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L‑Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration.

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 anti‑leukemic 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 L‑deprenyl, which is clinically available for the treatment of Parkinson's disease, exerts anti‑mitochondria activity in KG‑1α 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. L‑deprenyl is known to target monoamine oxidase‑B (MAO‑B) on the outer membrane of mitochondria, therefore, the activity of MAO‑A and ‑B was measured based on the fluorometric detection of H2O2 produced by the enzyme reaction. Notably, MAO‑A and -B activity was low in AML cells and the present findings suggested that the anticancer effect of L‑deprenyl was independent of MAO‑B. Change of mitochondrial respiration‑ and glycolysis‑related gene expression levels were measured by reverse transcription‑quantitative polymerase chain reaction. Consistent with the aforementioned results, treatment with L‑deprenyl reduced the mRNA level of mitochondrial respiration‑ and glycolysis‑related genes. Collectively, the present results identify L‑deprenyl as a novel candidate for the treatment of AML through inhibition of mitochondrial respiration.

journal_name

Oncol Rep

journal_title

Oncology reports

authors

Ryu I,Ryu MJ,Han J,Kim SJ,Lee MJ,Ju X,Yoo BH,Lee YL,Jang Y,Song IC,Chung W,Oh E,Heo JY,Kweon GR

doi

10.3892/or.2018.6753

subject

Has Abstract

pub_date

2018-12-01 00:00:00

pages

3869-3878

issue

eissn

1021-335X

issn

1791-2431

journal_volume

pub_type

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L‑Deprenyl exerts cytotoxicity towards acute myeloid leukemia through inhibition of mitochondrial respiration.