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The Croton genus (Euphorbiaceae) is recognized as a promising source for identifying bioactive compounds with antiproliferative activity. However, knowledge on the chemical composition and activity of Croton floribundus, Croton echinocarpus, and Croton zehntneri is limited. Thus, this study aimed to investigate the antiproliferative activity of these species on cells derived from tumoral breast, lung, and melanoma cells, and primary fibroblasts derived from human skin. Metabolomic strategies were applied via ultra-performance liquid chromatography coupled with high-resolution mass spectrometry and multivariate statistical analysis to target the main active compound. The C. floribundus leaf extract exhibited the highest activity, with an IC 50 value lower than that of the reference drug - temozolomide - in the most responsive cell line - SK-MEL-147 - and in all the evaluated melanoma cell lines (SK-MEL-147, CHL-1 and WM-1366). Four tetrahydrofurofuran lignans were isolated for the first time from the most promising fraction of the C. floribundus extract. According to the metabolomic and multivariate statistical analyses, the isolated lignan epi-yangambin constituted the main antiproliferative compound against SK-MEL-147; furthermore, it exhibited selective antiproliferative activity for this cell line (IC 50  = 13.09 μg/mL and selectivity index = 3.82; temozolomide, IC 50  = 121.50 μg/mL) due to, at least in part, its ability to inhibit cell cycle progression at G2/M. This is especially relevant considering the high resistance of melanoma cells to available drugs. Thus, epi-yangambin can serve as a prototype for further antiproliferative investigations., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Three new annonaceous acetogenins, annotemoyin L ( 1 ), annotemoyin Y ( 2 ) and annotemoyin X, ( 3 ) were isolated from the seeds of Annona squamosa Linn. Their structures were ascertained by chemical methods and spectral data. The cytotoxic activities of compounds against three multidrug-resistant cancer cell lines were evaluated, and compound 3 exerted strong cytotoxicity against SMMC 7721/ADR (IC 50 0.163 μM), A549/T (IC 50 0.064 μM) and MCF-7/ADR (IC 50 0.057 μM).

Today, herbal-derived compounds are being increasingly studied in cancer treatment. Over the past decade, Arctigenin has been introduced as a bioactive dibenzylbutyrolactone lignan which is found in Chinese herbal medicines. In addition to anti-microbial, anti-inflammatory, immune-modulatory functions, Arctigenin has attracted growing attention due to its anti-tumor capabilities. It has been shown that Arctigenin can induce apoptosis and necrosis and abolish drug resistance in tumor cells by inducing apoptotic signaling pathways, caspases, cell cycle arrest, and the modulating proteasome. Moreover, Arctigenin mediates other anti-tumor functions through several mechanisms. It has been demonstrated that Arctigenin can act as an anti-inflammatory compound to inhibit inflammation in the tumor microenvironment. It also downregulates factors involved in tumor metastasis and angiogenesis, such as matrix metalloproteinases, N-cadherin, TGF-β, and VEGF. Additionally, Arctigenin, through modulation of MAPK signaling pathways and stress-related proteins, is able to abolish tumor cell growth in nutrient-deprived conditions. Due to the limited solubility of Arctigenin in water, it is suggested that modification of this compound through amino acid esterification can improve its pharmacogenetic properties. Collectively, it is hoped that using Arctigenin or its derivates might introduce new chemotherapeutic approaches in future treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Northeast Thailand has the highest incidence of cholangiocarcinoma (CCA) in the world. The lack of promising diagnostic markers and appropriate therapeutic drugs is the main problem for metastatic stage CCA patients who have a poor prognosis. N-cadherin, a cell adhesion molecule, is usually upregulated in cancers and has been proposed as an important mediator in epithelial-mesenchymal transition (EMT), one of the metastasis processes. Additionally, it has been shown that arctigenin, a seed isolated compound from Arctium lappa, can inhibit cancer cell progression via suppression of N-cadherin pathway. In this study, we investigated the protein expression of N-cadherin and its correlation with clinicopathological data of CCA patients, as well as the impact of arctigenin on KKU-213A and KKU-100 CCA cell lines and its underlying mechanisms. Immunohistochemistry results demonstrated that high expression of N-cadherin was significantly associated with severe CCA stage (p = 0.027), and shorter survival time (p = 0.002) of CCA patients. The mean overall survival times between low and high expression of N-cadherin were 31.6 and 14.8 months, respectively. Wound healing assays showed that arctigenin significantly inhibited CCA cell migration by downregulating N-cadherin whereas upregulating E-cadherin expression. Immunocytochemical staining revealed that arctigenin suppressed the expression of N-cadherin in both CCA cell lines. Furthermore, flow cytometry and western blot analysis revealed that arctigenin significantly reduced CCA cell viability and induced apoptosis via the Bax/Bcl-2/caspase-3 pathway. This research supports the use of N-cadherin as a prognostic marker for CCA and arctigenin as a potential alternative therapy for improving CCA treatment outcomes., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: The effects of atractylodin (ATD), the bioactive compound from Atractylodes lancea, on migration and autophagy status of cholangiocarcinoma cell line were investigated., Methods: Cytotoxic activity and effects on cell migration and invasion were evaluated by MTT and trans-well assay, respectively. Autophagy and underlying molecular mechanisms were investigated using flow cytometry and western blot analysis., Key Findings: ATD regulated the activity of PI3K/AKT/mTOR and p38MAPK signalling pathways which contributed to autophagy induction. HuCCT-1 cell growth was inhibited by ATD in a time- and dose-dependent manner. ATD inhibited the migration and invasion of HuCCT1 cells in a concentration-dependent manner. It also induced autophagy in HuCCT1 cells in a time- and dose-dependent manner. The SB202190 (autophagy inducer) and 3-MA (autophagy inhibitor) significantly increased and decreased the rate of ATD-induced autophagy, respectively. The 24 h exposure of ATD inhibited the phosphorylation of phosphatidylinositol-3-kinase (PI3K), protein kinase B (AKT), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (p38MAPK) and increased Beclin-1 expression and LC3 conversion. It also reduced p-AKT/AKT, p-mTOR/mTOR and p-p38MAPK/p38MAPK., Conclusions: ATD inhibits the proliferation and induces CCA cell autophagy via regulating PI3K/AKT/mTOR and p38MAPK signalling pathways., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Salvia miltiorrhiza (Danshen) is a well-known traditional Chinese medicine for treating various diseases, such as breast cancer. However, knowledge regarding its mechanisms is scant. Herein, the active ingredient dihydrotanshinone I (DHT) in Salvia miltiorrhiza extract (SME), which binds ERp57 was identified and verified by an enzymatic solid-phase method combined with LC-MS/MS. DHT potentially inhibited ERp57 activity and suppressed ERp57 expression at both the RNA and protein levels. Molecular docking simulation indicated that DHT could form a hydrogen bond with catalytic site of ERp57. Moreover, ERp57 overexpression decreased DHT-induced cytotoxicity in MDA-MB-231 cells. Thereafter, the signaling pathway downstream of ERp57 was investigated by Western blot analysis. The mechanistic study revealed that DHT treatment resulted in activation of endoplasmic reticulum (ER) stress, the unfolded protein response (UPR), and cellular apoptosis. In conclusion, our data implied that DHT targeted ERp57 for inhibition and induced ER stress and UPR activation, which in turn triggered breast cancer cell apoptosis., (Copyright © 2021. Published by Elsevier Inc.)

Arctigenin (ARG), a natural lignans compound isolated from Arctium lappa L. In this study, the anti-tumor effect of ARG on prostate cancer cell PC-3M and the mechanism of apoptosis and autophagy induced by phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway were discussed, and further confirmed by the joint treatment of ARG and PI3K inhibitor LY294002. Here, the effect of ARG on cell viability was evaluated in PC-3M cells by Cell Counting Kit-8 reagent (CCK-8) assay. After the treatment of ARG, colony formation assay was used to detect the anti-proliferation effect. Annexin V-fluoresceine isothiocyanate/propidium iodide (FITC/PI) kit and 4',6-diamidino-2-phenylindole (DAPI) staining were used to detect the apoptosis level, and cell cycle changes were analyzed by flow cytometry. The expression of autophagy was detected by acridine orange staining. In addition, the expression levels of apoptosis and autophagy-related proteins were analyzed by Western blot. The result showed that different concentrations of ARG inhibited the proliferation of PC-3M cells. DAPI staining and flow cytometry showed that ARG induced PC-3M cell apoptosis and arrested cell in G0/G1 phase. Acridine orange staining showed that ARG induced autophagy in PC-3M cells. Western blot experiments showed that ARG inhibited the expression of Bcl-2, promoted the expression of Bax and cleaved caspase-3. At the same time, the expression of autophagy-related proteins LC3B-II and Beclin-1 increased after ARG treatment, but P62 decreased. In addition, further studies have shown that treatment with LY294002 enhanced the effects of ARG on the expression of proteins associated with apoptosis and autophagy, indicating that ARG may induce apoptosis and autophagy through PI3K/Akt/mTOR pathway.

Objective: Cryptotanshinone (CPT) and dihydrotanshinone (DHT) are diterpenoid anthraquinone compounds extracted from traditional Chinese herbal medicine (TCM). Recent studies have shown that CPT regulates the signal transduction pathways via microRNA (miRNA) alterations. However, few studies have investigated the role of DHT in miRNA alterations affecting cell-signaling pathways. This study aimed to investigate the miRNA alterations and post-transcriptional regulation activities of DHT in comparison to CPT., Methods: HepG2 and HT-29 cells were treated with DHT or CPT for 72 h. MiRNA, transcription factor encoding mRNA, and downstream gene expression were determined using real-time quantitative PCR. Protein expression was analyzed using western blotting., Results: The results revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via miR-15a-5p, miR-27a-5p, miR-100-5p, and miR-200a-5p alterations.In silico target predictions showed that downregulation of epidermal growth factor receptor (EGFR) mRNA expression by DHT might also suppress the expression of STAT family proteins and lead to anti-proliferation effects. We also found that, compared to CPT, DHT might possess higher potency in cell growth regulation via multi-miRNA and transcription factor alterations., Conclusion: This study revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via alterations in miRNAs and transcription factors. In addition, the findings of this study suggest that DHT is more potent than CPT in cancer chemopreventive activities. Therefore, DHT at a low dose is a TCM compound with less toxic side effects and may contribute to the development of natural medicine as a potential cancer chemopreventive agent., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Signal transducer and activator of transcription 3 (STAT3) is aberrantly activated in many human cancers. We tried to find STAT3 inhibitors from natural sources and found that Xanthium fruit extracts decreased phosphorylation of STAT3-Y705. 8-Epi-xanthatin (EXT) was isolated from the extracts. When DU145 cancer cells were treated with EXT, p-STAT3-Y705 was decreased with an IC 50 of 3.2 μM. EXT decreased the expression of STAT3 target genes, such as cyclin A, cyclin D1, and BCL-2, and induced PARP cleavage, indicating apoptotic cell death. Downregulation of EXT-induced p-STAT3-Y705 was rescued by pretreating DU145 cells with antioxidants, such as N-acetyl-L-cysteine (NAC), indicating that reactive oxygen species (ROS) were involved in the EXT-induced inhibition of STAT3 activation. Furthermore, we proved the association of EXT with STAT3 protein by using a drug affinity responsive target stability (DARTS) assay and a cellular thermal shift assay (CETSA). EXT inhibited proliferation of DU145 cells with a GI 50 of 6 μM and reduced tumor growth in mice xenografted with DU145 cells. Immunoblotting showed that phosphorylation of STAT3-Y705 was lower in EXT-treated tumor tissue than in control tissues. Collectively, we found that EXT binds to, and inhibits, STAT3 activation and could be a lead compound for anticancer therapy., (© 2020 John Wiley & Sons Ltd.)

Two new dihydrophenanthrofurans (1 and 2) and two new bisbibenzyl derivatives (3 and 4) were isolated from the traditional Chinese medicinal plant Dendrobium nobile, along with four known compounds (5-8). The absolute configurations of compounds 1 and 4 were elucidated through extensive NMR and ECD spectroscopic analyses. New compounds showed no antimicrobial activity against four gram-positive bacterial strains and four gram-negative bacteria at the concentration of 1 mg/mL, but displayed significant cytotoxic activity against HepG2 human hepatic cell line with the IC 50 values ranging from 1.25 μM to 19.47 μM., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Arctigenin is a natural lignan that is found in burdock with anti‑viral, ‑oxidative, ‑inflammatory and anti‑tumor activities. In the current study, the effect of arctigenin on metastatic potential was examined in 4T‑1 mouse triple‑negative breast cancer cells. The results indicated that arctigenin inhibited cell motility and invasiveness, which was determined using wound healing and transwell invasion assays. Arctigenin suppressed matrix metalloprotease‑9 (MMP‑9) activity via gelatin zymography, and protein expression of cyclooxygenase‑2 (COX‑2) and MMP‑3. Furthermore, arctigenin attenuated the mRNA expression of metastatic factors, including MMP‑9, MMP‑3 and COX‑2. Based on these results, the effect of arctigenin on the mitogen‑activated protein kinase (MAPK)/activating protein‑1 (AP‑1) signaling pathway was assessed in an attempt to identify the regulatory mechanism responsible for its anti‑metastatic effects. Arctigenin was demonstrated to inhibit the phosphorylation of extracellular signal‑regulated protein kinase (ERK) and c‑Jun N‑terminal kinase (JNK), and the nuclear translocations of the AP‑1 subunits, c‑Jun and c‑Fos. In summary, the present study demonstrated that in 4T‑1 mouse triple‑negative breast cancer cells the anti‑metastatic effect of arctigenin is mediated by the inhibition of MMP‑9 activity and by the inhibition of the metastasis‑enhancing factors MMP‑9, MMP‑3 and COX‑2, due to the suppression of the MAPK/AP‑1 signaling pathway. The results of the current study demonstrated that arctigenin exhibits a potential for preventing cell migration and invasion in triple negative breast cancer.

Xanthatin is a natural sesquiterpene lactone purified from Xanthium strumarium L., which has shown prominent antitumor activity against a variety of cancer cells. In the current study, we investigated the effect of xanthatin on the growth of glioma cells in vitro and in vivo, and elucidated the underlying mechanisms. In both rat glioma C6 and human glioma U251 cell lines, xanthatin (1-15 μM) dose-dependently inhibited cell viability without apparent effect on the cell cycle. Furthermore, xanthatin treatment dose-dependently induced glioma cell apoptosis. In nude mice bearing C6 glioma tumor xenografts, administration of xanthatin (10, 20, 40 mg·kg -1 ·d -1 , ip, for 2 weeks) dose-dependently inhibited the tumor growth, but did not affect the body weight. More importantly, xanthatin treatment markedly increased the expression levels of the endoplasmic reticulum (ER) stress-related markers in both the glioma cell lines as well as in C6 xenografts, including glucose-regulated protein 78, C/EBP-homologous protein (CHOP), activating factor 4, activating transcription factor 6, spliced X-box binding protein-1, phosphorylated protein kinase R-like endoplasmic reticulum kinase, and phosphorylated eukaryotic initiation factor 2a. Pretreatment of C6 glioma cells with the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 7 mM) or knockdown of CHOP using small interfering RNA significantly attenuated xanthatin-induced cell apoptosis and increase of proapoptotic caspase-3. These results demonstrate that xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating the ER stress-related unfolded protein response pathway involving CHOP induction. Xanthatin may serve as a promising agent in the treatment of human glioma.

The spiroketal moiety is an important privileged scaffold that occurs extensively in natural products, drugs, and bioactive molecules. Naturally occurring spiroketals are numerous, however aryl-fused spiroketals are relatively rare. The only comprehensive review disclosing the isolation, biological activity, and synthesis of benzannulated spiroketal natural products was published nearly a decade ago. This review will serve as an update of the 2009 review and include all known families of benzannulated spiroketals, detailing their isolation and biological activity where relevant. Although not exhaustive, endeavours towards their total synthesis will be discussed.

Retinoblastoma is an intraocular malignant tumor that may severely affect vision and represents a life‑threatening disease in children. Arctigenin (ATG) is an active compound that exhibits numerous pharmacological activities, which is isolated from the seeds of greater burdock (Arctium lappa Linnaeus), a plant used in traditional Chinese herbal medicine. The present study aimed to investigate the effects of ATG on cancer progression by analyzing the retinoblastoma cell line Y79. ATG exhibited a significant inhibitory effect on the viability of Y79 cells in a dose‑dependent manner. Furthermore, treatment with ATG promoted apoptosis, and increased the protein expression levels of B‑cell lymphoma 2 (BCL‑2)‑associated X protein and decreased the protein expression levels of BCL‑2. Cell migration was suppressed following treatment with ATG, as assessed by Transwell migration assay. Furthermore, the protein expression levels of jagged‑1 (JAG1) were decreased, and various factors involved in the Notch signaling pathway, including the Notch intracellular domain (NICD), transcription factor HES (HES)5 and HES1 were downregulated following treatment with ATG. The decreased expression levels of JAG1 were restored in response to JAG1 overexpression, alongside increases in the protein expression levels of NICD, HES5 and HES1. Furthermore, overexpression of JAG1 partly restored the cell viability and migration suppressed following treatment with ATG. In addition, ATG‑induced apoptosis was reduced by JAG1 overexpression. Collectively, the present results suggested that ATG may serve as an antitumor compound by suppressing the proliferation and migration of retinoblastoma cells, inducing apoptosis, downregulating the protein expression levels of JAG1, and decreasing the activity of the Notch signaling pathway.

Background: Colorectal cancer is one of the most common malignancies worldwide and is associated with high mortality rates. We previously reported that Xanthium strumarium L. induces mitotic arrest in proliferating cells, a process mediated by xanthatins., Hypothesis/aim: The aim of this work is to study if xanthatins, isolated from X. strumarium total extract, affect the proliferative capacity of CT26WT colon cancer cells and, in consequence, if tumor growth and proliferation of (lung) metastatic sites can also be arrested in vivo., Study Design: This study consisted of both in vitro and in vivo experiments involving the CT26WT cell line and a subcutaneous mouse model of colon cancer. In vitro cell cycle progression, in vivo tumoral growth and anti-metastatic activity were analyzed to investigate whether xanthatins of X. strumarium induce mitotic arrest in proliferating colorectal carcinoma., Results: Our in vitro results show that X. strumarium, mediated by xanthatins, induces G 2 /M arrest and impair anaphase entrance. This leads to a significant induction of apoptotic and necrotic in CT26WT cells, demonstrating their significant anti-proliferative activity through interfering with the mitotic apparatus. Furthermore, our in vivoresults reveal that X. strumarium inhibits both tumor growth and metastasis progression., Conclusion: X. strumarium antitumor activities are mainly mediated by xanthatins through inhibition of tumor growth and metastasis, inducing mitotic arrest and apoptosis in colon carcinoma cells. These findings further confirm the therapeutic potential of X. strumarium in colorectal cancer., (Copyright © 2018. Published by Elsevier GmbH.)

Background: Phytochemical naphtho[1,2-b] furan-4,5‑dione (NFD) presenting in Avicennia marina exert anti-cancer effects, but little is known regarding about DNA damage-mediated apoptosis in non-small-cell lung carcinoma (NSCLC)., Purpose: To examine whether NFD-induced apoptosis of NSCLC cells is correlated with the induction of DNA damage, and to investigate its underlying mechanism., Study Design: The anti-proliferative effects of NFD were assessed by MTS Assay Kit FACS assay, and in vivo nude mice xenograft assay. The DNA damage related proteins, the Bcl-2 family and pro-apoptotic factors were examined by immunofluorescence assay, q-PCR, and western blotting. The activity of NF-κB p65 in nuclear extracts was detected using a colorimetric DNA-binding ELISA assay. The inhibitory activity of topoisomerase II (TOPO II) was evaluated by molecular docking and TOPO II catalytic assay., Results: NFD exerted selective cytotoxicity against NSCLC H1299, H1437 and A549 cells rather than normal lung-embryonated cells MRC-5. Remarkably, we found that NFD activated the hull marker and modulator of DNA damage repairs such as γ-H2AX, ATM, ATR, CHK1, and CHK2 probably caused by the accumulation of intracellular reactive oxygen species (ROS) and inhibition of TOPO II activity. Furthermore, the suppression of transcription factor NF-κB by NFD resulted in significantly decreased levels of pro-survival proteins including Bcl-2 family Bcl-2, Bcl-xL and Mcl-1 and the endogenous inhibitors of apoptosis XIAP and survivin in H1299 cells. Moreover, the nude mice xenograft assay further validated the suppression of H1299 growth by NFD, which is the first report for evaluating the anti-cancer effect of NFD in vivo., Conclusion: These findings provide a novel mechanism indicating the inhibition of TOPO II activity and NF-κB signaling by NFD, leading to DNA damage and apoptosis of NSCLC tumor cells., (Copyright © 2018. Published by Elsevier GmbH.)

Objectives: To evaluate the cytotoxic activity of atractylodin and its potential effects on heme oxygenase (HO)-1 production, STAT1/3 phosporylation and major NF-κB protein expression in the cholangiocarcinoma-associated cell line CL-6., Methods: Standard MTT assay was used for accessing antiproliferative activity on CL-6 cells. Normal human embryonic fibroblast (OUMS) cell was taken as control cell line. Colony formation and wound healing assay were conducted to access the effects of atractylodin on cell proliferation and directional migration activity of CL-6 cells. Western blot was used for evaluating levels of protein expression and phosphorylation., Key Findings: Atractylodin exhibited selective cytotoxicity towards CL-6 as compared with OUMS with IC 50 of 216.8 (212.4-233.8) and 351.2 (345.7-359.5) μm [median (range)], respectively. Exposure to the compound dose-dependently inhibited colony formation ability and decreased wound closure potential of CL-6 cells. Atractylodin treatment suppressed HO-1 production in CL-6 cells. It dose-dependently inhibited STAT1/3 protein phosphorylation and moderately inhibited NF-κB (p50), NF-κB (p52), and NF-κB (p65) protein expression in both dose- and time-dependent manner., Conclusions: Atractylodin exerts significant cytotoxic activity against CL-6 cells which may be linked to its suppressive effect on HO-1 production, STAT1/3 phosphorylation and expression of key NF-κB proteins., (© 2018 Royal Pharmaceutical Society.)

Background: Glioblastoma multiforme (GBM) is the most common and deadly brain form of tumor. GBM exhibits high resistance to the standard treatment consisting of temozolomide (TMZ) combined with radiotherapy. Isofuranodiene (IFD) is a bioactive sesquiterpene occurring in the essential oils obtained from Alexanders (Smyrnium olusatrum L., Apiaceae). This compound has shown a broad spectrum of antitumoral activities in different human cancer cell lines both in vitro and in vivo. However, the mechanism of action of IFD on GBM and its potential effects in combination with chemotherapeutic drugs, have not been fully elucidated., Purpose: The aim of the present study was to evaluate the anticancer effects of IFD itself and in combination with TMZ in GBM., Methods: Sulforhodamine B-based proliferation assay, cell cycle analysis and Annexin V/PI staining were carried out to determine the IFD effects on three human GBM cell lines, U87, T98, U251 and in normal human astrocyte. Modulation of protein expression levels was determined by western blot analysis. Reactive oxygen species (ROS) production was evaluated by cytofluorimetry. Moreover, the effects on cell viability of the IFD and TMZ co-administration was evaluated through the calculation of combination index (CI)., Results: IFD exerted cytotoxic effects against the GBM cell lines, but not in normal cells (normal human astrocytes). This compound induced a cell cycle blockage and a necrotic cell death depending on the increase of intracellular ROS levels. Furthermore, the synergism between IFD and TMZ was demonstrated in GBM cell lines., Conclusion: This study demonstrated the glioma selectivity of IFD and its cytotoxic properties suggesting a new strategy for the treatment of GBM in order to overcome the TMZ resistance and to reduce its side effects., (Copyright © 2018. Published by Elsevier GmbH.)

To investigate the suppressive effects of xanthatin on glioma growth in a nude mouse xenograft model and rat orthotopic implantation model using magnetic resonance imaging (MRI) to dynamically monitor the antitumour growth and antiangiogenesis effects of xanthatin. The nude mouse xenograft tumour model and rat orthotopic implantation model were established to observe the antitumour effects of xanthatin in vivo. In the rat orthotopic implanted tumour model, MRI scanning was used to dynamically monitor the antitumour growth effect and evaluate the antiangiogenesis effect of xanthatin. We found that xanthatin at a dose of 0.4 mg/10 g dramatically decreased the growth of xenograft tumours in nude mice. The antiangiogenesis effect of xanthatin C6 glioma was evaluated by dynamic contrast-enhanced (DCE) MRI via comparison of the volume transfer constant (K trans ) value, a parameter that reflects vessel permeability. We found that xanthatin at the doses of 8 and 16 mg/kg significantly decreased the K trans value, which suggests that xanthatin has antiangiogenesis effects. These data demonstrate the suppressive effects of xanthatin on C6 glioma occur via antiangiogenesis. Meanwhile, this study also provides evidence for the application of quantitative parameters of DCE-MRI for dynamically evaluating the growth and angiogenesis of intracranial tumours and for experimental and clinical research., (© 2018 John Wiley & Sons, Ltd.)

Background: The high mortality rate of oral cancers has stimulated the search for effective herbal medicines and their pharmacological targets. Vernonia cinerea, a perennial tropical herb, is wildly used as a traditional folk medicine for treatment of intestinal diseases and various skin diseases in addition to possessing anti-cancer activity. However, the effect of 8α-tigloyloxyhirsutinolide-13-O-acetate (8αTGH) as a major sesquiterpene lactone compound found in V. cinerea and the underlying mechanism of its action on oral cancer cells remains unknown., Purpose: To investigate the anti-cancer activity of 8αTGH extracted from V. cinerea and the underlying mechanism of its action in oral cancer cells., Methods: The anti-proliferative effect of 8αTGH on oral squamous cell carcinoma (HSC4) and lung carcinoma (A549) was determined using the SRB colorimetric method. The molecular mechanism of 8αTGH was explored using kinase inhibitors, followed by Western blotting or RT-qPCR. Flow cytometry and Western blotting were used to assess cell cycle arrest., Results: 8αTGH inhibited cancer cell growth more effectively on HSC4 than A549 and was much less effective on tested normal oral cells. 8αTGH inhibited STAT3 phosphorylation on both cancer cells. Notably, 8αTGH was able to suppress the constantly activated STAT2 found only in HSC4. The STAT2 inhibition by 8αTGH consequently caused down-regulation of ISG15 and ISG15 conjugates. As a result, decreased expression of CDK1/2 and Cyclin B1 was detected leading to G2/M cell cycle arrest., Conclusion: 8αTGH isolated from V. cinerea preferentially inhibits the proliferation of oral cancer cells by causing G2/M cell cycle arrest via inhibition of both STAT3 and STAT2 phosphorylation. The results provide molecular bases for developing 8αTGH as a drug candidate or a complementary treatment of oral cancer., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Novel 2,3-dihydrofuran derivatives were synthesized through a tandem Knoevenagel-Michael cyclization in good yield by reacting α-tosyloxy ketone, 5,5-dimethyl-1,3-cyclohexanedione, and various aldehydes in the presence of phthalazine in acetonitrile. These compounds were subjected to in vitro antibacterial screening against eight micro-organisms by using diffusion method and also in vitro cytotoxicity screening against four human cancerous cell lines by applying MTT assay. Some of the compounds showed impressive activities., (© 2018 Wiley-VHCA AG, Zurich, Switzerland.)

Xanthatin (XT), a naturally occurring sesquiterpene lactone presented in cocklebur ( Xanthium strumarium L.), is under development as a potential anticancer agent. Despite the promising anticancer effect of XT, the molecular mechanism underlying its cellular action has not been well elucidated. The mammalian thioredoxin reductase (TrxR) enzymes, the essential seleno-flavoproteins containing a penultimate selenocysteine (Sec) residue at the C-terminus, represent a promising target for cancer chemotherapeutic agents. In this study, XT inhibits both the purified TrxR and the enzyme in cells. The possible binding mode of XT with the TrxR protein is predicted by the covalent docking method. Mechanism studies reveal that XT targets the Sec residue of TrxR and inhibits the enzyme activity irreversibly. Simultaneously, the inhibition of TrxR by XT promotes the oxidative stress-mediated apoptosis of HeLa cells. Importantly, the knockdown of the enzyme sensitizes the cells to XT treatment. Targeting TrxR thus discloses a novel molecular mechanism in accounting for the cellular action of XT and provides insights into the development of XT as an anticancer agent.

The emergence of multidrug resistance (MDR) is a significant challenge in breast carcinoma chemotherapy. Kokusaginine isolated from Dictamnus dasycarpus Turcz. has been reported to show cytotoxicity in several human cancer cell lines including breast cancer cells MCF-7. In this study, kokusaginine showed the potent inhibitory effect on MCF-7 multidrug resistant subline MCF-7/ADR and MDA-MB-231 multidrug resistant subline MDA-MB-231/ADR. Kokusaginine markedly induced apoptosis in a concentration-dependent manner in MCF-7/ADR cells. Furthermore, kokusaginine reduced P-gp mRNA and protein levels, and suppressed P-gp function especially in MCF-7/ADR cells. In addition, kokusaginine showed to inhibit tubulin assembly and the binding of colchicine to tubulin by binding directly to tubulin and affects tubulin formation in vitro. Taken together, these results support the potential therapeutic value of kokusaginine as an anti-MDR agent in chemotherapy for breast carcinoma., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Resveratrol, a naturally occurring polyphenolic antioxidant, is a potential chemoprophylactic agent for various cancers, including colorectal cancer. Although emerging evidence continually suggests that a number of resveratrol derivatives may be better cancer chemopreventive candidates than resveratrol, studies on the mechanism of action of these derivatives are limited. This is the first study which investigates the mechanism underlying the cytotoxic effect of a synthesized resveratrol analogue, (E)-N-(2-(4-methoxystyryl) phenyl) furan-2-carboxamide (CS) on colorectal cancer. Previously, our group reported a series of synthesized resveratrol analogues, which showed cytotoxicity against a panel of cancer cell lines, in particular on colon cancer cells. In this study, we further discovered that CS also exerts a potent suppressive effect on HCT116 colorectal cancer cells. In contrast, normal colon cells (CCD-112 Con) were not sensitive to CS up to 72 h post treatment. CS caused cytotoxicity in HCT116 cells through several apoptotic events including activation of the Fas death receptor, FADD, caspase 8, caspase 3, caspase 9, and cleaved PARP, which occurred alongside cell cycle arrest from the up-regulation of p53 and p21. The results show that CS causes apoptosis via the activation of an extrinsic pathway leading to caspase activation and cell cycle arrest from activated p53. These findings suggest that CS may be a potential candidate for development as an anti-tumor agent in the future.

A new sesquiterpene kalinturoside A (1), and 17 known compounds friedelan-3-ol (2), 24-ethyl-5a-cholesta-7, 22(E)-dien-3-one (3), friedelin (4), syringaresinol (5), α-spinasterol (6), ciwujiatone (7), syringic acid (8), scopoletin (9), apocynin (10), 1-(3-hydroxy-4, 5-dimethoxyphenyl)ethan-1-one (11), apigenin (12), 5-hydroxymethylfurfural (13), stigmasterol-3-O-β-d-glucopy-ranoside (14), bidenoside C (15), citrusin (16), irioresinol A (17) and syringaresinol-4-O-β-d-glucopyranoside (18) were isolated from the herbs of Kalimeris integrifolia. The structures of these compounds were elucidated using spectroscopic techniques such as NMR and MS. All of the compounds were isolated from this genus for the first time.

A novel compound Salvialactomine (1) along with two other unusual occurring natural products Pentatriacontanoic acid 1, 3-dihydroxypropyl ester (2) and 5-Methylflavone (3) were isolated from the callus of Salvia santolinifolia Boiss. Callus was initiated on MS medium containing NAA (0.5 mg/L) and further sub-cultured on MS medium supplemented with NAA with BA (0.5 + 1.5 mg/L). The structures of isolated compounds were determined by using mass spectrometry, 1D, and 2D-NMR techniques. Compounds 1, and 3 were tested for two different cancer cell lines, i.e. Hela (Cervical cancer cell) and PC-3 (Prostate cancer cells). IC 50 was found as > 30 using Doxorobicin (0.912 ± 0.12 μmol L -1 ) as a standard.

New clerodane diterpenes, 12- epi -megalocarpodolide D ( 2 ) and an epimeric mixture of crotonolins A ( 3 ) and B ( 4 ), were isolated from the bark of Croton oligandrus following a bioassay-guided isolation protocol. Known compounds, megalocarpodolide D ( 1 ), 12- epi -crotocorylifuran ( 5 ), cluytyl-ferulate ( 6 ), hexacosanoyl- ferulate ( 7 ), vanillin ( 8 ), acetyl-aleuritolic acid ( 9 ) and lupeol ( 10 ), were also isolated. The structures of the isolated compounds ( 1 - 10 ) were elucidated by spectroscopic means. The cytotoxicity of compounds 1 - 10 was assessed against A549, MCF7, PC3 and PNT2 cell lines using the MTT assay. Compounds 1 and 2 showed moderate levels of activity against both A549 and MCF7 cells with 1 being the most active with IC 50 values of 63.8 ± 13.8 and 136.2 ± 22.7 µM against A549 and MCF7 cells, respectively. The epimeric mixture of 3 and 4 was moderately active against A549 and PC3 cells (IC 50 = 128.6 ± 31.0 and 111.2 ± 2.9 µM, respectively)., Competing Interests: The authors declare no conflict of interest.

EtOAc extract from the leaves of Terminalia citrina collected in Bangladesh were separated, and seven previously undescribed α-keto tetrahydrofuran lignan glucosides (terminalosides Q to W) were isolated and characterized. NOESY analysis of 1 H NMR spectra and ECD spectroscopic data analysis revealed the absolute stereochemistry of the tetrahydrofuran ring of the isolated constituents as being a (7S,8R,8'S)- configuration in terminalosides Q to U and a (7R,8R,8'S)- configuration in terminalosides V and W. All of the isolated compounds were evaluated for their estrogenic and anti-estrogenic properties using two types of estrogen-responsive human breast cancer cell lines (MCF-7 and T47D). Terminaloside R, which has a dioxymethylene group in its aromatic ring, inhibited 90% of estradiol-enhanced cell proliferation in T47D and MCF-7 cells at concentrations of 0.01 μM and 0.1 μM, respectively. On the other hand, terminaloside T, the analogous compound which has two oxymethyl groups in place of dioxymethylene, suppressed 90% of cell proliferation selectively in T47D cells at a concentration of 0.01 μM. However, terminaloside W, the 7R-stereoisomer of terminaloside R, only showed moderate activity., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Context: Limonoids possess broad range of biological activities, including antitumour, antimicrobial and antioxidant activities, etc. Eudesmin (EDN) is a type of limonoid which also possesses various activities. However, there is no report on the antitumour lung cancer (LC) activities of this compound., Objective: The present study investigates the antitumour effects of EDN and its potential molecular mechanisms., Materials and Methods: The in vitro antitumour effects of EDN on LC A549 cells were evaluated by using MTT assay. The in vivo antitumour effects were investigated on a xenograft athymic nude mouse model. The mice were administered orally with EDN (10, 20 and 40 mg/kg) once daily for 28 days. Effects of EDN on apoptosis-related or signalling proteins (Bcl-2, Bax, caspase-3, caspase-9, P53, Akt and JNK) were assayed by western blot analysis., Results: EDN showed significant inhibitory effects on the growth of LC A549 cells in vitro with the half maximal inhibitory concentration (IC 50 ) of 18.3 μM. By treating with EDN (10, 20 and 40 μM), expression of caspase-3, caspase-9, Bax, P53 and phosphorylated JNK in A549 cells were significantly upregulated, whereas expression of Bcl-2 and Akt phosphorylation were significantly down-regulated. Interestingly, EDN-induced apoptosis could be attenuated by JNK inhibitor. In addition, in vivo experiments also indicated EDN (10, 20 and 40 mg/kg) had significant antitumour effects (p < 0.01) on nude mice., Conclusions: Overall, the results indicated that EDN possesses significant antitumour effects on LC and the possible mechanism might be related to induction of mitochondria-mediated apoptosis.

Arctigenin (ARC) is a lignan that is abundant in Asteraceae plants, which show anti-inflammatory and anti-cancer activities. The current study investigated whether ARC affects cancer progression and metastasis, focusing on EMT using invasive human non-small cell lung cancer (NSCLC) cells. No toxicity was observed in the cells treated with different doses of ARC (12-100 μM). The treatment of ARC repressed TGF-β-stimulated changes of metastatic morphology and cell invasion and migration. ARC inhibited TGF-β-induced phosphorylation and transcriptional activity of smad2/3, and expression of snail. ARC also decreased expression of N-cadherin and increased expression of E-cadherin in dose-dependent and time-dependent manners. These changes were accompanied by decreased amount of phospho-smad2/3 in nucleus and nuclear translocation of smad2/3. Moreover, ARC repressed TGF-β-induced phosphorylation of ERK and transcriptional activity of β-catenin. Our data demonstrate anti-metastatic activity of ARC in lung cancer model., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Four new special compounds with character of an iriflophene unit and a flavonoid unit connecting via a furan ring were isolated from the roots of Sedum aizoon L. Their corresponding structures were elucidated on the basis of spectroscopic analysis. The in vitro anti-proliferative activities against BXPC-3, A549, and MCF-7 tumor cell lines were evaluated. Compounds 3 and 4 exhibited moderate cytotoxic activities with IC 50 ranging from 24.84 to 37.22 μmol L -1 , which was capable for further drug exploration., Competing Interests: The authors declare no conflict of interest.

A new compound (microphybenzimidazole, 7) along with the six known compounds matairesinol (1), prestegane B (2), umbelliferone (3), daphnoretin (4), microphynolide A (5) and microphynolide B (6) were isolated from Thymelaea microphylla. The structures of the pure compounds were elucidated by spectroscopic and mass-spectrometric analyses, including 1D-, 2D-NMR, and HPLC-TOF/MS. Compounds 2 and 4, as well as three fractions (F6, F6-C5, and F6-W42) obtained from a 50% (v:v) CH 2 Cl 2 :MeOH extract exhibited a selective activity against rat brain glioma cells (C6). Moreover, compound 1 and other fractions obtained from 50% (v:v) CH 2 Cl 2 :MeOH and 70% (v:v) MeOH:H 2 O extracts exhibited dose- and time-dependent effects on human cervical cancer cell (HeLa), as measured by xCELLigence assay. Compound 2 (IC 50  = 14.0 ± 0.2 μg/mL) and fraction F5 (IC 50  = 12.4 ± 0.1 μg/mL) showed higher radical scavenging ability than the synthetic agent butylated hydroxytoluene (BHT, IC 50  = 22.7 ± 0.6 μg/mL).

High amount of the valuable lignan pinoresinol (PR) was determined in Carduus nutans fruit (7.8mg/g) for the first time. A preparative separation method using two consecutive, identical steps of centrifugal partition chromatography (CPC) was developed in order (i) to isolate PR and (ii) to subsequently isolate PR and its 7' epimer epipinoresinol (EPR) simultaneously after an optimized acid treatment which resulted in PR epimerization forming equal amounts of PR and EPR, from C. nutans fruit. As optimal conditions, a two-phase solvent system consisting of methyl tert-butyl ether:acetone:water (4:3:3, v/v/v) for CPC separation, and an acid treatment performed at 50°C for 30min for the epimerization were applied. Thus, 33.7mg and 32.8mg PR and EPR, in as high as 93.7% and 92.3% purity, were isolated from 10.0gC. nutans fruit, representing 86.4% and 84.1% efficiency, respectively. Conversion characteristic of PR and EPR in acidic medium, determined as a function of time and temperature of acid treatment provides their unambiguous identification by on-line high performance liquid chromatography (HPLC). Antiproliferative assay of isolated PR and EPR in two different types of colon cancer cell lines (HCT116 and SW480) confirmed that both epimers caused a more significant decrease of viability in HCT116 cells than in SW480 cells, suggesting their similar mechanism of antiproliferative action., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The treatment of breast cancer cells obtained by blocking the aberrant activation of the proliferation signaling pathways PI3K/Akt/mTOR and MEK/ERK has received considerable attention in recent years. Previous studies showed that Taiwanin A inhibited the proliferation of several types of cancer cells. In this study, we report that 3,4-bis-3,4,5-trimethoxybenzylidene-dihydrofuran (BTMB), a novel derivative of Taiwanin A, significantly inhibited the proliferation of triple-negative breast cancer (TNBC) cells both in vitro and in vivo The results show that BTMB inhibited the proliferation of human TNBC cells by the induction of cell-cycle arrest and apoptosis in a dose-dependent fashion. BTMB inhibited the expression of β-catenin, cdc2 and the cell-cycle regulatory proteins, cyclin A, cyclin D1, and cyclin E. The mechanism of action was associated with the suppression of cell survival signaling through inactivation of the Akt and ERK1/2 signaling pathways. Moreover, BTMB induced cell apoptosis through an increase in the expression of BAX, cleaved caspase-3, and cleaved PARP. Moreover, BTMB inhibited TNBC cell colony formation and sensitized TNBC cells to cisplatin, a chemotherapeutic drug. In a TNBC mouse xenograft model, BTMB significantly inhibited the growth of mammary carcinomas through decreased expression of cyclin D1. BTMB was shown to significantly suppress the growth of mammary carcinoma and therefore to have potential as an anticancer therapeutic agent. Mol Cancer Ther; 16(3); 480-93. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Altholactone, a natural compound isolated from Goniothalamus spp., has demonstrated anti-inflammatory and anticancer activities, but its molecular mechanisms are still not fully defined. Nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play pivotal roles in the cell survival of many human tumors. The objective of this study was to elucidate the mechanism of action of altholactone against prostate cancer DU145 cells and to evaluate whether its effects are mediated by inhibition of NF-κB and STAT3 activity. Altholactone inhibited proliferation of DU145 cells and induced cell cycle arrest in S phase and triggered apoptosis. Reporter assays revealed that altholactone repressed p65- and TNF-α-enhanced NF-κB transcriptional activity and also inhibited both constitutive and IL-6-induced transcriptional activity of STAT3. Consistent with this, altholactone down-regulated phosphorylation of STAT3 and moreover, decreased constitutively active mutant of STAT3 (STAT3C)-induced transcriptional activity. Altholactone treatment also results in down-regulation of STAT3 target genes such as survivin, and Bcl-2 followed by up regulation of pro-apoptotic Bax protein. However, pre-treatment with the antioxidant N-acetylcysteine (NAC) significantly inhibited the activation of Bax and prevented down-regulation of STAT3 target genes. Collectively, our findings suggest that altholactone induces DU145 cells death through inhibition of NF-κB and STAT3 activity.

Forsythiae Fructus, Lianqiao in Chinese, is one of the most fundamental herbs in Traditional Chinese Medicine. Both green Forsythia (GF) and ripe Forsythia (RF) are referred to Forsythiae Fructus in medicinal applications. In most cases, they are used without distinction. In this study, a metabolomics approach was performed to compare componential differences of two Forsythiae Fructus aqueous extracts subtypes. Principal component analysis (PCA) score plots from the UPLC-MS data showed clear separation between the two subtypes, indicating there are significant differences in the chemical components between GF and RF. Meanwhile, the anticancer activity of them was also compared. GF exhibited much stronger antitumor activity than RF against B16-F10 murine melanoma both in vitro and in vivo. 15 chemical compounds were identified as specific markers for distinguishing GF and RF. Among these marker compounds, forsythoside I, forsythoside A, forsythoside E and pinoresinol were demonstrated to be key important active compounds that account for the different anticancer efficacies of GF and RF. Our data suggest that GF and RF should be distinctively used in clinical applications, particularly in the anticancer formulas, in which GF should be preferentially prescribed.

Background: Consumption of virgin olive oil (VOO) has been associated with a low breast cancer incidence. Pinoresinol is a phytoestrogen that is typically found in VOO. Considering the role of oestrogen in breast cancer development and progression, we investigated the potential antitumor activity of pinoresinol in breast cancer cells., Methods: To address this question, we treated MDA-MB-231 (oestrogen receptor [ER] negative) and MCF7 (ER+) human breast tumour cells and MCF10A human mammary epithelial cells (ER-) with different concentrations of pinoresinol. The cytotoxic activity, cell proliferation, cell cycle profile, apoptosis induction, reactive oxygen species production and DNA damage were assessed., Results: Pinoresinol showed cytotoxic, anti-proliferative and pro-oxidant activity in human breast tumour cells, independent of their oestrogen receptor status. In addition, pinoresinol exerted antioxidant activity and prevented DNA damage associated with oxidative stress in human mammary epithelial cells., Conclusions: Overall, the results suggest that pinoresinol may have antitumor activity in human breast cancer cells independently of oestrogen receptor status. Furthermore, the results show that the pinoresinol has the typical characteristics of a chemopreventive compound.

Breast cancer, the most frequent cancer in women, is the second leading cause of cancer-related death. Estrogens and estrogen receptors are well recognized to play predominant roles in breast cancer development and growth. Neo-tanshinlactone is a natural product isolated from Salvia miltiorrhiza and showed selective growth inhibition of ER+ breast cancer cell lines as demonstrated by cell proliferation assay and colony formation assay. The selective anti-proliferative effect of neo-tanshinlactone was associated with the induction of apoptosis in ER+ breast cancer cells. We also found that neo-tanshinlactone decreased steady state ESR1 mRNA levels in ER+ breast cancer cells, which was further confirmed by analysis of ER protein levels as well as the mRNA levels of target genes of this transcription factor, such as ESR2, BRCA1, CCND1, GREB1, TFF1, SERPINB9 and ABCA3. Furthermore, analysis of heterogeneous nuclear RNA (hnRNA) demonstrated that neo-tanshinlactone inhibited ESR1 mRNA de novo synthesis. The decrease of steady state ESR1 mRNA upon neo-tanshinlactone treatment was not abolished by protein synthesis inhibitor cycloheximide. And inhibition of mRNA synthesis with actinomycin D revealed no significant effect of neo-tanshinlactone on ESR1 mRNA stability. These results indicated that transcriptional down-regulation of ESR1 mRNA could contribute to the selective activity of neo-tanshinlactone on ER+ breast cancer cells. And as expected, the combination of neo-tanshinlactone and antiestrogen reagent tamoxifen showed a synergistic effect on growth of ER+ MCF7 cells. Our results suggest that neo-tanshinlactone is a promising regimen for ER+ breast tumors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Xanthatin, a xanthanolide sesquiterpene lactone isolated from Xanthium strumarium L. (Asteraceae), has prominent anti-tumor activity. Initial mechanism of action studies suggested xanthatin triggered activation of Wnt/β-catenin. We examined the effects of xanthatin on signaling pathways in A459 lung cancer cells and mouse embryonic fibroblasts to ascertain requirements for xanthatin-induced cell death and tumor growth in xenografts. Genetic inactivation of GSK-3β, but not the related isoform GSK-3α, compromised xanthatin cytotoxicity while inactivation of β-catenin enhanced xanthatin-mediated cell death. These data provide insight into how xanthatin and related molecules could be effectively targeted toward certain tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Chemical investigation of Cassia grandis leaves resulted in the isolation of the new 2-methoxy 6,7,2',6'-tetrahydroxy flavanone 6-O-β-glucoside together with the known flavonol glycosides, kaempferol-3-O-α-rhamnoside, and quercetin 3-O-α-rhamnoside. The structure assign ments were based on conventional analytical methods and confirmed by HRFTESIMS, 1H and 13C NMR, COSY, HSQC and HMBC data. The total phenolic content of the extract was estimated by Folin-Ciocalteu's method. The antioxidant capacity was investigated using DPPH radical scavenging assay. The ethyl acetate and the n-butanol fractions showed poor cytotoxic activity only at high concentrations against the three different cancer cell lines, hepatocellular (HepG-2), breast (MCF-7), and prostate (PC3) by the neutral red uptake assay.

Arctigenin (ARC) has been shown to have an anti-cancer effect in various cell types and tissues. However, there have been no studies concerning metastatic colorectal cancer (CRC). In this study, we investigated the anti-metastatic properties of ARC on colorectal metastasis and present a potential candidate drug. ARC induced cell cycle arrest and apoptosis in CT26 cells through the intrinsic apoptotic pathway via MAPKs signaling. In several metastatic phenotypes, ARC controlled epithelial-mesenchymal transition (EMT) through increasing the expression of epithelial marker E-cadherin and decreasing the expressions of mesenchymal markers; N-cadherin, vimentin, β-catenin, and Snail. Moreover, ARC inhibited migration and invasion through reducing of matrix metalloproteinase-2 (MMP-2) and MMP-9 expressions. In an experimental metastasis model, ARC significantly inhibited lung metastasis of CT26 cells. Taken together, our study demonstrates the inhibitory effects of ARC on colorectal metastasis.

Lariciresinol (LA) is a traditional Chinese medicine possessing anticancer activity, but its mechanism of action remains unclear. The present study explored the effects of LA on human HepG2 cells and the underlying mechanism. Our data indicated that LA inhibited cell proliferation and induced cell cycle arrest in S phase, subsequently resulting in apoptosis in HepG2 cells. Using a proteomics approach, eight differentially expressed proteins were identified. Among them, three proteins, glyceraldehyde-3-phosphate, UDP-glucose 4-epimerase, and annexin A1, were upregulated, while the other five proteins, heat shock protein 27, haptoglobin, tropomodulin-2, tubulin alpha-1A chain, and brain acid soluble protein 1, were downregulated; all of these proteins are involved in cell proliferation, metabolism, cytoskeletal organization, and movement. Network analysis of these proteins suggested that the ubiquitin-conjugating enzyme (UBC) plays an important role in the mechanism of LA. Western blotting confirmed downregulation of heat shock protein 27 and upregulation of ubiquitin and UBC expression levels in LA-treated cells, consistent with the results of two-dimensional electrophoresis and a STRING software-based analysis. Overall, LA is a multi-target compound with anti-cancer effects potentially related to the ubiquitin-proteasome pathway. This study will increase our understanding of the anticancer mechanisms of LA., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Furanodiene is a bioactive sesquiterpene isolated from the spice-producing Curcuma wenyujin plant (Y. H. Chen and C. Ling) (C. wenyujin), which is a commonly prescribed herb used in clinical cancer therapy by modern practitioners of traditional Chinese medicine. Previously, we have shown that furanodiene inhibits breast cancer cell growth both in vitro and in vivo, however, the mechanism for this effect is not yet known. In this study, therefore, we asked (1) whether cultured breast cancer cells made resistant to the chemotherapeutic agent doxorubicin (DOX) via serial selection protocols are susceptible to furanodiene's anticancer effect, and (2) whether AMP-activated protein kinase (AMPK), which is a regulator of cellular energy homeostasis in eukaryotic cells, participates in this effect. We show here (1) that doxorubicin-resistant MCF-7 (MCF-7/DOX(R)) cells treated with furanodiene exhibit altered mitochondrial function and reduced levels of ATP, resulting in apoptotic cell death, and (2) that AMPK is central to this effect. In these cells, furanodiene (as opposed to doxorubicin) noticeably affects the phosphorylation of AMPK and AMPK pathway intermediates, ACLY and GSK-3β, suggesting that furanodiene reduces mitochondrial function and cellular ATP levels by way of AMPK activation. Finally, we find that the cell permeable agent and AMPK inhibitor compound C (CC), abolishes furanodiene-induced anticancer activity in these MCF-7/DOX(R) cells, with regard to cell growth inhibition and AMPK activation; in contrast, AICAR (5-aminoimidazole-4-carboxamide-1-β-4-ribofuranoside, acadesine), an AMPK activator, augments furanodiene-induced anticancer activity. Furthermore, specific knockdown of AMPK in MCF-7/DOX(R) cells protects these cells from furanodiene-induced cell death. Taken together, these findings suggest that AMPK and its pathway intermediates are promising therapeutic targets for treating chemoresistant breast cancer, and that furanodiene may be an important chemical agent incorporated in next-generation chemotherapy protocols.

Context: Cipura paludosa Aubl. (Iridaceae) is widely used in folk medicine to treat several ailments. Experimental studies have confirmed its anti-inflammatory, antinociceptive, and neuroprotective effects., Objective: This study evaluates the possible antiproliferative potential of the crude methanol extract and three isolated compounds from the bulbs of C. paludosa., Materials and Methods: Phytochemical analysis was carried out by conventional chromatographic techniques, and the resulting compounds were identified by NMR (1)H and (13)C. The antiproliferative activity was analysed using the sulforhodamine B assay., Results: Crude methanol extract of C. paludosa bulbs showed GI50 values of between 1.6 and 30.8 μg/mL. The naphthoquinone derivatives (eleutherine, isoeleutherine, and eleutherol) isolated from the bulbs of C. paludosa exhibited promising cytotoxicity against several human tumour cell lines, especially the two main compounds, eleutherine and isoeleutherine, against glioma and breast cancer cell lines, with TGI values of between 2.6 and 13.8 μg/mL., Conclusion: Cipura paludosa bulbs produce active principles with relevant antiproliferative potential, such as naphthoquinone derivatives, identified as eleutherine, isoeleutherine, and eleutherol. This is the first report indicating C. paludosa with antiproliferative potential.

A new 2H-tetrahydropyran derivative, 6-epi-goniothalesdiol A (1), together with nine known styryllactones (2-10) and five known aristolactams (11-15) were isolated from the bark of Goniothalamus elegants Ast. The structures were elucidated by spectroscopic methods. The isolated compounds were evaluated for their cytotoxicity toward the KB, MCF7 and NCI-H187 cell lines as well as antimalarial and antimycobacterial activities. Compounds 4 and 10 showed strong activity against all three human cancer cell lines with IC50 values in the range of 0.538 to 4.25 μg/ml, while compounds 2, 4, 10 and 14 showed potent cytotoxicity against NCI-H187 with IC50 values in the range of 0.072 to 2.17 μg/ml. In addition, compounds 4, 6, 7, 9, 10 and 13 showed strong antiplasmodial activity with IC50 in the range of 2.28 to 5.89 μg/ml., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A chemical study of the nonpolar fraction of a methanol-soluble extract of Bursera microphylla resin yielded a variety of di- and triterpenoids. In total, 15 compounds were isolated, of which three are new, namely, malabaricatrienone (1), malabaricatrienol (2), and microphyllanin (3). The antiproliferative activity of the major compounds was evaluated in different murine cancer cell lines (M12.C3.F6 and RAW264.7) and human cancer cells (A549, HeLa, and PC-3). The new compounds (1-3) did not show significant antiproliferative activity. The known compounds ariensin (4), burseran (5), and dihydroclusin diacetate (6) were effective against the RAW264.7 cell line, with IC50 values in the micromolar range.

Arctigenin (ARG) has been previously reported to exert high biological activities including anti-inflammatory, antiviral and anticancer. In this study, the anti-tumor mechanism of ARG towards human hepatocellular carcinoma (HCC) was firstly investigated. We demonstrated that ARG could induce apoptosis in Hep G2 and SMMC7721 cells but not in normal hepatic cells, and its apoptotic effect on Hep G2 was stronger than that on SMMC7721. Furthermore, the following study showed that ARG treatment led to a loss in the mitochondrial out membrane potential, up-regulation of Bax, down-regulation of Bcl-2, a release of cytochrome c, caspase-9 and caspase-3 activation and a cleavage of poly (ADP-ribose) polymerase in both Hep G2 and SMMC7721 cells, suggesting ARG-induced apoptosis was associated with the mitochondria mediated pathway. Moreover, the activation of caspase-8 and the increased expression levels of Fas/FasL and TNF-α revealed that the Fas/FasL-related pathway was also involved in this process. Additionally, ARG induced apoptosis was accompanied by a deactivation of PI3K/p-Akt pathway, an accumulation of p53 protein and an inhibition of NF-κB nuclear translocation especially in Hep G2 cells, which might be the reason that Hep G2 was more sensitive than SMMC7721 cells to ARG treatment.

The aqueous extraction of the sesquiterpene lactone xanthatin from Xanthium spinosum L. favours the conversion of xanthinin (1) to xanthatin (2) via the loss of acetic acid. The cytotoxic (Hep-G2 and L1210 human cell lines) and antiviral activities of isolated xanthatin are established. This natural compound shows significant cytotoxicity against the Hep-G2 cell line and our experimental results reveal its strong anti-angiogenesis capacity in vitro. The structure of xanthatin is determined by spectroscopic methods and for the first time confirmed by X-ray diffraction., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

In this study, we propose a single solution for prevention of postoperative complications and recurrence of highly metastatic gastrointestinal tract cancers. Here, we demonstrate preparation and characterization of Taiwanin A incorporated polyurethane fiber sheets with excellent mechanical properties and sustained drug release. Sheets with elastic modulus of 8 MPa and ultimate tensile strength of 30 MPa will provide support on surgical staple line preventing leakage at anastomosis. Slight burst release of the drug within 7 days (15%) and further sustained release will inhibit proliferation and migration of remaining cancer cells and maintain locoregional high drug concentration to prevent recurrence of the disease. High elasticity of the material will promote healing process without impeding natural peristalsis movement of gastrointestinal organs.

The anti-proliferative activities of the lichen substances (-)-usnic acid and vulpinic acid on the viability of HepG2 hepatocarcinoma cells, NS20Y neuroblastoma cells and HUVEC endothelial cells were studied by the MTT assay. The anti-angiogenic potential of the substances was determined by the endothelial tube formation assay. Both lichen substances exhibited strong anti-angiogenic activity and were more cytotoxic to the cancer cell lines than to the normal cell line, but vulpinic acid has more potential as an anti-angiogenic substance because of its low cytotoxicity and stronger anti-angiogenic activity on the HUVEC cell line.