Retinoic Acid and Arsenic Synergize to Eradicate Leukemic Cells in a Mouse Model of Acute Promyelocytic Leukemia

Abstract

In acute promyelocytic leukemia (APL) patients, retinoic acid (RA) triggers differentiation while arsenic trioxide (arsenic) induces both a partial differentiation and apoptosis. Although their mechanisms of action are believed to be distinct, these two drugs both induce the catabolism of the oncogenic promyelocytic leukemia (PML)/RARα fusion protein. While APL cell lines resistant to one agent are sensitive to the other, the benefit of combining RA and arsenic in cell culture is controversial, and thus far, no data are available in patients. Using syngenic grafts of leukemic blasts from PML/RARα transgenic mice as a model for APL, we demonstrate that arsenic induces apoptosis and modest differentiation, and prolongs mouse survival. Furthermore, combining arsenic with RA accelerates tumor regression through enhanced differentiation and apoptosis. Although RA or arsenic alone only prolongs survival two- to threefold, associating the two drugs leads to tumor clearance after a 9-mo relapse-free period. These studies establishing RA/arsenic synergy in vivo prompt the use of combined arsenic/RA treatments in APL patients and exemplify how mouse models of human leukemia can be used to design or optimize therapies.

The Drug-Induced Degradation of Oncoproteins: An Unexpected Achilles' Heel of Cancer Cells?

“…Moreover, agents targeting each moiety for proteolysis should be synergistic and are not expected to display cross-resistance. This scenario is perfectly exemplified by the combination of arsenic and RA in PML/RARA-driven APL, which elicits the clearance of the malignant clone with little or no toxicity in normal cells (21,23,24,55,72). Other diseases driven by fusion oncogenes might be highly susceptible to therapies aimed at degrading the fusion protein.…”

“…The pathophysiologic importance of fusion proteins together with the ability to target their function or stability places them at the pinnacle of "druggable" targets. Indeed, in murine malignancy models driven by a fusion protein, genetic or pharmacologic targeting of the leukemia-associated fusion protein is sufficient to induce rapid leukemia clearance, despite the requirement of cooperating events to yield full-blown disease (21,22 An example, highly relevant to the clinical situations described below, is the fact that transcriptional activation is tightly coupled to proteolysis of transcription factors and coactivators. Although modulation of transcriptional activity was considered to be the key factor underlying biological response, some recent studies have suggested that degradation may also play an important role.…”

Pathways of retinoic acid- or arsenic trioxide-induced PML/RARα catabolism, role of oncogene degradation in disease remission

“…Arsenic trioxide was initially proposed to trigger apoptosis ex vivo, although later studies have shown that it can also induce non-terminal di erentiation (Chen et al, 1996. In vivo, either in treated patients or in animal models of the disease, both di erentiation and apoptosis appear to take place and it is di cult to evaluate the respective contribution of each of these processes to disease remission (Lallemand-Breitenbach et al, 1999). PML/RARa targeting by RA: activation, degradation or both?…”

How to manage acute promyelocytic leukemia

“…29,58 Second, combination of the two agents allows a significantly prolonged survival or even disease eradication in APL animals. 63,64 Third, the two compounds target PML --RARa and modulate key networks involved in apoptosis/ differentiation via distinct but related pathways. 24,65,66 Mechanistically, the combined use of ATO with ATRA has brought about a conceptual revolution of synergistic targeting of leukemia and thus impacts the conventional chemotherapy-based treatment.…”