Arsenic trioxide combined with heat shock proteins to fight acute myeloid leukaemia

Scientists at Roswell Park Cancer Institute have created a pharmacodynamic model to understand how arsenic trioxide (ATO), combined with specific heat shock protein (HSP) 90 inhibitors, may enhance cancer cell death in acute myeloid leukaemia (AML), a cancer with poor outcomes. The analysis, led by Meir Wetzler, MD, Department of Medicine, Roswell Park Cancer Institute (RPCI), was presented at the American Association for Cancer Research (AACR) 100th Annual Meeting 2009, Denver, CO.

Arsenic and its derivatives have been used for more than 2000 years, both as poisons and as therapeutic agents. Scientists are now characterising the underlying mechanisms of arsenic trioxide and its interactions with different proteins to enhance its potential as a treatment for patients diagnosed with AML. Using a pharmacodynamic drug-drug model, Dr Wetzler and colleagues from the University at Buffalo Department of Pharmacology analysed arsenic trioxide’s effect on transcription 3 (STAT3) and heat shock proteins 70 and 90.

In a previous study, they found that patients whose AML cells have activated STAT3 have a worse outcome. Arsenic trioxide appears to downregulate STAT3 activity. To augment arsenic trioxide’s effectiveness, Dr Wetzler targeted heat shock protein 90, which protects from arsenic trioxide degradation. HSP 90 inhibitor augmented ATO’s effect. However, both upregulated heat shock protein 70, which prevents cancer cell death.

"We believe that pharmacodynamic modelling offers a method to better understand the interactions among cancer cell proteins and drugs. This understanding will help us to develop more effective clinical trials and lead to the development of new therapeutic options for patients diagnosed with AML," said Dr Wetzler.

More than 13,290 new AML cases are diagnosed each year in the United States. AML is the most common type of acute leukaemia, and more than 8,820 die from the disease. AML is a fast-growing cancer in which the bone marrow makes abnormal myeloblasts. Normally, myeloblasts develop into white blood cells that fight infection.

(Source: Roswell Park Cancer Institute: American Association for Cancer Research (AACR) 100th Annual Meeting 2009, Denver: May 2009)