Apoptosis in leukemias: regulation and therapeutic targeting

Abstract

Nearly 25 years after the seminal publication of John Foxton Kerr that first described apoptosis, the process of regulated cell death, our understanding of this basic physiological phenomenon is far from complete [39]. From cardiovascular disease to cancer, apoptosis has assumed a central role with broad ranging therapeutic implications that depend on a complete understanding of this process, yet have also identified an incredibly complex regulatory system that is critical for development and is at the core of many diseases, challenging scientist and clinicians to step into its molecular realm and modulate its circuitry for therapeutic purposes. This chapter will review our understanding of the molecular circuitry that controls apoptosis in leukemia and the pharmacological manipulations of this pathway that may yield therapeutic benefit.

Figure 1

The extrinsic apoptotic pathway.

Figure 2

The intrinsic apoptotic pathway.

Figure 3

The CDDO derivative, CDDO-Me, directly induces MOMP via disruption of inner mitochondrial membrane impermeability. Top – U937 cells treated with 0.1% DMSO. Bottom – U937 cells treated with 300 nM CDDO-Me for 3 h. Images on left were captured at 10,000X direct magnification (bar = 2 microns); images on right correspond to 50,000X direct magnification of boxed area (bar = 500 nm).

Figure 4

Subcellular distribution of nutlin 3a-induced p53 is cell context regulated. COX-IV is a mitochondrial OXPHOS protein used to delineate cytoplasmic localization of p53.

Figure 5

ABT-737, but not AraC, induces apoptosis in the CD34+/38-/123+ leukemia stem cell compartment.

Figure 6

Targeting the apoptotic circuitry in leukemia cells.