B4 suppresses lymphoma progression by inhibiting fibroblast growth factor binding protein 1 through intrinsic apoptosis.

Lymphoma positions as the fifth most common cancer, in the world, reporting remarkable deaths every year. Several promising strategies to counter this disease recently include utilizing small molecules that specifically target the lymphoma cellular proteins to overwhelm its progression. FGFBP1 is a soluble intracellular protein that progresses cancer cell proliferation and is upregulated in several cancers. Therefore, inhibiting FGFBP1 could significantly slow down lymphoma progression through triggering apoptosis. Thus, in this study, a flavonoid B4, isolated from Cajanus cajan, has been investigated for its effects of B4 on lymphoma, specifically as an FGFBP1 inhibitor. B4 could selectively hinder the growth of lymphoma cells by inducing caspase-dependent intrinsic apoptosis through G1/S transition phase cell cycle arrest. RNA sequencing analysis revealed that B4 regulates the genes involved in B-cell proliferation and DNA replication by inhibiting FGFBP1 in vitro. B4 increases the survival rate of lymphoma mice. B4 also represses the growth of patient-derived primary lymphoma cells through FGFBP1 inhibition. Drug affinity responsive target stability experimentations authorize that B4 powerfully binds to FGFBP1. The overexpression of FGFBP1 raises the pharmacological sensitivity of B4, supplementing its specific action on lymphoma cells. This study pioneers the estimation of B4 as a possible anticancer agent for lymphoma treatment. These outcomes highlight its selective inhibitory effects on lymphoma cell growth by downregulating FGFBP1 expression through intrinsic apoptosis, causing mitochondrial and DNA damage, ultimately leading to the inhibition of lymphoma progression. These suggest B4 may be a novel FGFBP1 inhibitor for the lymphoma treatment.

Monoterpene-chalcone conjugates and diarylheptanoids isolated from the seeds of Alpinia katsumadai Hayata with cytotoxic activity.

Five undescribed monoterpene-chalcone conjugates (1-5), one undescribed hypothetical precursor of diarylheptanoid (6), two undescribed diarylheptanoids (7-8), and fourteen known compounds (9-22) were isolated from the seeds of Alpinia katsumadai. Their structures were elucidated through the interpretation of HRESIMS, NMR, ECD, and X-ray diffraction data. MTT assays on human cancer cell lines (HepG2, A549, SGC7901, and SW480) revealed that compounds 3-8, 11, and 13 exhibited broad-spectrum antiproliferative activities with IC50 values ranging from 3.59 to 21.78 µM. B cell lymphoma 2 was predicted as the target of sumadain C (11) by network pharmacology and verified by homogeneous time-resolved fluorescence assay and molecular docking.

Stilbene B10 induces apoptosis and tumor suppression in lymphoid Raji cells by BTK-mediated regulation of the KRAS/HDAC1/EP300/PEBP1 axis.

Lymphoma is a cancer of the lymphoid cells that originated in matured B or T cells. The bioactive natural compounds can efficiently treat this disease with lesser side effects. Thus, in this study, a natural stilbene B10 (3-methoxy 5-hydroxy stilbene) isolated from Cajanus cajan (Pigeon Pea) was screened for its anti-proliferative efficacy against 13 cancer cell lines. B10 showed a potential effect on the human lymphoma (Raji) cells. Cytotoxicity analysis of B10 has revealed IC50 concentrations in Raji cells at low doses (18 µM) than other cancer cell lines. The B10 could significantly cause dose and time-dependent inhibition in the proliferation of Raji cells triggering intrinsic apoptosis and S/G1 phase cellular arrest. There was an increased expression of phospho-γ-H2A.X and decreased expression of cyclin D1, causing DNA damage and cell cycle arrest, post- B10 treatments. The mitochondrial membrane potential (MMP) variations observed after B10 treatment led to changes in Bax/Bcl-2 ratio, cytochrome C release, and enhanced expression of cleaved caspase3, 9, PARP-1, and APAF-1. The B10 inhibited the proliferation of Raji cells by significantly downregulating the expression of KRAS, BTK, MDM2, P-JAK2, P-STAT3, PI3K, HDAC1/2, SIRT7, and EP300. The treatment upregulated the tumor suppressor genes PEBP1 and SAP18. Thus, the study could reveal the selective inhibitory effects of B10 on lymphoma, suggesting it as a probable innovative chemotherapeutic agent.

Baicalein resensitizes tamoxifen-resistant breast cancer cells by reducing aerobic glycolysis and reversing mitochondrial dysfunction via inhibition of hypoxia-inducible factor-1α.

Drug resistance is a major hurdle for the effectiveness of tamoxifen (TAM) to provide clinical benefit. Therefore, it is essential to identify a sensitizer that could be used to improve TAM efficacy in treating TAM-resistant breast cancer. Here, we investigated the ability of baicalein to reverse TAM resistance. We found that baicalein increased the efficacy of TAM in inhibiting proliferation and inducing apoptosis of TAM-resistant cells. It also enhanced the TAM-induced growth reduction of resistant cells from NOD/SCID mouse mammary fat pads, without causing obvious systemic toxicity. Analyses using the CellMiner tool and the Kaplan-Meier plotter database showed that HIF-1α expression was inversely correlated with TAM therapeutic response in NCI-60 cancer cells and breast cancer patients. HIF-1α expression was increased in TAM-resistant cells due to an increase in mRNA levels and reduced ubiquitin-mediated degradation. Baicalein reduced HIF-1α expression by promoting its interaction with PHD2 and pVHL, thus facilitating ubiquitin ligase-mediated proteasomal degradation and thereby suppressing the nuclear translocation, binding to the hypoxia-response element, and transcriptional activity of HIF-1α. As a result, baicalein downregulated aerobic glycolysis by restricting glucose uptake, lactate production, ATP generation, lactate/pyruvate ratio and expression of HIF-1α-targeted glycolytic genes, thereby enhancing the antiproliferative efficacy of TAM. Furthermore, baicalein interfered with HIF-1α inhibition of mitochondrial biosynthesis, which increased mitochondrial DNA content and mitochondrial numbers, restored the generation of reactive oxygen species in mitochondria, and thus enhanced the TAM-induced mitochondrial apoptotic pathway. The HIF-1α stabilizer dimethyloxallyl glycine prevented the baicalein-induced downregulation of glycolysis and mitochondrial biosynthesis and reduced the effects of baicalein on reversing TAM resistance. Our results indicate that baicalein is a promising candidate to help overcome TAM resistance by sensitizing resistant cells to TAM-induced growth inhibition and apoptosis. The mechanism underlying the effects of baicalein consists of inhibition of HIF-1α-mediated aerobic glycolysis and mitochondrial dysfunction.

Oxymatrine Synergistically Enhances Doxorubicin Anticancer Effects in Colorectal Cancer.

The combination of chemotherapy with natural products is a common strategy to enhance anticancer effects while alleviating the dose-dependent adverse effects of cancer treatment. Oxymatrine (OMT) has been extensively reported as having anticancer activity. Doxorubicin (DOX) is a chemotherapeutic DNA-damaging agent used for the treatment of carcinoma. In this study, we investigated whether synergistic effects exist with the combination treatment with OMT and DOX using human colorectal cancer cell (CRC) lines and the potential mechanisms involved in in vitro and in vivo activities. The MTT and colony formation assay results showed that compared to either OMT or DOX monotherapy, the combination of OMT + DOX markedly inhibited the growth of HT-29 and SW620 cells. Wound healing assays showed significant inhibition of cell migration with co-treatment, supported by the change in E-cadherin and N-cadherin expressions in Western blotting. Furthermore, flow cytometry analysis revealed that OMT + DOX co-treatment enhanced cell apoptosis as a result of ROS generation, whereas NAC attenuated OMT + DOX-induced apoptosis. Similarly, the apoptosis-related proteins (cleaved caspase-3, cleaved caspase-9, and the ratio of Bax/Bcl-2) were determined by Western blotting, which showed that the expressions of these markers were notably increased in the co-treatment group. Furthermore, co-administration of a low dose of DOX and OMT inhibited xenograft tumor growth in a dose-dependent manner. TUNEL assay and Ki67 staining images indicated more apoptosis and less proliferation occurred in OMT plus DOX-treated xenograft tumors. Meanwhile, the combination strategy decreased cardiotoxicity, which is the most serious side effect of DOX. RNA sequencing was performed to explore the precise molecular alterations involved in the combination group. Among the numerous differentially expressed genes, downregulated FHL-2 and upregulated cleaved SPTAN1 were validated in both mRNA and protein levels of HT-29 and SW620 cells. These two proteins might play a pivotal role involving in OMT + DOX synergistic activity. Overall, OMT in combination with DOX presented an outstanding synergistic antitumor effect, indicating that this beneficial combination may offer a potential therapy for CRC patients.

Oxymatrine reverses epithelial-mesenchymal transition in breast cancer cells by depressing αâ ¤ß3 integrin/FAK/PI3K/Akt signaling activation.

PURPOSE: Oxymatrine, an alkaloid extracted from the Chinese herb Sophora flavescens Aiton, possesses anti-inflammatory, anti-immune, anti-hepatic fibrosis, and anti-cancer properties. However, the effects of oxymatrine on epithelial-mesenchymal transition (EMT) of breast cancer cells are still unclear. AIM: The present study was performed to investigate whether oxymatrine reverses EMT in breast cancer cells and to explore the underlying molecular mechanisms. MATERIALS AND METHODS: MTT assay was performed to evaluate cell viability. Wound-healing assay and transwell chamber assay were used to assess cell migration and invasion, respectively. Immunofluorescence and Western blot were used to study the expression of EMT-related molecules and αⅤß3 integrin/focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling transduction. Fibronectin, a physiologic ligand of αⅤß3 integrin, was used to stimulate αⅤß3 integrin signaling. RESULTS: Our results demonstrated that oxymatrine effectively suppressed the viability of MDA-MB-231 and 4T1 breast cancer cells, and oxymatrine showed less cytotoxicity on normal breast mammary epithelial MCF-10A cells. In addition, oxymatrine reversed EMT in the MDA-MB-231 and 4T1 cells at nontoxic concentrations. Oxymatrine significantly inhibited cell migration and invasion, downregulated the expression of N-cadherin, vimentin, and Snail in MDA-MB-231 and 4T1 cells, but upregulated the expression of E-cadherin in 4T1 cells. The mechanism revealed that oxymatrine decreased the expression of αⅤ and ß3 integrin and their co-localization. It also inhibited αⅤß3 integrin downstream activation by suppressing the phosphorylation of FAK, PI3K, and Akt. Furthermore, oxymatrine prevented fibronectin-induced EMT and αⅤß3 integrin/FAK/PI3K/Akt signaling activation. CONCLUSION: Our results revealed that oxymatrine effectively reversed EMT in breast cancer cells by depressing αⅤß3 integrin/FAK/PI3K/Akt signaling. Thus, oxymatrine could be a potential therapeutic candidate with anti-metastatic potential for the treatment of breast cancer.

Two new cytotoxic stilbenoid dimers isolated from Cajanus cajan.

Two new stilbenoid dimers, cajanstilbenoids A (1) and B (2), were isolated from the leaves of Cajanus cajan. Planar structures of these compounds were verified by NMR (1D and 2D) and high-resolution electrospray ionization mass spectroscopy (HR-ESI-MS). Absolute configurations were assigned by comparing experimental and calculated electronic CD values. The cytotoxicity of 1 and 2 against human hepatoma (HepG2), human breast adenocarcinoma (MCF-7), and human lung cancer (A549) cells were evaluated in vitro. Compound 1 showed strong cytotoxicity against all the tested cell lines (IC50 values: 2.14-2.56 µM), whereas compound 2 showed strong toxicity only against HepG2 (IC50 value: 5.99 µM) and A549 cells (IC50 value: 6.18 µM).

Two new sesquiterpene lactones from the fruits of Illicium jiadifengpi.

Two new seco-prezizaane-type sesquiterpenes, 3,4-dehydroneomajucin (1) and 1,2,3,4-tetradehydroneomajucin (2), were isolated from the fruits of Illicium jiadifengpi. The structure of these compounds was determined using 1D and 2D NMR and ESI-MS. The isolates were evaluated for their anti-hepatitis B virus activities on the Hep G2.2.15 cell line. The inhibitory rates of compounds 1 and 2 on the HBeAg and HBsAg expression were 30.08 ± 3.09% and 11.43 ± 1.92% at a concentrations of 68.00 µM and 7.88 ± 1.21% and 16.96 ± 4.24% at a concentration of 68.50 µM, respectively.

A Halogen-Containing Stilbene Derivative from the Leaves of Cajanus cajan that Induces Osteogenic Differentiation of Human Mesenchymal Stem Cells.

A new natural halogen-containing stilbene derivative was isolated from the leaves of Cajanus cajan (L.) Millsp. and identified as 3-O-(3-chloro-2-hydroxyl-propanyl)-longistylin A by comprehensive spectroscopic and chemical analysis, and named cajanstilbene H (1). It is the first halogen-containing stilbene derivative found from plants. In human mesenchymal stem cells (hMSC) from bone marrow, 1 did not promote cell proliferation, but distinctly enhanced osteogenic differentiation of hMSC in time- and dose-dependent manners. In six human cancer cell lines, 1 showed a moderate inhibitory effect on cell proliferation, with IC50 values of 21.42-25.85 µmol·L(-1).

Synthesis and cytotoxicity of longistylin C derivatives.

The present study was designed to identify potent anti-tumor compounds from a series of new longistylin C derivatives. Ten longistylin C derivatives were synthesized and their structures were confirmed by (1)H NMR, MS, and elemental analyses. Their cytotoxicity in vitro against three human cancer cell lines (A549, HepG2, and MCF-7) were evaluated by the MTT assay. Among these compounds, DT-6 and DT-9 displayed much better cytotoxicity against A549, HepG2, and MCF-7 cells, DT-1 exhibited selective cytotoxicity against HepG2, and the structure-activity relationships were investigated. In conclusion, Compounds DT-6 and DT-9 may serve as potential lead compounds for the discovery of new anti-cancer drugs.

A new inositol triester from Taraxacum mongolicum.

One new inositol triester, 4,5,6-tri-O-p-hydroxyphenylacetyl-chiro-inositol (1), was isolated from the ethanolic extract of Taraxacum mongolicum, along with two known compounds, 11ß,13-dihydrotaraxinic acid (2) and taraxinic acid ß-d-glucopyranosyl ester (3). The isolates were tested for their anti-hepatitis B virus (HBV) activities; 11ß,13-dihydrotaraxinic acid (2) exhibited an IC50 value of 0.91 mM inhibiting the secretion of the HBV surface antigen and an IC50 value of 0.34 mM inhibiting the secretion of the HBV e antigen using HBV transfected Hep G2.2.15 cell line.

A new quassinoid from fruits of Brucea javanica.

A new minor quassinoid named bruceine M (1), together with 12 known quassinoids (2-13), was isolated from the fruits of Brucea javanica (Simaroubaceae). Their structures were determined by interpretation of NMR and HR-ESI-MS data. The structures of the known compounds were confirmed by comparison of their spectral data with those reported in the literatures. In vitro cytotoxicity of the isolated compounds against cancer cell lines Bel-7404, MCF-7 and A549 was evaluated. Compounds 4, 6 and 9 exhibited significant growth inhibitory activity against three cancer cell lines.

A new flavanocoumarin from the root of Flemingia philippinensis.

One new flavanocoumarin, flemicoumarin A (1) was isolated from the EtOAc-soluble partition of the root of Flemingia philippinensis, along with three known compounds, namely 4,2'-epoxy-4',5-dihydroxy-7,5'-dimethoxy-3-phenylcoumarin (2), kaempferol 6-C-glucoside (3) and dracocephaloside (4). The structure of compound 1 was elucidated on the basis of its 1D, 2D NMR, CD and MS data. The structures of the known compounds were identified by comparison of their spectroscopic data with those reported in the literature. Compounds 1-4 exhibited inactivity against MCF-7, A549 and Hep-G2 human cancer cell lines in vitro by MTT colorimetric assay.

Two new lignans from the stems of Schisandra bicolor.

Two new lignans, named zuihonins E (1) and F (2), were isolated from the stems of Schisandra bicolor Cheng var. tuberculata Law. The structures of the new lignans were elucidated on the basis of extensive spectroscopic analysis, including 1D, 2D NMR, and MS experiments, and their absolute stereochemistry was determined by circular dichroism spectrum. Compounds 1 and 2 did not inhibit the growth of hepatoma carcinoma cell (HepG2), lung carcinoma cell (A549), and human breast carcinoma (MCF-7) cell lines.