has been detected in blasts of myeloid leukemia patients as well as in patients with other hematologic malignancies. [27][28][29][30][31][32][33] Interestingly, we demonstrated that inhibition of SIRT2 or NAMPT resulted in dephosphorylation/activation of GSK3β and subsequent phosphorylation/deactivation of β-catenin, which is the first step in β-catenin degradation. Because inhibition of either SIRT2 or NAMPT induced dephosphorylation/inactivation of AKT, this process is most likely AKT-dependent.…”

“…33 Inhibition of SIRT2 by the specific inhibitor AC93253 induces cell death in a variety of solid cancer cell lines. 34 We compared the effects of NAMPT inhibition with FK866 and SIRT2 inhibition with AC93253 on the proliferation and apoptosis of the leukemia cell lines (NB4 and HL60) and primary AML blasts (AML M2) (n = 3).…”

High Visfatin Expression in Breast Cancer Tissue Is Associated with Poor Survival

“…The visfatin inhibitor APO866 selectively inhibited tumor growth through the depletion of intracellular NAD, the product catalyzed by visfatin, in murine gastric and bladder tumor models (34). In addition, the addition of APO866 synergistically increases the caspase-dependent apoptotic activity of TNF-related apoptosis-inducing ligand in leukemia cells by enhancing NAD þ depletion, mitochondrial transmembrane potential dissipation, and ATP depletion (35)(36)(37). In our study, visfatin expression was higher in breast cancer tissues and significantly associated with poor survival and disease prognosis (Figs.…”

Exploiting tumor vulnerabilities: NAD+-depleting agents combined with anti-tumor drugs as innovative strategy to treat hematological malignancies

“…Starting from the early 2000s, Nampt inhibitors such as FK866 [2] have become available, rapidly proving to be valuable tools to study the effects of NAD + depletion in several disease models. As a result, Nampt inhibitors as monotherapy have demonstrated potent antitumor activity in preclinical cancer models [3][4][5][6][7]. In such a scenario, investigators have also tested NAD + -depleting agents in combination with antineoplastic agents, chemotherapy, or radiotherapy in a wide range of hematological malignancies, including AML, MM, and lymphomas, observing an increased activity and overall tolerability of these agents [8][9][10][11][12].…”