Combo delivers one-two punch to AML cells
Credit: AACR/Phil McCarten
WASHINGTON, DC—Results of preclinical research have shown that combining dichloroacetate (DCA) and arsenic trioxide (ATO) can cause significantly more damage to acute myeloid leukemia (AML) cells than either drug alone.
The researchers found that delivering the 2 agents concurrently successfully induced apoptosis in 3 AML cell lines.
And pretreating the cells with DCA before introducing ATO further increased apoptosis by increasing the loss of mitochondrial membrane potential.
“We’re calling it ‘priming’ the cells,” said study investigator Ashkan Emadi, MD, PhD, of the University of Maryland Greenebaum Cancer Center in Baltimore.
“With DCA, you prime your mitochondria. Then, you come in with the arsenic, at a small dose. And this puts holes in the mitochondrial membrane, decreases their potential, and kills the cells via apoptosis.”
Dr Emadi and his colleagues presented these findings during a poster session at the recent AACR Annual Meeting 2013 (abstract 3268*).
The team began this research with the theory that the combination of DCA, as a mitochondrial respiration enhancer, and ATO, which impairs mitochondrial activity, would have synergistic antileukemic effects.
To test that, the researchers first determined IC50s for ATO and DCA for the AML cell lines MOLM-14, MV4-11, and MonoMac-6. For MOLM-14, the IC50 was 0.88 ± 0.02 μM for ATO and 15.87 ± 1.22 mM for DCA.
For MV4-11, the IC50 was 0.53 ± 0.03 μM for ATO and 19.08 ± 2.25 mM for DCA. And for MonoMac-6, the IC50 was 1.08 ± 0.01 μM for ATO and 25.11 ± 2.00 mM for DCA.
The investigators then treated cells with DCA at IC30 and ATO at IC50 concurrently for 72 hours. They compared this to treatment with either agent alone, as well as to pretreatment with DCA for 48 hours, followed by 48 hours of ATO at 4.5 nM – 5 μM.
The team assessed the potentiation of cytotoxicity and found that, with concurrent treatment of the drugs, the potentiation factors were 1.81 for MOLM-14, 1.32 for MV4-11, and 1.71 for MonoMac-6.
However, when the cells were first primed with DCA and then exposed to ATO, the potentiation factors were 2.0 for MOLM-14, 1.82 for MV4-11, and 2.16 for MonoMac-6.
In other words, pretreatment with DCA increased the cytotoxicity of ATO by 30% to 120% in the different cell lines.
Dr Emadi pointed out that, in MOLM-14 cells, the priming regimen increased apoptosis by about 85% and increased the loss of mitochondrial membrane potential by about 55%, when compared to concurrent use of DCA and ATO.
When compared to ATO alone, the priming regimen increased apoptosis of MOLM-14 cells by about 162% and increased the loss of mitochondrial membrane potential by about 254%.
Because of these favorable results, the researchers are conducting additional studies of the DCA-ATO regimen. They are currently testing the treatment in a FLT3-wild-type cell line.
The team is also planning a clinical trial to test the combination in AML patients who are elderly, medically unfit, or have relapsed or refractory disease.
“A lot of patients with AML—55% of all patients with AML—are over the age of 65,” Dr Emadi noted. “You cannot give a lot of these patients chemotherapy because they cannot tolerate it.”
“The beauty of [the DCA-ATO regimen] is that, if proven successful, it could provide a new option for patients who are elderly or medically unfit, with conditions such as diabetes or heart problems.”
*Information in the abstract differs from that presented at the meeting.
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