Induction of apoptosis by obovatol as a novel therapeutic strategy for acute myeloid leukemia

Kim,Hyeng-Soo; Lim,Ga  Young; Hwang,Junmo; Ryoo,Zae  Young; Huh,Tae-Lin; Lee,Sanggyu

doi:10.3892/ijmm.2014.1957

Induction of apoptosis by obovatol as a novel therapeutic strategy for acute myeloid leukemia

Authors:
- Hyeng-Soo Kim
- Ga Young Lim
- Junmo Hwang
- Zae Young Ryoo
- Tae-Lin Huh
- Sanggyu Lee
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Affiliations: School of Life Science, BK21 plus KNU Creative BioResearch Group, Kyungpook National University, Daegu 702-701, Republic of Korea
Published online on: October 2, 2014 https://doi.org/10.3892/ijmm.2014.1957
Pages: 1675-1680

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Abstract

Obovatol, a compound isolated from the bark cortex of Magnolia officinalis (cortex Magnoliae officinalis; M. officinalis), has been studied for use in the treatment of solid cancers. However, the mechanisms of action and the effects of obovatol against acute myeloid leukemia (AML) remain unclear and require further investigation. Therefore, this study was conducted using a human AML cell line (MM6). Obovatol increased pro-apoptotic (Bax) and decreased anti-apoptotic (Bcl-2) protein expression, resulting in caspase-3 and caspase-9 activation measured by caspase-Glo 3/7 assay. Furthermore, obovatol activated the mitogen-activated protein kinase (MAPK) signaling pathway [c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK) and p38] and inhibited the activation of the nuclear factor-κB (NF-κB) signaling pathway analyzed by western blot analysis. Taken together, these findings provide evidence that obovatol inhibits cell proliferation in AML and induces apoptosis through the activation of the MAPK pathway in addition to the intrinsic apoptotic pathway. In addition, obovatol suppressed the expression of mixed-lineage leukemia (MLL) target genes by inhibiting the activation of the NF-κB pathway. Therefore, these results suggest that obovatol may have potential for use in the treatment of leukemia.

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1	Teng CL, Yu CT, Hwang WL, et al: Effector mechanisms of sunitinib-induced G1 cell cycle arrest, differentiation, and apoptosis in human acute myeloid leukaemia HL60 and KG-1 cells. Ann Hematol. 92:301–313. 2013. View Article : Google Scholar : PubMed/NCBI
2	Nagase H, Ikeda K and Sakai Y: Inhibitory effect of magnolol and honokiol from Magnolia obovata on human fibrosarcoma HT-1080. Invasiveness in vitro. Planta Med. 67:705–708. 2001.
3	Park J, Lee J, Jung E, et al: In vitro antibacterial and anti-inflammatory effects of honokiol and magnolol against Propionibacterium sp. Eur J Pharmacol. 496:189–195. 2004. View Article : Google Scholar : PubMed/NCBI
4	Wang T, Chen F, Chen Z, et al: Honokiol induces apoptosis through p53-independent pathway in human colorectal cell line RKO. World J Gastroenterol. 10:2205–2208. 2004.PubMed/NCBI
5	Wang X, Wang Y, Geng Y, Li F and Zheng C: Isolation and purification of honokiol and magnolol from cortex Magnoliae officinalis by high-speed counter-current chromatography. J Chromatogr A. 1036:171–175. 2004.PubMed/NCBI
6	Chang B, Lee Y, Ku Y, Bae K and Chung C: Antimicrobial activity of magnolol and honokiol against periodontopathic microorganisms. Planta Med. 64:367–369. 1998. View Article : Google Scholar : PubMed/NCBI
7	Ho KY, Tsai CC, Chen CP, Huang JS and Lin CC: Antimicrobial activity of honokiol and magnolol isolated from Magnolia officinalis. Phytother Res. 15:139–141. 2001. View Article : Google Scholar : PubMed/NCBI
8	Palayoor ST, Youmell MY, Calderwood SK, Coleman CN and Price BD: Constitutive activation of IkappaB kinase alpha and NF-kappaB in prostate cancer cells is inhibited by ibuprofen. Oncogene. 18:7389–7394. 1999. View Article : Google Scholar : PubMed/NCBI
9	Ikeda K, Sakai Y and Nagase H: Inhibitory effect of magnolol on tumour metastasis in mice. Phytother Res. 17:933–937. 2003. View Article : Google Scholar : PubMed/NCBI
10	Yang SE, Hsieh MT, Tsai TH and Hsu SL: Down-modulation of Bcl-XL, release of cytochrome c and sequential activation of caspases during honokiol-induced apoptosis in human squamous lung cancer CH27 cells. Biochem Pharmacol. 63:1641–1651. 2002. View Article : Google Scholar : PubMed/NCBI
11	Battle TE, Arbiser J and Frank DA: The natural product honokiol induces caspase-dependent apoptosis in B-cell chronic lymphocytic leukemia (B-CLL) cells. Blood. 106:690–697. 2005. View Article : Google Scholar : PubMed/NCBI
12	Hibasami H, Achiwa Y, Katsuzaki H, et al: Honokiol induces apoptosis in human lymphoid leukemia Molt 4B cells. Int J Mol Med. 2:671–673. 1998.PubMed/NCBI
13	Hirano T, Gotoh M and Oka K: Natural flavonoids and lignans are potent cytostatic agents against human leukemic HL-60 cells. Life Sci. 55:1061–1069. 1994. View Article : Google Scholar : PubMed/NCBI
14	Ishitsuka K, Hideshima T, Hamasaki M, et al: Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis. Blood. 106:1794–1800. 2005. View Article : Google Scholar : PubMed/NCBI
15	Choi MS, Lee SH, Cho HS, et al: Inhibitory effect of obovatol on nitric oxide production and activation of NF-kappaB/MAP kinases in lipopolysaccharide-treated RAW 264.7cells. Eur J Pharmacol. 556:181–189. 2007. View Article : Google Scholar : PubMed/NCBI
16	Kelly PN and Strasser A: The role of Bcl-2 and its pro-survival relatives in tumourigenesis and cancer therapy. Cell Death Differ. 18:1414–1424. 2011. View Article : Google Scholar : PubMed/NCBI
17	Ulukaya E, Acilan C and Yilmaz Y: Apoptosis: why and how does it occur in biology? Cell Biochem Funct. 29:468–480. 2011. View Article : Google Scholar : PubMed/NCBI
18	Lee SY, Yuk DY, Song HS, et al: Growth inhibitory effects of obovatol through induction of apoptotic cell death in prostate and colon cancer by blocking of NF-kappaB. Eur J Pharmacol. 582:17–25. 2008. View Article : Google Scholar : PubMed/NCBI
19	Kuo HP, Wang Z, Lee DF, et al: Epigenetic roles of MLL oncoproteins are dependent on NF-κB. Cancer cell. 24:423–437. 2013.PubMed/NCBI
20	Lucia SP: Leukemia: Evaluation of the Therapy. Cal West Med. 55:119–123. 1941.
21	Cory S, Huang DC and Adams JM: The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene. 22:8590–8607. 2003. View Article : Google Scholar : PubMed/NCBI
22	Pearson G, Robinson F, Beers Gibson T, et al: Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 22:153–183. 2001.PubMed/NCBI
23	Kane LP, Shapiro VS, Stokoe D and Weiss A: Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol. 9:601–604. 1999. View Article : Google Scholar : PubMed/NCBI