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

Ryu,Ilhwan; Ryu,Min Jeong; Han,Jeongsu; Kim,Soo Jeong; Lee,Min Joung; Ju,Xianshu; Yoo,Byeong Hyeon; Lee,Yu Lim; Jang,Yunseon; Song,Ik‑Chan; Chung,Woosuk; Oh,Eungseok; Heo,Jun Young; Kweon,Gi Ryang

doi:10.3892/or.2018.6753

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

Authors:
- Ilhwan Ryu
- Min Jeong Ryu
- Jeongsu Han
- Soo Jeong Kim
- Min Joung Lee
- Xianshu Ju
- Byeong Hyeon Yoo
- Yu Lim Lee
- Yunseon Jang
- Ik‑Chan Song
- Woosuk Chung
- Eungseok Oh
- Jun Young Heo
- Gi Ryang Kweon
View Affiliations

Affiliations: Department of Biochemistry, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea, Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, Republic of Korea, Department of Internal Medicine, Chungnam National University Hospital, Daejeon 35015, Republic of Korea, Department of Neurology, Chungnam National University Hospital, Daejeon 35015, Republic of Korea
Published online on: October 1, 2018 https://doi.org/10.3892/or.2018.6753
Pages: 3869-3878

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

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.

View Figures

View References

1	De Kouchkovsky I and Abdul-Hay M: ‘Acute myeloid leukemia: A comprehensive review and 2016 update’. Blood Cancer J. 6:e4412016. View Article : Google Scholar : PubMed/NCBI
2	Löwenberg B and Rowe JM: Introduction to the review series on advances in acute myeloid leukemia (AML). Blood. 127:12016. View Article : Google Scholar : PubMed/NCBI
3	Liehr T: Thorough discussion of cancer research-thoughts against the main stream. Eur J Hum Genet. 25:9022017. View Article : Google Scholar :
4	Wilson CS, Davidson GS, Martin SB, Andries E, Potter J, Harvey R, Ar K, Xu Y, Kopecky KJ, Ankerst DP, et al: Gene expression profiling of adult acute myeloid leukemia identifies novel biologic clusters for risk classification and outcome prediction. Blood. 108:685–696. 2006. View Article : Google Scholar : PubMed/NCBI
5	Sallmyr A, Fan J, Datta K, Kim KT, Grosu D, Shapiro P, Small D and Rassool F: Internal tandem duplication of FLT3 (FLT3/ITD) induces increased ROS production, DNA damage, and misrepair: Implications for poor prognosis in AML. Blood. 111:3173–3182. 2008. View Article : Google Scholar : PubMed/NCBI
6	Adam-Vizi V and Chinopoulos C: Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharm Sci. 27:639–645. 2006. View Article : Google Scholar : PubMed/NCBI
7	Marlein CR, Zaitseva L, Piddock RE, Robinson SD, Edwards DR, Shafat MS, Zhou Z, Lawes M, Bowles KM and Rushworth SA: NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood. 130:1649–1660. 2017.PubMed/NCBI
8	Watson AS, Riffelmacher T, Stranks A, Williams O, De Boer J, Cain K, MacFarlane M, McGouran J, Kessler B, Khandwala S, et al: Autophagy limits proliferation and glycolytic metabolism in acute myeloid leukemia. Cell Death Discov. 1:150082015. View Article : Google Scholar : PubMed/NCBI
9	Robottom BJ: Efficacy, safety, and patient preference of monoamine oxidase B inhibitors in the treatment of Parkinson's disease. Patient Prefer Adherence. 5:57–64. 2011. View Article : Google Scholar : PubMed/NCBI
10	Youdim MB, Edmondson D and Tipton KF: The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci. 7:295–309. 2006. View Article : Google Scholar : PubMed/NCBI
11	Magyar K and Szende B: (−)-Deprenyl, A selective MAO-B inhibitor, with apoptotic and anti-apoptotic properties. Neurotoxicology. 25:233–242. 2004. View Article : Google Scholar : PubMed/NCBI
12	ThyagaRajan S, Tran L, Molinaro CA, Gridley DS, Felten DL and Bellinger DL: Prevention of mammary tumor development through neuroimmunomodulation in the spleen and lymph nodes of old female sprague-dawley rats by L-Deprenyl. Neuroimmunomodulation. 20:141–151. 2013. View Article : Google Scholar : PubMed/NCBI
13	Lajkó E, Polgár L, Láng O, Lengyel J, Kőhidai L and Magyar K: Basic cell physiological activities (cell adhesion, chemotaxis and proliferation) induced by selegiline and its derivatives in Mono Mac 6 human monocytes. J Neural Transm (Vienna). 119:545–556. 2012. View Article : Google Scholar : PubMed/NCBI
14	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
15	Chi Y, Lindgren V, Quigley S and Gaitonde S: Acute myelogenous leukemia with t(6;9)(p23;q34) and marrow basophilia: An overview. Arch Pathol Lab Med. 132:1835–1837. 2008.PubMed/NCBI
16	Lee BH, Tothova Z, Levine RL, Anderson K, Buza-Vidas N, Cullen DE, McDowell EP, Adelsperger J, Fröhling S, Huntly BJ, et al: FLT3 mutations confer enhanced proliferation and survival properties to multipotent progenitors in a murine model of chronic myelomonocytic leukemia. Cancer Cell. 12:367–380. 2007. View Article : Google Scholar : PubMed/NCBI
17	Sharpe MA and Baskin DS: Monoamine oxidase B levels are highly expressed in human gliomas and are correlated with the expression of HiF-1α and with transcription factors Sp1 and Sp3. Oncotarget. 7:3379–3393. 2016. View Article : Google Scholar : PubMed/NCBI
18	Jayanthi S, Deng X, Noailles PA, Ladenheim B and Cadet JL: Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades. FASEB J. 18:238–251. 2004. View Article : Google Scholar : PubMed/NCBI
19	Balaban RS, Nemoto S and Finkel T: Mitochondria, oxidants, and aging. Cell. 120:483–495. 2005. View Article : Google Scholar : PubMed/NCBI
20	Pfeiffer T, Schuster S and Bonhoeffer S: Cooperation and competition in the evolution of ATP-producing pathways. Science. 292:504–507. 2001. View Article : Google Scholar : PubMed/NCBI
21	Oliver D: The structure and activity of selegiline, its functional groups, and congeners. Bioorg Chem. 2002.
22	Sriskanthadevan S, Jeyaraju DV, Chung TE, Prabha S, Xu W, Skrtic M, Jhas B, Hurren R, Gronda M, Wang X, et al: AML cells have low spare reserve capacity in their respiratory chain that renders them susceptible to oxidative metabolic stress. Blood. 125:2120–2130. 2015. View Article : Google Scholar : PubMed/NCBI
23	Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, Kaluarachchi K, Bornmann W, Duvvuri S, Taegtmeyer H and Andreeff M: Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. 120:142–156. 2010. View Article : Google Scholar : PubMed/NCBI
24	Jacque N, Ronchetti AM, Larrue C, Meunier G, Birsen R, Willems L, Saland E, Decroocq J, Maciel TT, Lambert M, et al: Targeting glutaminolysis has antileukemic activity in acute myeloid leukemia and synergizes with BCL-2 inhibition. Blood. 126:1346–1356. 2015. View Article : Google Scholar : PubMed/NCBI
25	Yen K, Travins J, Wang F, David MD, Artin E, Straley K, Padyana A, Gross S, DeLaBarre B, Tobin E, et al: AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations. Cancer Discov. 7:478–493. 2017. View Article : Google Scholar : PubMed/NCBI
26	Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, et al: Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 340:622–626. 2013. View Article : Google Scholar : PubMed/NCBI
27	ThyagaRajan S, Felten SY and Felten DL: Antitumor effect of L-deprenyl in rats with carcinogen-induced mammary tumors. Cancer Lett. 123:177–183. 1998. View Article : Google Scholar : PubMed/NCBI
28	Thyagarajan S, Meites J and Quadri SK: Deprenyl reinitiates estrous cycles, reduces serum prolactin, and decreases the incidence of mammary and pituitary tumors in old acyclic rats. Endocrinology. 136:1103–1110. 1995. View Article : Google Scholar : PubMed/NCBI
29	ThyagaRajan S and Quadri SK: L-Deprenyl inhibits tumor growth, reduces serum prolactin, and suppresses brain monoamine metabolism in rats with carcinogen-induced mammary tumors. Endocrine. 10:225–232. 1999. View Article : Google Scholar : PubMed/NCBI
30	Tatton WG and Chalmers-Redman RM: Modulation of gene expression rather than monoamine oxidase inhibition: (−)-deprenyl-related compounds in controlling neurodegeneration. Neurology. 47:S171–S183. 1996. View Article : Google Scholar : PubMed/NCBI
31	Simon L, Szilágyi G, Bori Z, Telek G, Magyar K and Nagy Z: Low dose (−)deprenyl is cytoprotective: It maintains mitochondrial membrane potential and eliminates oxygen radicals. Life Sci. 78:225–231. 2005. View Article : Google Scholar : PubMed/NCBI
32	Yi H, Maruyama W, Akao Y, Takahashi T, Iwasa K, Youdim MB and Naoi M: N-Propargylamine protects SH-SY5Y cells from apoptosis induced by an endogenous neurotoxin, N-methyl(R)salsolinol, through stabilization of mitochondrial membrane and induction of anti-apoptotic Bcl-2. J Neural Trans. 113:21–32. 2006. View Article : Google Scholar
33	Liberti MV and Locasale JW: The Warburg effect: How does it benefit cancer cells? Trends Biochem Sci. 41:211–218. 2016. View Article : Google Scholar : PubMed/NCBI