metabolic challenges might promote cell death via activation of the proapoptotic Bcl 2 protein Bim, we examined whether inhibition of FAO modulates the expression of this protein in monocultures and MSC cocultures of leukemia cells. Intriguingly, as shown in Figure second, MSC coculture triggered decreased expression of the CHK1 inhibitor proapoptotic Bcl 2 family protein Bim, and this result was partially antagonized by EX in a dose-dependent fashion in MOLM13 cells, although not OCI AML3 cells. Inhibition of FAO didn’t alter Bcl 2, Mcl 1, Puma, or Bax degrees. Because reduced expression of Bim may possibly hinder activation of Bax and Bak and subsequent apoptosis, we examined whether OCI AML3 and MOLM13 cells cultured on MSC feeder sheets will be resistant to apoptosis induction by ABT 737 and how 100 mol/l EX modulated the response of leukemia cells to this BH3 mimetic. We employed 100 mol/l EX because this dose maximally inhibited oxygen usage without inducing significant apoptosis at 48-hours. Furthermore, Meristem since we and others have reported that increased p53 levels induce apoptosis via direct and indirect Bcl 2 antagonism, we similarly tested the connection of EX with the MDM 2 villain Nutlin 3a under the same conditions. As shown in Figure 3A, OCI AML3 and MOLM13 cells grown on MSC feeder layers were less vulnerable to the effects of ABT 737, which supports the concept that reduced Bim expression and/or the increased FAO observed in coculture opposes the effects of BH3 mimetics. Nonetheless, EX sensitized both leukemia cell types, alone and in coculture, to apoptosis induction by ABT 737, suggesting that FAO per se may antagonize the effects of this agent. In contrast, MSC feeder sheets did not somewhat decrease apoptosis induction by Nutlin 3a in OCI AML3 or MOLM13 cells, even though EX sensitized both cell types grown in monoculture to apoptosis induced by this agent. The above observations suggest that in wild type p53 cells, FAO inhibition order Fostamatinib might elicit p53 dependent and independent responses. Likewise, OCI AML3 cells treated with ranolazine or siRNA targeting CPT1 were sensitized to apoptosis induction by Nutlin 3a and ABT 737. Because our results suggest that in leukemia cells, fatty-acid synthase/lipase inhibition by orlistat influences FAO, we investigated whether this agent could also sensitize leukemia cells to apoptosis induction by ABT 737. Orlistat sensitized OCI AML3 cells alone and in coculture with MSCs to apoptosis induction by ABT 737, further supporting the notion that de novo synthesized and/or lipolysis made free fatty acids help success in leukemia cells, as shown in Figure 3D. Eventually, while EX therapy did not increase p53 amounts, EX sensitized OCI AML3 cells in which the expression of p53 was reduced by shRNA strategy to ABT 737, which implies that the proapoptotic effect of EX is independent of p53 activation. Related sensitization to ABT 737 occurred in U937 cells, which carry a mutated p53.