Inhibition of Bcl-2 antiapoptotic members by obatoclax potently enhances sorafenib-induced apoptosis in human myeloid leukemia cells through a Bim-dependent process.

Interactions between the multikinase inhibitor sorafenib and the BH3-mimetic obatoclax (GX15-070) were examined in human acute myeloid leukemia (AML) cells. Treatment with sorafenib/obatoclax induced pronounced apoptosis in and reduced the clonogenic growth of multiple AML lines and primary AML cells but not normal CD34(+) cells. Sorafenib triggered rapid and pronounced Mcl-1 down-regulation accompanied by enhanced binding of Bim to Bcl-2 and Bcl-xL, effects that were abolished by obatoclax coadministration. Notably, shRNA knockdown of Bim, Bak, or Bax, but not Noxa, significantly attenuated obatoclax/sorafenib lethality, whereas ectopic expression of Mcl-1 exerted a protective effect. Furthermore, exposure of leukemia cells to sorafenib and obatoclax markedly induced autophagy, reflected by rapid and pronounced LC3 processing and LC3-green fluorescent protein (GFP) punctate formation. Multiple autophagy inhibitors or VPS34 knockdown, significantly potentiated sorafenib/obatoclax lethality, indicating a cytoprotective role for autophagy in this setting. Finally, studies in a xenograft mouse model revealed that combined sorafenib/obatoclax treatment markedly reduced tumor growth and significantly prolonged survival in association with Mcl-1 down-regulation and apoptosis induction, whereas agents administered individually had only modest effects. These findings suggest that combining sorafenib with agents that inhibit Mcl-1 and Bcl-2/Bcl-xL such as obatoclax may represent a novel and potentially effective strategy in AML.

Effects of stress management on PNI-based outcomes in persons with HIV disease.

A pretest-posttest, repeated-measures design was used to evaluate the effects of two stress management interventions on a battery of outcomes derived from a psychoneuroimmunological (PNI) framework. The effects of cognitive-behavioral relaxation training groups (CBSM) and social support groups (SSG) were compared with a WAIT-listed control group on the outcomes of psychosocial functioning, quality of life, neuroendocrine mediation, and somatic health. Participants were 148 individuals (119 men, 29 women), diagnosed with HIV disease; 112 (76%) completing the study groups. Using analysis of covariance, the CBSM group was found to have significantly higher postintervention emotional well-being and total quality-of-life scores than did either the SSG or WAIT groups. SSG participants had significantly lower social/family well-being scores immediately postintervention and lower social support scores after 6 months. The findings point to a pressing need for further, well-controlled research with these common intervention modalities.