Obtusilactone B from <i>Machilus Thunbergii</i> Targets Barrier-to-Autointegration Factor to Treat Cancer

Kim, Wanil; Lyu, Ha-Na; Kwon, Hyunji; Kim, Ye Seul; Lee, Kyung-Ha; Kim, Do-Yeon; Chakraborty, Goutam; Choi, Kwan Yong; Yoon, Ho Sup; Kim, Kyong‐Tai

doi:10.1124/mol.112.082578

Cited by 26 publications

(33 citation statements)

References 31 publications

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“…Consistently, depletion of VRK1 from breast cancer cells results in retarded tumor growth and reduced incidence of metastasis in a murine orthotopic xenograft model 110 . Furthermore, the first inhibitor of BAF phosphorylation with an in vitro anti-cancer activity was recently isolated from a species of tree used in traditional medicine 111 . Another approach might aim to target the inhibitory interaction between LBR and importin-β because perturbation of this interaction also results in NE assembly failure, abnormal chromatin decondensation, and daughter cell death 88 .…”

Section: Synthetic Lethality With Abnormal Nuclear Architecture Of Camentioning

confidence: 80%

“…However, it is possible that the anti-cancer activity is linked to other roles of p97, such as the ER-associated protein degradation. Obtusilactone B is a new inhibitor of BAF phosphorylation by VRK1, and it also inhibits the proliferation of few cancer cells in vitro 111 . In line with this, drugs that directly or indirectly activate PP2A (e.g., ceramide, FTY7220, dithiolethione, etc.…”

Section: Synthetic Lethality With Abnormal Nuclear Architecture Of Camentioning

confidence: 88%

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Nuclear assembly as a target for anti-cancer therapies

Gorjánácz

2014

Nucleus

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Current anti-cancer therapies have a great deal of undesirable side effects; therefore, there is a need to develop efficient and cancer cell-specific new drugs without strong dose-limiting side effects. In my opinion, mechanisms of nuclear assembly and organization represent a novel platform for drug targets, which might fulfill these criteria. The nuclear stiffness and organization of some cancer types are often compromised, making them more vulnerable for further targeting the mechanisms of nuclear integrity than their normal counterparts. Here I will discuss the nuclear organization of normal cells and cancer cells, the molecular mechanisms that govern nuclear assembly with emphasis on those that, in my view, might be considered as targets for future anti-cancer therapies.

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Section: Synthetic Lethality With Abnormal Nuclear Architecture Of Camentioning

confidence: 80%

Section: Synthetic Lethality With Abnormal Nuclear Architecture Of Camentioning

confidence: 88%

Nuclear assembly as a target for anti-cancer therapies

Gorjánácz

2014

Nucleus

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“…We have reported that Obtusilactone B, an inhibitor of BAF phosphorylation, perturbs detachment of chromosomes from the nuclear envelope at S phase and M phase entry, thus displaying anticancer activity (Kim et al, 2013). However, treatment with Obtusilactone B did not result in obstruction of telophase, which would be more effective.…”

Section: Discussionmentioning

confidence: 99%

“…An in vitro kinase assay was performed in accordance with methods previously described elsewhere (Kim et al, 2013). In brief, an in vitro kinase assay was performed with His-VRK1 and its substrates, including His-BAF and His-H3 histone, in kinase buffer (50 mM 3-Nmorpholino)propanesulfonic acid, pH 7.2, 25 mM b-glycerophosphate, 10 mM EGTA, 4 mM EDTA, 50 mM MgCl, 0.5 mM dithiothreitol) containing [g-32 P]ATP (PerkinElmer) or ATP (Sigma-Aldrich).…”

Section: Protein Kinase Assay and Immunoblottingmentioning

confidence: 99%

Brazilin Isolated fromCaesalpinia sappanSuppresses Nuclear Envelope Reassembly by Inhibiting Barrier-to-Autointegration Factor Phosphorylation

Kim

Lyu

Kim

et al. 2014

J Pharmacol Exp Ther

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To date, many anticancer drugs have been developed by directly or indirectly targeting microtubules, which are involved in cell division. Although this approach has yielded many anticancer drugs, these drugs produce undesirable side effects. An alternative strategy is needed, and targeting mitotic exit may be one alternative approach. Localization of phosphorylated barrierto-autointegration factor (BAF) to the chromosomal core region is essential for nuclear envelope compartment relocalization. In this study, we isolated brazilin from Caesalpinia sappan Leguminosae and demonstrated that it inhibited BAF phosphorylation in vitro and in vivo. Moreover, we demonstrated direct binding between brazilin and BAF. The inhibition of BAF phosphorylation induced abnormal nuclear envelope reassembly and cell death, indicating that perturbation of nuclear envelope reassembly could be a novel approach to anticancer therapy. We propose that brazilin isolated from C. sappan may be a new anticancer drug candidate that induces cell death by inhibiting vaccinia-related kinase 1-mediated BAF phosphorylation.

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“…The bark of this plant has been used as a folk medicine for the treatment of leg oederma, abdominal pain and abdominal distension in Korea [15]. Lignans, alkaloids [20], flavonoids [9], butanolids [10] and essential oils [11] have been reported as components from M. thunbergii, some of which have hepatoprotective activity as antioxidants [27], antibacterial activity [7], and inhibitory activity on nitric oxide synthesis in activated macrophages [9]. Macelignan and meso-dihydroguaiaretic acid (MDGA), an active lignan compounds were isolated from the stem bark of M. thunbergii [20].…”

Section: Introductionmentioning

confidence: 99%

Tyrosinase Inhibitory Activities of Meso-dihydroguaiaretic Acid from Machilus thunbergii

Kwon¹,

Lee²,

Kim³

et al. 2015

Journal of Life Science

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Machilus thunbergii (Lauraceae) is an evergreen tree cultivated in Korea and Japan. M. thunbergii has long been used as a traditional medicine in Korea, China, and Japan to treat various diseases, including edema, abdominal pain, and abdominal distension. In this study, dried stem bark of M. thunbergii extracted in methanol and extract was partitioned into n-hexane, CHCl3, and BuOH. The CHCl3-soluble extracts chromatographed on silica gel column using a CHCl3/acetone and n-hexane/EtOAc mixture to afford Compound 1 and 2. Two dibenzylbutane lignans, macelignan (1) and meso-dihydroguaiaretic acid (2), were isolated from the CHCl3-soluble extract of M. thunbergii stem bark. The structures of 1 and 2 were determined by 1 H-and 13 C-NMR spectroscopic data analyses and a comparison with literature data. The tyrosinase inhibitory activity of the isolated compounds was evaluated. Among these compounds, Compound 2 strongly inhibited the monophenolase (IC50=10.2 μM) activity of tyrosinase. A kinetic analysis showed that Compound 2 was a competitive inhibitor. The apparent inhibition constant (Ki) for Compound 2 binding to free enzyme was 4.8 μM. Based on these results, it can be concluded that meso-dihydroguaiaretic acid (2) is a potential candidate for the treatment of melanin biosynthesis-related skin diseases.

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Obtusilactone B from Machilus Thunbergii Targets Barrier-to-Autointegration Factor to Treat Cancer

Cited by 26 publications

References 31 publications

Nuclear assembly as a target for anti-cancer therapies

Nuclear assembly as a target for anti-cancer therapies

Brazilin Isolated fromCaesalpinia sappanSuppresses Nuclear Envelope Reassembly by Inhibiting Barrier-to-Autointegration Factor Phosphorylation

Tyrosinase Inhibitory Activities of Meso-dihydroguaiaretic Acid from Machilus thunbergii

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