LDeprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration.
Oncol Rep
; 40(6): 3869-3878, 2018 Dec.
Article
in En
| MEDLINE
| ID: mdl-30272370
ABSTRACT
The identification of large numbers of genetic mutations in immature myeloid cells has made it difficult to identify specific targets for acute myeloid leukemia (AML) therapy. Although current pharmacological targets for controlling cancer are focused on identifying genetic mutations, it is hard to develop the specific drugs to achieve complete remission due to complex and variable genetic mutations. To overcome the failure of the genetic mutation theory, the present study targeted mitochondrial metabolism as a strategy for inducing antileukemic activity, based on evidence that AML cells have an abnormally high amount of mitochondria and that somatic mutations can alter metabolic flux in cancer. It was found that Ldeprenyl, which is clinically available for the treatment of Parkinson's disease, exerts antimitochondria activity in KG1α cells, as assessed by detection of oxygen consumption rate (OCR) and extracellular acidification (ECAR) using XF analyzer, respectively. Using a luciferase assay for detecting adenosine triphosphate (ATP) content, it was found that suppression of mitochondrial activity led to ATP depletion and was associated with potent cytotoxic activity. Ldeprenyl is known to target monoamine oxidaseB (MAOB) on the outer membrane of mitochondria, therefore, the activity of MAOA and B was measured based on the fluorometric detection of H2O2 produced by the enzyme reaction. Notably, MAOA and -B activity was low in AML cells and the present findings suggested that the anticancer effect of Ldeprenyl was independent of MAOB. Change of mitochondrial respiration and glycolysisrelated gene expression levels were measured by reverse transcriptionquantitative polymerase chain reaction. Consistent with the aforementioned results, treatment with Ldeprenyl reduced the mRNA level of mitochondrial respiration and glycolysisrelated genes. Collectively, the present results identify Ldeprenyl as a novel candidate for the treatment of AML through inhibition of mitochondrial respiration.
Full text:
1
Database:
MEDLINE
Main subject:
Selegiline
/
Leukemia, Myeloid, Acute
/
Mitochondria
/
Monoamine Oxidase
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Year:
2018
Type:
Article