Ursolic acid exerts anti-cancer activity by suppressing vaccinia-related kinase 1-mediated damage repair in lung cancer cells.

Many mitotic kinases have been targeted for the development of anti-cancer drugs, and inhibitors of these kinases have been expected to perform well for cancer therapy. Efforts focused on selecting good targets and finding specific drugs to target are especially needed, largely due to the increased frequency of anti-cancer drugs used in the treatment of lung cancer. Vaccinia-related kinase 1 (VRK1) is a master regulator in lung adenocarcinoma and is considered a key molecule in the adaptive pathway, which mainly controls cell survival. We found that ursolic acid (UA) inhibits the catalytic activity of VRK1 via direct binding to the catalytic domain of VRK1. UA weakens surveillance mechanisms by blocking 53BP1 foci formation induced by VRK1 in lung cancer cells, and possesses synergistic anti-cancer effects with DNA damaging drugs. Taken together, UA can be a good anti-cancer agent for targeted therapy or combination therapy with DNA damaging drugs for lung cancer patients.

Brazilin Isolated from Caesalpinia sappan suppresses nuclear envelope reassembly by inhibiting barrier-to-autointegration factor phosphorylation.

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 barrier-to-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.

Luteolin suppresses cancer cell proliferation by targeting vaccinia-related kinase 1.

Uncontrolled proliferation, a major feature of cancer cells, is often triggered by the malfunction of cell cycle regulators such as protein kinases. Recently, cell cycle-related protein kinases have become attractive targets for anti-cancer therapy, because they play fundamental roles in cellular proliferation. However, the protein kinase-targeted drugs that have been developed so far do not show impressive clinical results and also display severe side effects; therefore, there is undoubtedly a need to investigate new drugs targeting other protein kinases that are critical in cell cycle progression. Vaccinia-related kinase 1 (VRK1) is a mitotic kinase that functions in cell cycle regulation by phosphorylating cell cycle-related substrates such as barrier-to-autointegration factor (BAF), histone H3, and the cAMP response element (CRE)-binding protein (CREB). In our study, we identified luteolin as the inhibitor of VRK1 by screening a small-molecule natural compound library. Here, we evaluated the efficacy of luteolin as a VRK1-targeted inhibitor for developing an effective anti-cancer strategy. We confirmed that luteolin significantly reduces VRK1-mediated phosphorylation of the cell cycle-related substrates BAF and histone H3, and directly interacts with the catalytic domain of VRK1. In addition, luteolin regulates cell cycle progression by modulating VRK1 activity, leading to the suppression of cancer cell proliferation and the induction of apoptosis. Therefore, our study suggests that luteolin-induced VRK1 inhibition may contribute to establish a novel cell cycle-targeted strategy for anti-cancer therapy.

Flavonoids from the grains of C1/R-S transgenic rice, the transgenic Oryza sativa spp. japonica, and their radical scavenging activities.

The transgenic rice cultivar of Oryza sativa spp. japonica cv. Hwa-Young, C1/R-S transgenic rice (C1/R-S rice), is a flavonoid-rich cultivar of rice. The grains of C1/R-S rice were extracted with aqueous MeOH, and the concentrated extract was partitioned with EtOAc, n-BuOH, and H2O, successively. Repeated silica gel, octadecyl silica gel (ODS), and Sephadex LH-20 column chromatographies for the EtOAc and n-BuOH fractions afforded four new flavonoids (compounds 2, 3, 7, and 8) along with four known flavonoids: (+)-3'-O-methyltaxifolin (1), brassicin (4), isorhamnetin-4'-O-ß-D-glucosyranoside (5), and 3'-O-methyltaxifolin-5-O-ß-D-glucopyranoside (6). The new flavonoids were identified as 3'-O-methyltaxifolin-7-O-ß-D-glucopyranoside (2), 3'-O-methyltaxifolin-4'-O-ß-D-glucopyranoside (3), isorhamnetin-7-O-ß-D-cellobioside (brassicin-4″-O-ß-D-glucopyranoside) (7), and brassicin-4'-O-ß-D-glucosyranoside (8) from the result of spectroscopic data including nuclear magnetic resonance spectrometry (NMR), mass spectrometry (MS), and infrared spectroscopy (IR). Also, quantitative analysis of major flavonoids (compounds 2, 3, and 8) in C1/R-S rice, O. sativa spp. japonica cv. Hwa-Young (HY), and a hybrid of two cultivar (C1/R-S rice/HY) extracts was performed using HPLC experiment. The isolated flavonoids were evaluated for their radical-scavenging effect on DPPH and ABTS radicals.

Obtusilactone B from Machilus Thunbergii targets barrier-to-autointegration factor to treat cancer.

Targeting specific molecules is a promising cancer treatment because certain types of cancer cells are dependent on specific oncogenes. This strategy led to the development of therapeutics that use monoclonal antibodies or small-molecule inhibitors. However, the continued development of novel molecular targeting inhibitors is required to target the various oncogenes associated with the diverse types and stages of cancer. Obtusilactone B is a butanolide derivative purified from Machilus thunbergii. In this study, we show that obtusilactone B functions as a small-molecule inhibitor that causes abnormal nuclear envelope dynamics and inhibits growth by suppressing vaccinia-related kinase 1 (VRK1)-mediated phosphorylation of barrier-to-autointegration factor (BAF). BAF is important in maintaining lamin integrity, which is closely associated with diseases that include cancer. Specific binding of obtusilactone B to BAF suppressed VRK1-mediated BAF phosphorylation and the subsequent dissociation of the nuclear envelope from DNA that allows cells to progress through the cell cycle. Obtusilactone B potently induced tumor cell death in vitro, indicating that specific targeting of BAF to block cell cycle progression can be an effective anticancer strategy. Our results demonstrate that targeting a major constituent of the nuclear envelope may be a novel and promising alternative approach to cancer treatment.

Lignans from the fruits of the red pepper (Capsicum annuum L.) and their antioxidant effects.

The fruits of Capsicum annuum were extracted using 80% aqueous MeOH, and fractionated using EtOAc and water. Repeated column chromatography using silica gel, octadecyl silica gel, and Sephadex LH-20 for the EtOAc fraction led to the isolation of a new lignan glycoside and a known one, icariside E(5). From the results of spectroscopic data, including EIMS, FABMS, UV, IR, (1)H and (13)C-NMR, DEPT, and 2D-NMR (COSY, HSQC, HMBC), the chemical structure of the new lignan glycoside was determined as (8R)-isodehydrodiconiferyl alcohol-4'-O-(6''-vanilloyl)-beta-D-glucopyranoside named vanilloylicariside E(5). All isolated compounds were tested for antioxidant activities using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Icariside E(5) (2) and (8R)-Isodehydrodiconiferyl alcohol (3) exhibited a strong scavenging effect on DPPH (2: IC(50)=42.1 microM, 3: IC(50)=4.5 microM).