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Nine polyacetylenes, including five new compounds named sadivaethynes E -I (1 – 5), were isolated from the roots of Saposhnikovia divaricata. Structural elucidation of compounds 1 – 5 was established by extensive spectroscopic analysis, quantum chemical calculations and DP4+ probability analysis. Among them, the absolute configuration of compound 1 – 2 , 4 – 5 was unambiguous determined by ECD. Also, all compounds were evaluated for cytotoxicity against two human cancer cell lines (A549, HEPG2) in vitro, compound 9 showed moderate inhibitory effect with an IC 50 value of 11.66 μM against HEPG2. [Display omitted] • Five undescribed compounds were isolated from the roots of Saposhnikovia divaricata. • The structures were characterized chemically by NMR, quantum chemical calculations and CD data analysis. • Compound 9 showed moderate inhibitory effect with an IC 50 value of 11.66 μM against HEPG2. [ABSTRACT FROM AUTHOR]

Five new sesquiterpenoids, dictamtrinorguaianols E and F (1–2), and dictameudesmnosides F, G, and H (3–5), along with seven known sesquiterpenoids (6–12) were isolated from Dictamnus dasycarpus Turcz. The structures of all new compounds were characterized by spectroscopic methods, including UV, IR, HR-ESI-MS, and 1D and 2D NMR. The In-vitro anti-proliferative activities of all the compounds against two human cancer cell lines (SW982 and A549) were evaluated by CCK-8 assay. Compounds 1 and 4 showed medium anti-proliferative activity against SW982 cells, with IC 50 values of 3.49 ± 0.10 and 6.42 ± 1.23 μM, respectively. Additionally, compounds 2 , 7 , and 8 exhibited medium anti-proliferative activity against A549 cells, with IC50 values ranging from 0.80 ± 0.05 to 6.60 ± 0.46 μM. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Twenty-four diterpenoids of abietane family, including thirteen undescribed compounds and eleven known ones, were isolated from the leaves of Leucosceptrum canum. Their structures were elucidated by comprehensive spectroscopic analyses (including 1D and 2D-NMR and HRMS), and in the case of 15-hydroxy-abieta-8,11,13-trien-3-one by single-crystal X-ray diffraction. Their frameworks are highly diversified, involving normal abietane, 9,10-epoxy-9,10- seco -abietane, 18(4 → 3)- abeo -abietane, 3,4- seco -18(4 → 3)- abeo -abietane, and 16- nor -abietane. Selected compounds were evaluated for their cytotoxic activity against three human tumor cell lines, NCI-H1975, HepG2 and MCF-7. Among them, 3β-hydroxy-abieta-8,13-diene, 3β-hydroxy-abieta-8,11,13,15-tetraene, and 3β-hydroxy-9,10-epoxy-9,10- seco -abieta-8,11,13-triene exhibited moderate cytotoxicity against all three cell lines with IC 50 values ranging from 8.11 to 50.73 μM, while 3α-hydroxy-abieta-8,11,13,15-tetraene, 3β-hydroxy-abieta-8,11,13,15-tetraen-7-one, and 15-hydroxy-18(4 → 3)- abeo -abieta-3,8,11,13-tetraene were selectively active with IC 50 values ranging from 28.80 to 71.29 μM. Graphical abstract Thirteen undescribed abietane family diterpenoids along with eleven known ones were isolated from the aerial parts of Leucosceptrum canum. Six of them showed moderate cytotoxic activity. Image 1 Highlights • Twenty-four including 13 undescribed abietanoids were isolated from Leucosceptrum canum. • Their skeletons included normal, seco- , abeo -, seco - abeo- and nor -abietanes. • Six abietanoids showed moderate cytotoxicity against three tumor cell lines. • This is the first report of abietane family diterpenoids from Leucosceptrum canum. [ABSTRACT FROM AUTHOR]

A series of novel 1,2,3-triazole-linked isosteviol derivatives were designed and synthesized via Huisgen-click reaction. Their cytotoxicities in vitro against HCT-116 and JEKO-1 cells were screened. The preliminary bioassays indicated that most of the title compounds exhibited noteworthy cytotoxic activities. Particularly, the compound 10b revealed the most potent inhibitory activities against HCT-116 cells with IC 50 value of 2.987 ± 0.098 μM, which was better than that (3.906 ± 0.261 μM) of positive control cisplatin. On the basis of these bioactivity data, hologram quantitative structure–activity relationship (HQSAR) was performed, and a statistically reliable model with good predictive power ( r 2 = 0.848, q 2 = 0.544 and R 2 pred = 0.982) was achieved. Additionally, the contribution maps derived from the optimal model explained the individual atomic contributions to the activity for each molecule. [ABSTRACT FROM AUTHOR]

Matrine, a sophora alkaloid, has been demonstrated to exert antitumor effects on many types of cancer. However, its bioactivity is weak and its potential druggability is low. We modified the structure of matrine and obtained a new matrine derivative, WM130 (C 30 N 4 H 40 SO 5 F), which exhibited better pharmacological activities than matrine. In this study, we investigated the antitumor activity and the underlying mechanisms of WM130 on hepatocellular carcinoma (HCC) cells in vitro and in vivo , and found that WM130 inhibited the proliferation, invasion, migration and induced apoptosis of HCC cells in a dose-dependent manner. Furthermore, after treatment with WM130, the expressions of p-EGFR, p-ERK, p-AKT, MMP-2 and the ratio of Bcl-2/Bax were significantly down-regulated, whereas the expression of PTEN was increased in HCC cells. Moreover, WM130 inhibited Huh-7 xenograft tumor growth in a dose-dependent manner after intravenous administration. Immunohistochemistry results demonstrated that WM130 treatment resulted in down-regulation of p-EGFR, MMP-2, and Ki67 and up-regulation of PTEN. The findings indicated that WM130 could inhibit cell proliferation, invasion, migration and induced apoptosis in HCC cells by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways and may be a novel effective candidate for HCC treatment. [ABSTRACT FROM AUTHOR]

Increasing evidence has suggested that bispecific and multivalent antibodies which have more antigen binding sites will improve their immunogenicity. The bispecific anti-idiotype antibody vaccine G22-I50 was obtained through genetic engineering to enhance the immunogenicity of anti-idiotype antibody vaccines G22 and I50. G22-I50 vaccination could induce anti-tumor immunity in the Balb/c mouse model. The protective and therapeutic efficacy of G22-I50 was also evaluated using the hu-PBL–SCID mouse model injected three times with G22-I50, G22, or I50 mixed with Freund's adjuvant. Results demonstrated that the protective anti-tumor effect of G22-I50 could be relevant with the production of Ab3 antibody and activation of CD8 + cytotoxic T-lymphocytes. In preventive and therapeutic experiments, G22-I50 could reduce tumor size and prolong the survival time of HNE2-bearing mice ( p < 0.05). Human CD8 + T lymphocytes infiltrated the tumor sites, and high levels of human IFN-γ, TNF-α, and caspase-3 were also detected in the tumors from G22-I50-vaccinated and -treated mice. Therefore, the bispecific anti-idiotype antibody vaccine G22-I50 can induce strong humoral and cell-mediated immune responses. This vaccine can be potentially applied to prevent and treat nasopharyngeal carcinoma. [ABSTRACT FROM AUTHOR]

Six positional isomers of triptolide–glucose conjugates (TG1α, TG1β, TG2, TG3, TG4 and TG6) were designed and synthesized. These conjugates exhibited better water solubility, and had selective cytotoxicity between tumor cells with high expression of glucose transport-1 (Glut-1) and non-tumor cells with low expression of Glut-1, in which TG2 formed by triptolide (TPL) and d -glucose C2–OH had the strongest cytotoxicity to tumor cells and lowest toxicity in non-tumor cells, therefore the highest relative therapeutic index, which was 5.7 times that of triptolide and consequent the most powerful selective antitumor activity in vitro. The cytotoxicity of TG2 was highly correlated with Glut-1 function. As a prodrug of triptolide, TG2 could promote RNA Pol II degradation and induce apoptosis as TPL does. TG2 had a stronger dose-dependent antitumor effect in vivo than TPL and no adverse reaction occurred when its tumor inhibition was higher than 90%, which was associated with its selective distribution in tumor tissues. TG2 could be used as a promising drug candidate for the treatment of solid tumors with high expression of Glut-1, which is worthy of further study. [Display omitted] TG2 conjugated by triptolide and d -glucose C2–OH has a stronger selective antitumor activity than triptolide due to selective transport of TG2 into tumor cells via glucose transporters. • ●Triptolide-Glucose Conjugate TG2 formed by triptolide C14–OH and d -glucose C2–OH. • ●The cytotoxicity of TG2 is highly dependent on Glut-1 function. • ●TG2 distributes in tumor selectively and has a highly selective antitumor activity. [ABSTRACT FROM AUTHOR]

Cyclic RGDyK (cRGDyK)-conjugated pH-sensitive polymeric micelles were fabricated for targeted delivery of paclitaxel to prostate cancer cells based on pH-sensitive copolymer poly(2-ethyl-2-oxazoline)-poly( d , l -lactide) (PEOz-PLA) and cRGDyK-PEOz-PLA to enhance antitumor efficacy. The prepared micelles with an average diameter of about 28 nm exhibited rapid release behavior at endo/lysosome pH, effectively enhanced the cytotoxicity of paclitaxel to PC-3 cells by increasing the cellular uptake, which was correlated with integrin α v β 3 expression in tumor cells. The active targeting activity of the micelles was further confirmed by in vivo real time near-infrared fluorescence imaging in PC-3 tumor-bearing nude mice. Moreover, the active targeting and pH-sensitivity endowed cRGDyK-conjugated micelles with a higher antitumor effect in PC-3 xenograft-bearing nude mice compared with unmodified micelles and Taxol with negligible systemic toxicity. Therefore, these results suggested that cRGDyK-conjugated pH-sensitive polymeric micelles may be a promising delivery system for efficient delivery of anticancer drugs to treat integrin α v β 3 -rich prostate cancers. [ABSTRACT FROM AUTHOR]

Abstract: Two new dimeric diarylheptanoids, named Alpinin C (1) and D (2), a new natural product of diarylheptanoid (3) along with three known diarylheptanoids (4–6) were isolated from the rhizomes of Alpinia officinarum Hance. Their structures were elucidated based on extensive spectroscopic analyses (1D and 2D NMR, HRTOFMS, IR). The isolated compounds were evaluated for their cytotoxicity against human tumor cell lines HepG2, MCF-7, T98G and B16-F10. Compound 1 showed selective cytotoxicity against cell lines of MCF-7 and T98G, while compound 6 showed significant cytotoxicity to the all tested tumor cell lines with IC50 in the range from 8.46 to 22.68μmol/L. [Copyright &y& Elsevier]

Abstract: To construct an improved biological missile, an immunoconjugate ADM–Dex–ScFv-SA3 was synthesized, which was composed of a hepatocellular carcinoma-specific, single-chain Fv antibody (ScFv-SA3) and a highly potent cytotoxic drug, adriamycin (ADM), as the warhead. Oxidized Dextran T10 (Dex-T10) was used as a linker to connect these two moieties. The 40 KD soluble anti-hepatoma human Trx-ScFv-SA3 protein was expressed in E. coli BL21 (DE3), using a prokaryotic expression vector, pET21a (+)-Trx-ScFv-SA3-His. It was purified using a His-Tag Ni-Agarose column and identified by western blot. The activity of Trx-ScFv-SA3 was verified by enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry to confirm that it specifically binds to the hepatocellular carcinoma cell line HepG2. To prepare ADM–Dex–ScFv-SA3, ADM was conjugated to the antibody at a molar ratio of 14.21:1. The antitumor effect of the conjugate was tested by MTT assay, plate colony formation assay and xenografts in a nude mice experimental model. In vitro experiments revealed that ADM–Dex–ScFv-SA3 could bind to tumor cells selectively and inhibit the proliferation and the colony formation ability of HepG2 cells. In vivo experiments showed that ADM–Dex–ScFv-SA3 suppressed the tumor growth and prolonged the median survival time in tumor-bearing mice. Tumor histology slides indicated a significantly slower tumor tissue proliferation in the ADM–Dex–ScFv-SA3 group. These data indicate that the targeted drug, ADM–Dex–ScFv-SA3, may be a highly potent and selective therapy for the treatment of hepatoma. [Copyright &y& Elsevier]

Abstract: [Zn2(ClQ)4(CH3OH)2] (1), [Zn(BrQ)2(H2O)2] (2), [Zn2(ClIQ)4] (3) and [Cu(BrQ)2] (4) (H-ClQ = 5,7-dichloro-8-hydroxylquinoline, H-BrQ = 5,7-dibromo-8-hydroxylquinoline, and H-ClIQ = 5-chloro-7-iodo-8-hydroxylquinoline) were synthesized. Compounds 1–4 showed high anti-proliferative cytotoxicities against BEL-7404, SK-OV-3, NCI-H460 tumor cells, and HL-7702 normal cells in vitro, with IC50 values in the 1.4 nM to 32.13 μM range. Compounds 2–4 exhibited significantly enhanced cytotoxicity against BEL-7404 cell line, comparing with free 5,7-dihalo-8-quinolinol. Western blotting analysis showed that 2, 3 depleted mutant p53 protein in MDA-MB-231, and compound 2 decreased the ratio of Bcl-2/Bax in NCI-H460 significantly. The binding abilities of 1–4 to DNA were stronger than that of free quinolinol ligand. Intercalation is the probable binding mode for the complexes and free quinolinol ligands with DNA. [Copyright &y& Elsevier]

Abstract: The interactions between erlotinib (ET) and bovine serum albumin (BSA) in the absence and presence of Cu(II) and Fe(III) in aqueous solution were investigated by using fluorescence, circular dichroism and three-dimensional (3D) fluorescence spectroscopic methods under simulative physiological conditions. Erlotinib effectively quenched the intrinsic fluorescence of BSA with slight redshifts in the absence and presence of Cu(II) and Fe(III). Cu(II) decreased the binding affinity and reduced the binding sites of erlotinib to BSA, while Fe(III) increased the binding affinity and binding sites of erlotinib to BSA. The negative values of ΔH and ΔS illustrate that the binding is mainly driven by the hydrogen bond and van der Waals force. The conformation of BSA was changed through ET binding in the presence of Cu(II) and Fe(III), which was revealed by circular dichroism, synchronous fluorescence and 3D fluorescence spectroscopic methods. The results indicate that the binding capability of erlotinib to BSA is affected by the types of metal ions. [Copyright &y& Elsevier]

Abstract: Malignant melanoma is one of the most lethal and aggressive human malignancies. It is notoriously resistant to all of the current therapeutic modalities, including chemotherapy. Suppressed apoptosis and extraordinary invasiveness are the distinctive features that contribute to the malignancy of melanoma. Dacarbazine (DTIC) has been considered as the gold standard for melanoma treatment with a response rate of 15–20%. Unfortunately, the resistance to this chemotherapeutic agent occurs frequently. ZD55-IL-24 is a selective conditionally replicating adenovirus that can mediate the expression of interleukin-24 (IL-24) gene, which has a strong anti-tumor effect. In this study, we hypothesized that a combination of ZD55-IL-24-mediated gene virotherapy and chemotherapy using DTIC would produce an increased cytotoxicity against human melanoma cells in comparison with these agents alone. Our results showed that the combination of ZD55-IL-24 and DTIC significantly enhanced the anti-tumor activity by more effectively inducing apoptosis in melanoma cells than either agent used alone without any overlapping toxicity against normal cells. This additive or synergistic effect of ZD55-IL-24 in combination with DTIC in killing human malignant melanoma cells implies a promising novel approach for melanoma therapy. [Copyright &y& Elsevier]

Ethnopharmacological relevance: Lysimachia clethroides Duby is a traditional Chinese medicinal herb has been used in China to treat edema, jaundice diseases, hepatitis, tumor and inflammations, but the anti-tumor mechanisms are unclear. Aim of the study: The present study was undertaken to investigate if total flavonoids from Lysimachia clethroides Duby (ZE4) possesses anti-cancer effects through apoptotic pathways in human chronic myeloid leukemia K562 cells. Materials and methods: K562 cells were treated with different concentrations of ZE4 at different time intervals. Cell viability was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Cell apoptosis was assessed by flow cytometry, Hoechst 33258 staining and COMET assay. Western blot analysis was used to detect Bcl-2, Trail and DR5 expressions. Results: 15 flavonoids were isolated and identified from ZE4. ZE4 could inhibit the growth of K562 cells significantly by induction of apoptosis. Marked morphological changes of apoptosis, DNA fragmentation and single DNA strand breakages were observed clearly after treatment of ZE4. Bcl-2 expression was down-regulated remarkably while Fas, Trail and DR5 up-regulated when apoptosis occurred. Conclusions: This result suggests that total flavonoids of Lysimachia clethroides Duby exert potential anti-cancer activity through growth inhibition and apoptosis in K562 cells. [Copyright &y& Elsevier]

[Display omitted] • 41 novel FAK covalent inhibitors were synthesized. • Compound 11w displayed highest inhibition of FAK and tumor cells. • 11w inhibited the clone formation and migration of tumor cells, inducing apoptosis. • 11w covalently inhibited the autophosphorylation of FAK in a dose-dependent manner. • 11w showed adequate oral bioavailability and significant antitumor efficacy in vivo. Forty-one new focal adhesion kinase (FAK) covalent inhibitors were designed and synthesized based on FAK inhibitor TAE226. Compound 11w displayed the highest inhibition of FAK with an IC 50 value of 35 nM and exhibited potent anticancer activity against Hela, HCT116 and MDA-MB-231 cell lines with IC 50 values of 0.41, 0.01 and 0.11 μM respectively, compared to TAE226 (2.68, 0.64 and 4.19 μM respectively). 11w also inhibited the clone formation and migration of HCT-116 cells and stimulated cell cycle arrest in the G 2 /M phase, inducing tumor cell apoptosis. Compound 11w formed a covalent bond with the Cys427 residue of FAK in a docking model, inhibiting the autophosphorylation of FAK and downstream proteins in a dose-dependent manner. Moreover, 11w showed adequate oral bioavailability of 21.02%. A 74.20% inhibition of tumor growth in the HCT116 xenograft model was also observed. These data indicate that 11w is a promising covalent inhibitor of FAK. [ABSTRACT FROM AUTHOR]

• A new derivative of podophyllotoxin (GHGT-17) was synthesized by incorporation of cyclopropyl, formyl, piperazinyl groups. • GHGT-17 exhibits significant cytotoxicity against a variety of cancer cells. • The IC 50 of GHGT-17 was less than 100 nM against A549 and H460 cells and greater than 100 µM against 16HBE cells. • In silico ADMET analysis suggests GHGT-17 is unlikely to toxic to normal organs. • Molecular docking study indicates that GHGT-17 could directly bind to the colchicine binding pocket of tubulin. Podophyllotoxin (PPT) is a naturally occurring lignan extracted from the rhizomes of the Podophyllum plant. It exhibits toxicity towards a broad spectrum of cancer cells and can induce cell death by inhibiting the polymerization of microtubule proteins. In our pursuit of more potent anticancer drug candidates, 4α-(cyclopropyl formylpiperazinyl)-4-deoxypodophyllotoxin (GHGT-17) was successfully synthesized by introducing a piperazine group, formyl group, and cyclopropyl group at the C-4 position of PPT. The activity of GHGT-17 against various types of cancer cells was evaluated using the MTT assay. It exhibited significant potency against lung cancer cells, with IC 50 values of 0.080 ± 0.020 μM (A549) and 0.086 ± 0.004 μM (H460), without obvious toxicity towards lung epithelial cells 16HBE (IC 50 > 100 μM). Further investigations demonstrated that GHGT-17 induced morphological changes in A549 and H460 cells, inhibited proliferation in a time- and dose-dependent manner. Furthermore, GHGT-17 inhibited the formation of cell colonies in a dose-dependent manner. It was found to inhibit cell migration, arrest the cell cycle in the G2/M phase, induce nuclear wrinkling, decrease mitochondrial membrane potential, and inhibit microtubule protein polymerization. These effects ultimately contribute to the induction of endogenous apoptosis. In silico studies, ADMET analysis revealed that GHGT-17 exhibited a satisfactory bioavailability with good water solubility, easy absorption, and well-proportioned distribution in the body. Molecular docking was performed to predict the binding mode and interactions of GHGT-17 with tubulin protein (1SA0). Additionally, GHGT-17 was submitted to molecular dynamics simulation and RMSD, RMSF, Rg, hydrogen bonding was analyzed. The complex showed a rather low binding free energy (−36.37 kJ mol−1) and thus exhibited a superior binding affinity towards to tubulin protein. In summary, the combined results indicated that GHGT-17 exhibits promise as a prospective potential novel drug candidate worthy of further investigation for its potential application in lung cancer therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Implementing the concept of turning waste into treasure, the conversion of biomass waste into high-value carbon materials, especially carbon dots (CDs), has pointed out a new direction for disease diagnosis, tumor treatment, and other aspects. In this work, we have reported the GL-CDs(Fe) via a simple synthesis route exploiting Ganoderma lucidum waste as the precursor. Thanks to their excellent optical property and peroxidase mimetic activity, a novel GL-CDs(Fe)-based ratio fluorescence/colorimetric/smartphone triple mode sensing platform is cleverly fabricated for glucose determination with the LOD of 0.28, 0.37, and 0.52 μΜ separately. Especially, this triple mode biosensor is successfully utilized for glucose detection in serum samples with the relative error of less than ±8 % compared with clinical reports. Surprisingly, the GL-CDs(Fe) also presents immense application prospects in high-level anti-counterfeiting aspects due to their excellent luminescent properties, high water-solubility, and easy availability. Furthermore, GL-CDs(Fe) can catalyze excessive H 2 O 2 inside tumor cells to produce massive hydroxyl radicals (· OH) which break down the redox levels of cancer cells and thereby eliminate tumor cells. Thus, this integrated "Three-in-One" multifunctional platform based on GL-CDs(Fe) unveils enormous research and application prospects for bio-sensing, anti-counterfeiting, cancer treatment. [Display omitted] • GL-CDs(Fe) with ideal optical and peroxidase-like property was derived from biomass waste. • A novel GL-CDs(Fe)-based triple mode sensing platform was fabricated for glucose analysis. • GL-CDs(Fe) was also used for anti-counterfeiting ink and anticancer cell effect. [ABSTRACT FROM AUTHOR]

Danggui Buxue Decoction (DBD) as a traditional Chinese medicine (TCM) has been widely used to treat blood deficiency. With the immune regulation and hematopoietic effect, DBD improved the quality of life in non-small-cell lung cancer (NSCLC) patients. We previously reported that DBD sensitized the response of NSCLC to Gemcitabine (Gem); however, the synergism and attenuation mechanism on the combination of Gem and DBD has not yet been elucidated. To investigate the mechanisms of DBD in enhancing the anticancer activity of Gem and alleviating Gem-induced myelosuppression. A549 nude mice model was established to study the effect on the combination of Gem and DBD. The organ indices, peripheral blood cells and the hematopoiesis-related cytokines were analyzed in Gem-induced myelosuppressive mice. Then we studied the whole process from Gem-induced bone marrow suppression to self-healing, and the mechanism of DBD's attenuation by the experiments of bone marrow nucleated cells (BMNCs). There were an enhanced anticancer effect and an improvement of hematopoietic function by combining of Gem and DBD in A549 nude mice model. DBD regulated Hu antigen R (HuR), deoxycytidine kinase (dCK) and nuclear factor erythroid 2-related factor (Nrf2), increased the expression of thrombopoietin (TPO) and granulocyte-macrophage colony stimulating factor (GM-CSF). For Gem-induced myelosuppressive mice, DBD improved the number of peripheral blood cells and the levels of hematopoiesis-related cytokines. Moreover, DBD was observed to reduce deoxyribonucleic acid (DNA) content at the G1 phase, promoted BMNCs proliferation and up-regulated cycle-related proteins. The results indicated that DBD not only improved the sensitivity of Gem but also alleviated Gem-induced myelosuppression. This study may provide a pharmacological basis for the combination of DBD and Gem in clinical application. [Display omitted] • The combination of Gem and DBD has enhanced anticancer effect and improved the hematopoietic function. • Danggui Buxue Decoction improved the sensitivity of gemcitabine through regulating the expressions of Hu antigen R (HuR), deoxycytidine kinase (dCK), nuclear factor erythroid 2-related factor (Nrf2). • For the first time, we studied the whole process from gemcitabine-induced bone marrow suppression to self-healing, and the mechanism of Danggui Buxue Decoction's attenuation. • Danggui Buxue Decoction alleviated gemcitabine-induced myelosuppression via promoting cell cycle transformation and regulating cycle-related proteins in bone marrow nucleated cells. [ABSTRACT FROM AUTHOR]

Mcl-1 is an anti-apoptotic member of Bcl-2 family proteins. The development of inhibitors of Mcl-1 has been challenging. To develop metal-based Mcl-1inhibitors, twenty two copper(II) complexes 25 – 46 with 9-substituted β-carboline derivatives were reported. Complexes 38 and 39 showed higher cytotoxicity than the corresponding ligands or cisplatin. The most potent complex 39 presented higher selectivity to Mcl-1 than other Bcl-2 family proteins, and killed cancer cells via Bax/Bak mediated apoptosis. Complex 39 showed an excellent safety profile in mouse model, and significantly inhibited the tumor growth in NCI-H460 tumor bearing model, which is more potent than AZD5991 at the same dosage. Complex 39 prolonged the survival time of the tumor bearing mice. Complex 39 is the first metal-based Mcl-1 inhibitor acting as a potential anticancer agent. Image 1 • Complex 39 is a novel metal-based Mcl-1 inhibitor with strong antitumor activity. • Complex 39 induced Bax/Bak mediated apoptosis. • Complex 39 significantly inhibited tumor growth in mouse xenograft model. • Complex 39 increased the survival time in mouse xenograft model. • Complex 39 showed a good safety margin in mice. [ABSTRACT FROM AUTHOR]

Abstract Ganglioside GM3, belonging to glycosphingolipid family, has been known as tumor-associated carbohydrate antigen on several types of tumor. Many studies have revealed that GM3 plays a role in cell proliferation, adhesion and differentiation, which is crucial in the process of cancer development. In the present study, we firstly synthesized novel mannose-containing GM3 analogues by enzymatic hydrolysis and chemical procedures. Then the antiproliferative activity of the novel analogues along with galactose-containing analogues we prepared previously was investigated and the data demonstrated that these analogues exhibited antiproliferative effect on K562 and HCT116 cells. Finally, the influence of these analogues on tumor cell migration was studied on B16, B16-F10 and HCCLM3 cells by wound healing test, because the migration of tumor cells represents one of the relevant factors in assessing the malignancy of cancer. This study could lay the foundation for optimizing leading compounds and provide valuable information for finding new antitumor drugs for cancer therapy. Graphical abstract Image 1 Highlights • Two novel mannose containing ganglioside GM3 analogues were synthesized by chemoenzymatic method. • Synthesized GM3 analogues exhibit inhibitory effects on tumor cell growth and migration. • This work can facilitate the study of GM3 analogues with antitumor activities. [ABSTRACT FROM AUTHOR]

A series of novel isosteviol derivatives bearing amino alcohol and thiourea fragments have been stereo-selectively synthesized and screened for their in vitro cytotoxic activities against three human cancer cell lines (HCT-116, HGC-27 and JEKO-1). The results demonstrated that these compounds exhibited prominent cytotoxicities. Especially, the compound Iw displayed the most potent anticancer activities against HCT-116 cell with IC 50 value of 1.450 μM. On the basis of this bioassay results, these derivatives were further investigated by the hologram quantitative structure–activity relationship (HQSAR) technique. The optimal HQSAR model with q 2 = 0.663, r 2 = 0.895, SEE = 0.179 was generated using A/B/H/Ch as fragment distinction parameters and 4–7 as fragment size. This model was employed to predict the cytotoxic activities of test set compounds, and the predicted values were in good agreement with the experimental results. The contribution maps derived from the optimal model explained the individual atomic contribution to the total activity of single molecule. [ABSTRACT FROM AUTHOR]

Chemical examination of the ethanol extract of rhizomes of Iris tectorum led to the isolation and characterization of three new lignans, (7 R ,7′ R ,8 S ,8′ S )-5′-methoxy-neo-olivil (1a), (7 S ,7′ S ,8 R ,8′ R ) -5′-methoxy-neo-olivil (1b), (7 S ,7′ R ,8 S ,8′ S )-neo-olivil (2a), (7 R ,7′ S ,8 R ,8′ R )-neo-olivil (2b), (7 R ,7′ R ,8 S ,8′ S ,7′′ S ,8′′ S )- threo -neo-olivil-4′-O-8-guaiacylglycerol ether (3), together with six known ones (4–9). Among them, compounds 1 and 2 were found to be racemic mixtures, respectively, which were verified by chiral HPLC analysis, compound 3 was a new sesquineolignan. The structures were elucidated on the basis of extensive spectroscopic analysis. To our knowledge, this is the first report of lignan constituents isolated from I. tectorum . All compounds were evaluated for their cytotoxicity against five human tumor cell lines and none of them displayed significant toxicity in tested cell lines at a concentration of 10 μM. [ABSTRACT FROM AUTHOR]

Seven new iridals ( 1 – 7 ), designated as iritectols C–F, 22-epiiritectol D, 22-epiiritectol E, 22-epiiritectol F together with three known analogues were isolated from the rhizomes of Iris tectorum . Among them, compounds 2 and 3 , 4 and 5 , and 6 and 7 were found to be three pairs of C-22 epimers, some of which were separated by chiral column chromatography. This is the first report on the occurrence of epimers of monocyclic iridals. Their structures were elucidated on the basis of extensive spectroscopic analysis. The isolates were evaluated for their cytotoxic activities against five human tumor cell lines. Compound 1 but not others exhibited moderate cytotoxic activities, with IC 50 values ranging from 4.1 to 9.8 μM. The structure–activity relationship of the tested compounds was briefly discussed. [ABSTRACT FROM AUTHOR]

Five new phorbol esters, (four phorbol diesters, 1 – 4 , and one 4-deoxy-4α-phorbol diester, 5 ), as well as four known phorbol esters analogues ( 6 – 9 ) were isolated and identified from the branches and leaves of Croton tiglium . Their structures were elucidated mainly by extensive NMR spectroscopic, and mass spectrometric analysis. Among them, compound ( 1 ) was the first example of a naturally occurring phorbol ester with the 20-aldehyde group. Compounds 2 – 5 , and 7 – 9 showed potent cytotoxicity against the K562, A549, DU145, H1975, MCF-7, U937, SGC-7901, HL60, Hela, and MOLT-4 cell lines, with IC 50 values ranging from 1.0 to 43 μM, while none of the compounds exhibited cytotoxic effects on normal human cell lines 293T and LX-2, respectively. In addition, compound 3 exhibited moderate COX-1 and COX-2 inhibition, with IC 50 values of 0.14 and 8.5 μM, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Three new copper(II) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g]isoquinoline (PYP), i.e. [Cu2(PYP)2Cl4] (1), [Cu4(PYP)4(ClO4)2(H2O)2](ClO4)2·2H2O (2), and [Cu2(PYP)2Cl4] n (3), were synthesized and fully characterized. In comparison to free PYP, complexes 1–3 exhibited enhanced cytotoxicity against tested human tumor cell lines BEL-7404, SK-OV-3, A549, A375, MGC-803 and NCI-H460, with IC50 values ranging from 0.31 to 30.76 μM. Complexes 1–3 exhibited lower cytotoxicity to HL-7702 than them to cancer cells. Complex 1 induced apoptotic death of BEL-7404, which involved mitochondria in the process. Caspase-3 activation assay indicated that 1 could be an efficient activator of caspase-3. DNA binding studies by UV–vis, DNA-melting, competitive binding, CD, viscosity measurement and agarose gel electrophoresis, revealed that intercalation might be the most likely binding mode of 1 with DNA. [Copyright &y& Elsevier]

Abstract: Aims: Although showing an anti-tumor activity, evodiamine also up-regulated IL-8 production of human gastric cancer AGS cells. This study aimed to assess this effect and to examine whether co-administration with berberine counteracts it. Main methods: MTT assay was used to assess the cell proliferation and adhesive ability. Flow cytometry was performed to measure the cell cycle distribution. Wound healing assay was used to detect the migration ability of cells. IL-8 production was determined by ELISA. Levels of mRNA expression of IL-8, VCAM-1 and ICAM-1 were measured by real-time PCR. Molecular pathways involved were evaluated by ELISA and western-blotting methods. Key findings: Evodiamine triggered proliferative inhibition and cell cycle arrest, and decreased migration of AGS cells. IL-8 expression and the adhesive ability of AGS cells to HUVECs were significantly increased by evodiamine, but were inhibited after being co-treated with berberine in AGS cells. As IL-8 was neutralized, increased adhesion of AGS cells to HUVECs induced by evodiamine was abolished. Berberine significantly suppressed the up-regulation of VCAM-1 and the down-regulation of ICAM-1 induced by evodiamine. Evodiamine provoked IL-8 secretion via ERK1/2, SAPK/JNK, JAK2 and AP-1 pathways which could be counteracted by berberine. Significance: Although showing anti-proliferative and anti-migratory activities in AGS cells, evodiamine displayed a potential tendency to promote metastasis of gastric cancer cells by increasing IL-8 secretion and adhesion molecules. However, berberine could counteract the side-effect and simultaneously keep anti-proliferative and anti-migratory properties of evodiamine on AGS cells, which reduces the risk to use evodiamine in therapy of gastric cancers. [Copyright &y& Elsevier]

Three cerium complexes: [Ce(ClQ)4] (1) (H-ClQ = 5,7-dichloro-8-hydroxylquinoline), [Ce(ClIQ)4]·CH2Cl2·0.5H2O (2) (H-ClIQ = 5-chloro-7-iodo-8-hydroxylquinoline) and [Ce2(BrQ)4(H-BrQ)(H2O)3Cl2]·1.5H2O (3) (H-BrQ = 5,7-dibromo-8-hydroxylquinoline) were synthesized. The structures of 1 and 2 are mononuclear whereas 3 has a binuclear structure. Compared with the H-ClQ, H-ClIQ and H-BrQ, complexes 1–3 exhibited significantly higher cytotoxicity (IC50 = 0.09–5.23 μM) to SK-OV-3 and BEL-7404, 1 and 2 exhibited higher cytotoxicity to NCI-H460. Most the complexes and ligands exhibited higher cytotoxicity than cisplatin. Complexes 1–3 are much more sensitive to SK-OV-3 than to human normal liver cell HL-7702. Their antitumor activities were achieved through cell apoptosis and arrest at G0/G1-phase. Studies on the binding properties of 1–3 to DNA indicate that intercalation is the most probable binding mode. [ABSTRACT FROM AUTHOR]

The root of Croton crassifolius has been used as a traditional Chinese medicine (TCM), called Radix Croton Crassifolius, and commonly known as "Ji Gu Xiang" in Chinese. Its medicinal value has been recorded in several medical books or handbooks, such as "Sheng Cao Yao Xing Bei Yao", "Ben Cao Qiu Yuan" and "Zhong Hua Ben Cao". It has been traditional employed for treating sore throat, stomach-ache, rheumatism and cancer. At present, there are limited studies on the evaluation of low-polarity extracts of roots in C. crassifolius. Consequently, the aim of this study was to evaluate the antitumor effect of the low-polarity extract of C. crassifolius root. Extracts were obtained by supercritical fluid extraction. The extracts were tested for antitumor effects in vitro on several cancer cell lines. A CCK-8 kit was used for further analysis of cell viability. A flow cytometer and propidium iodide staining were used to evaluate the cell cycle and apoptosis. Hoechst staining, JC-1 staining and the fluorescence probe DCFH-DA were used to evaluate apoptotic cells. Molecular mechanisms of action were analyzed by quantitative RT‒PCR and Western blotting. Immunohistochemistry was used for the evaluation of xenograft tumors in male BALB/c mice. Finally, molecular docking was employed to predict the bond between the desired bioactive compound and molecular targets. Eleven diterpenoids were isolated from low-polarity C. crassifolius root extracts. Among the compounds, chettaphanin II showed the strongest activity (IC 50 = 8.58 μM) against A549 cells. Evaluation of cell viability and the cell cycle showed that Chettaphanin II reduced A549 cell proliferation and induced G2/M-phase arrest. Chttaphanin II significantly induced apoptosis in A549 cells, which was related to the level of apoptosis-related proteins. The growth of tumor tissue was significantly inhibited by chettaphanin II in experiments performed on naked mice. The antitumor mechanism of chettaphanin II is that it can obstruct the mTOR/PI3K/Akt signaling pathway in A549 cells. Molecular docking established that chettaphanin II could bind to the active sites of Bcl-2 and Bax. Taken together, the natural diterpenoid chettaphanin II was identified as the major antitumor active component, and its potential for developing anticancer therapies was demonstrated for the first time by antiproliferation evaluation in vitro and in vivo. [Display omitted] • Eleven diterpenoids were obtained from the SFE extract of C. crassifolius roots. • Chettaphanin II showed the strongest antitumor activity against A549 cells. • Chettaphanin II inhibited A549 cell proliferation and arrested cells in G2/M-phase. • Chettaphanin II induced A549 cell apoptosis by inhibiting PI3K/AKT/mTOR pathway. • Chettaphanin II significantly inhibited the growth of tumor tissue in nude mice. [ABSTRACT FROM AUTHOR]

Abstract: Six new platinum(II) complexes with mono-aminophosphonate ester were synthesized and characterized by elemental analysis, 1H NMR, ESI-MS as well as single crystal X-ray diffraction analysis. They are mononuclear structures. In all the crystal structures of complexes 1–6, the platinum centre adopts an approximately square-planar geometry, which were found to possess excellent solubility in both organic solvents and water and exhibit considerable cytotoxicity against MG-63, SK-OV-3 and HepG2 cell lines, but low cytotoxicity towards normal human liver cell HL-7702. In contrast to cisplatin, their antitumour activities are achieved through the induction of cell apoptosis by G1 cell-cycle arrest. [Copyright &y& Elsevier]

Abstract: Recent evidence has suggested that breast cancer contains a rare population of cells called cancer stem cells (CSCs), which have an extensive self-renewal ability and contribute to metastasis and therapeutic resistance. This study evaluated the in vitro and in vivo effects of RAD001 (Everolimus) alone or in combination with docetaxel on stem cells from primary breast cancer cells and two breast cancer cell lines (MCF-7 and MDA-MB-231). In In vitro studies, we sorted ESA+CD44+CD24−/low cells as stem cells using flow cytometry from primary breast cancer cells, MCF-7 and MDA-MB-231 cell lines. MTT assays were used to quantify the inhibitory effect of the drugs on total cells and stem cells. Apoptosis and the cell cycle distributions of stem cells were examined by flow cytometry. The tumourigenicity of stem cells after treatment was investigated by soft agar colony formation assays. In In vivo studies, the BALB/c mice were injected with MDA-MB-231 stem cells and the different treatments were administered. After necropsy, the expression of Ki67, CD31, AKT1, and phospho-AKT (Thr308) was analysed by immunohistochemistry. In In vitro studies, all three populations of stem cells were resistant to the standard treatment doses of docetaxel compared with total cells treated with the same drug. Treatment with RAD001 resulted in growth inhibition of all stem cells in a dose-dependent manner. An additive growth inhibitory effect of the combination treatment on the three stem cells was observed in in vitro compared with treatment with RAD001 alone (P <0.001). In addition, an increase in G2/M cell cycle arrest and an increased population of cells in early apoptosis were seen in the combination treatment group compared with either single-agent group (P <0.01). In vivo, the volumes of the xenograft tumours significantly decreased in RAD001 alone group compared to control group (P =0.008), and RAD001 plus docetaxel therapy was much more effective at reducing tumour volume in mice compared with either single-agent alone (P <0.05). Compared with RAD001 alone, the combination of RAD001 and docetaxel reduced the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308) (P <0.05). We conclude that the combination treatment of RAD001 and docetaxel can inhibit the growth of stem cells in vitro and in vivo by inhibiting cell proliferation, inducing apoptosis, cell cycle arrest and reducing the expression of Ki67, CD31, AKT1 and phospho-AKT (Thr308). These data indicate that combination treatment with RAD001 and docetaxel may represent an effective therapy for breast cancer. However, further studies are required to evaluate the drug interaction between RAD001 and docetaxel in the clinical setting. [Copyright &y& Elsevier]

Abstract: Although supranutrition of selenium (Se) is considered a promising anti-cancer strategy, recent human studies have shown an intriguing association between high body Se status and diabetic risk. This study was done to determine if a prolonged high intake of dietary Se actually induced gestational diabetes in rat dams and insulin resistance in their offspring. Forty-five 67-day-old female Wistar rats (n =15/diet) were fed a Se-deficient (0.01mg/kg) corn–soy basal diet (BD) or BD+Se (as Se-yeast) at 0.3 or 3.0mg/kg from 5weeks before breeding to day 14 postpartum. Offspring (n =8/diet) of the 0.3 and 3.0mg Se/kg dams were fed with the same respective diet until age 112days. Compared with the 0.3mg Se/kg diet, the 3.0mg/kg diet induced hyperinsulinemia (P <0.01), insulin resistance (P <0.01), and glucose intolerance (P <0.01) in the dams at late gestation and/or day 14 postpartum and in the offspring at age 112days. These impairments concurred with decreased (P <0.05) mRNA and/or protein levels of six insulin signal proteins in liver and muscle of dams and/or pups. Dietary Se produced dose-dependent increases in Gpx1 mRNA or GPX1 activity in pancreas, liver, and erythrocytes of dams. The 3.0mg Se/kg diet decreased Selh (P <0.01), Sepp1 (P =0.06), and Sepw1 (P <0.01), but increased Sels (P <0.05) mRNA levels in the liver of the offspring, compared with the 0.3mg Se/kg diet. In conclusion, supranutrition of Se as a Se-enriched yeast in rats induced gestational diabetes and insulin resistance. Expression of six selenoprotein genes, in particular Gpx1, was linked to this metabolic disorder. [Copyright &y& Elsevier]

Abstract: Transferrin has shown potential in the delivery of anticancer drugs into primarily proliferating malignant cells that over-express transferrin receptors. Constructing transferrin receptor targeted drug delivery system has been widespread concerned. In this study, whether transferrin could transport noncovalent binding drugs into cancer cells has been investigated. Two representative compounds, doxorubicin hydrochloride (Dox) and vanadocene dichloride (Cp2VCl2), have been chosen to study the interactions with h-Tf and apo-Tf, and the influences in the presence of h-Tf and apo-Tf by using fluorescence spectroscopy, circular dichroism (CD) spectroscopy and MTT assay. The results have shown that both doxorubicin and Cp2VCl2 could bind to h-Tf and apo-Tf but with different binding modes. The results of MTT assay demonstrate that the presence of both h-Tf and apo-Tf has enhanced the antiproliferative activity of Cp2VCl2. However, the anticancer activity of the mixture of doxorubicin and h-Tf is basically the same as that of doxorubicin does. Our studies indicate that transferrin plays an important role in the transport and targeted delivery of Cp2VCl2 into cancer cells. [Copyright &y& Elsevier]

• A new anthrahydrazone ligand (9-THA) and its three metal complexes were synthesized. • The tested cancer cell lines were most sensitive to the Cu(II) complex, 9-THA-Cu. • 9-THA-Cu could bind with DNA in an intercalative mode by its planar structure. • The Cu(II) center play a key role to exert anticancer activity and induce apoptosis. In the present study, we synthesized and extensively characterized a novel ligand, 9-THA, based on 9-benzothiazolanthrahydrazone, along with its three corresponding transition metal complexes: 9-THA-Co (1), 9-THA-Ni (2), and 9-THA-Cu (3). The crystallographic analysis revealed distinct coordination geometries - six-coordinate for 9-THA-Co and 9-THA-Ni, binding three and two 9-THA ligands, respectively, and four-coordinate for 9-THA-Cu, binding one 9-THA ligand. In vitro anticancer screening demonstrated that 9-THA-Cu exhibited significant growth inhibition in HeLa-229, NCI-H460, and SK-OV-3 cancer cells with IC 50 values of 12.10 ± 0.54, 12.12 ± 0.58, and 17.65 ± 0.66 μM, respectively. Moreover, it displayed comparable cytotoxicity to cisplatin on HL-7702 normal liver cells. In contrast, 9-THA and 9-THA-Co/9-THA-Ni did not exhibit significant growth inhibition in the tested cancer cells, suggesting that Cu(II) played a pivotal role in its anticancer mechanism. Further investigation revealed the intercalative DNA binding mode of 9-THA-Cu by UV–Vis and fluorescent spectral analyses. It also exhibited competitive binding with two typical DNA intercalators, Gel-red (GR) and ethidium bromide (EB). Cell cycle and cell apoptosis experiments indicated that 9-THA-Cu at a concentration of 22 μM could induce cell cycle arrest in the S phase in 40 % of HeLa-229 cancer cells. Simultaneously, it induced 33.2 % apoptosis in HeLa-229 cells, suggesting that 9-THA-Cu may employ multiple mechanisms to exert its anticancer effects. [Display omitted] [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) has been documented in many malignancies as participating in the progression of cancer cells. Here, we present a novel EGFR tyrosine kinase inhibitor, ZZC4, and examine its effect on cancer cell proliferation, migration, and tumor-bearing xenograft models. The antiproliferative effect of ZZC4 was assessed in vitro by MTT assay, colony formation, and wound healing assay and in vivo with tumor-bearing xenograft nude mice. Further, Western blotting analysis and computational network pharmacology were used to explore and understand the mechanism of ZZC4. The results showed that ZZC4 potently inhibited the proliferation of lung, breast, and melanoma cells, and was more sensitive to lung cancer cells HCC827, H1975, and breast cancer cell T47D. In vitro findings were corroborated in vivo as results showed the suppressive effect of ZZC4 on HCC827 and H1975 tumor growth. Western blotting analysis confirmed that ZZC4 is an effective inhibitor of the EGFR pathways as it down-regulated p-EGFR, p-Akt, and p-MAPK. Computational molecular docking confirmed the strong binding affinity between ZZC4 and EGFR. Moreover, network pharmacology suggested that ZZC4 might play a suppressive role in the progression of malignancies with EGFR/PI-3K/Akt axis dysregulation or in cancer-related drug resistance. Our study showed that ZZC4 is an anticancer drug candidate. • ZZC4 is a novel purine-containing EGFR tyrosine kinase inhibitor. • ZZC4 potently inhibited the proliferation and tumor growth of lung and breast cancer cells. • Network pharmacology can be used the determine the possible target of small molecules drugs. [ABSTRACT FROM AUTHOR]

Abstract In the present study, one novel Pt(II) complex, [Pt(CTD)(DMSO)Cl 2 ] (1) with 9‑chloro‑5,6,7,8‑tetrahydroacridine (CTD) as ligand, was synthesized and fully characterized. The CTD Pt(II) complex 1 was an anti-cancer drug candidate, and it possessed potent therapeutic efficacy for hepatocellular carcinoma (HCC). To explore its mechanism against HCC, Hep‑G2 cells were treated with the CTD Pt(II) complex 1 in vitro. MTT assay showed that the CTD Pt(II) complex 1 had inhibitory activity against five human cancer cells, such as SK‑OV‑3, Hep‑G2, NCI‑H460, MGC80‑3 and HL‑7702, and it displayed the strongest inhibitory activity against Hep‑G2 cells with an IC 50 value of 10.48 ± 0.83 μM. Moreover, the CTD Pt(II) complex 1 also exhibited selective cytotoxicity toward the cancer cells. In addition, the CTD Pt(II) complex 1 had low toxicity against non-cancerous HL‑7702 cells. The CTD Pt(II) complex 1 caused mitochondrial dysfunction, leading to the down-regulation of bcl‑2 protein and up-regulation of some mitochondria-initiated apoptotic proteins (including apaf‑1, cytochrome c and bax) in Hep‑G2 cells. Taken together, the CTD Pt(II) complex 1 -triggered Hep‑G2 cell apoptosis was mainly mediated via interaction with c‑myc promoter and disruption of mitochondrial pathway. Collectively, our findings supported that the CTD Pt(II) complex 1 could be used as a potential drug candidate for chemoprevention or chemotherapy of HCC. Graphical abstract The CTD Pt(II) complex 1 triggered Hep‑G2 cell apoptosis mainly through inhibiting telomerase activity by interacting with c‑myc promoter elements and disruption of mitochondrial pathway. Unlabelled Image Highlights • The CTD Pt(II) complex 1 with 9‑chloro‑5,6,7,8‑tetrahydroacridine was designed and synthesized. • The CTD Pt(II) complex 1 was more selective for Hep‑G2 tumor cells versus normal cells (HL‑7702). • The CTD Pt(II) complex 1 was a potent inhibitor of telomerase. • The CTD Pt(II) complex 1 also caused mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Abstract Two platinum(II) complexes, [Pt(ClQ)(DMSO)Cl] (ClQ-Pt) and [Pt(BrQ)(DMSO)Cl] (BrQ-Pt), with 5,7-dichloro-2-methyl-8-quinolinol (H-ClQ) and 5,7-dibromo-2-methyl-8-quinolinol (H-BrQ) as ligands, respectively, have been synthesized and characterized. The single-crystal X-ray diffraction characterization as well as other spectroscopic and analytical studies of ClQ-Pt and BrQ-Pt revealed that the coordination geometry of Pt(II) can be described as a four-coordinated square planar geometry. By MTT assay, ClQ-Pt displayed the most potent activity, with IC 50 values of 5.02–34.38 μM against MGC80-3, T-24, Hep-G2 and BEL-7402 tumor cells. Among them, the T-24 cells the highest sensitivity to ClQ-Pt and BrQ-Pt with IC 50 value of 5.02 ± 0.62 μM and 18.02 ± 1.05 μM, respectively. In addition, ClQ-Pt caused a higher percentage of apoptotic T-24 cells (ca. 33.75%) than that of BrQ-Pt (ca. 23.85%) and cisplatin (ca. 12.82%). Mechanistic studies revealed that ClQ-Pt and BrQ-Pt caused T-24 cell cycle arrest at the S phase, as shown by the down-regulation of cyclin A and CDK2 expression levels. In addition, ClQ-Pt and BrQ-Pt also caused mitochondrial dysfunction. Interestingly, the in vitro anticancer activity of ClQ-Pt was higher than those of BrQ-Pt and cisplatin, more selective for T-24 tumor cells than for normal HL-7702 cells. Taken together, we concluded that the 5- and 7-substitution groups of the ClQ ligands play an important role in determining the anti-proliferation activity of the corresponding Pt(II) complexes. Graphical abstract Image 1 Highlights • New complexes ClQ-Pt and BrQ-Pt with H-ClQ and H-BrQ have been synthesized and characterized. • T-24 cells was found to be the most sensitive towards both ClQ-Pt and BrQ-Pt. • ClQ-Pt and BrQ-Pt also caused mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Graphical abstract Pt(II) complex 1- induced mitochondrial dysfunction could be an valuable target for the development of new anticancer drugs. Abstract Two new Pt(II) and Ru(II) complexes, [Pt(BFCY)Cl 2 ] (1) and [RuCl 2 (BMCY)(DMSO)] (2) with 3-(1H-benzoimidazol-2-yl)-8-fluoro-chromen-2-ylideneamine (BFCY) and 3-(1H-benzoimidazol-2-yl)-8-methyl-chromen-2-ylideneamine (BMCY), were synthesized. The BFCY Pt(II) complex 1 adopted an approximately four-coordinated square planar geometry, while BMCY complex 2 formed a distorted octahedral geometry. Among the seven selected human cancer cell lines, the two new Pt(II) and Ru(II) complexes 1 and 2 exhibited more potent activities against cisplatin-resistant SK-OV-3/DDP tumor cells (IC 50 = 2.08 ± 1.04 μM and 18.06 ± 0.36 μM, respectively), compared with the free BFCY and BMCY ligands as well as cisplatin. In addition, the BFCY Pt(II) complex 1 could induce cell cycle arrest in S phase and regulate the S-phase cell cycle-related proteins. Remarkably, the BFCY Pt(II) complex 1 also induced mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Abstract In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH 3 OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4′-dimethyl-2,2′-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1 Pt7 exhibited cytotoxic activity against the tested NCI H460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC 50 value of 0.13 ± 0.16 μM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1 Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug. Graphical abstract Pt5 induced SK-OV-3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity and activation of the p53 signaling pathway. Image 1 Highlights • We designed and synthesized tacrine platinum(II) complexes Pt1 Pt7 as telomerase inhibitors and p53 activators. • Pt5 display high in vivo and in vitro anticancer activity. • Pt5 may trigger cell apoptosis via a mitochondrial dysfunction pathway. [ABSTRACT FROM AUTHOR]

Abstract A dinuclear palladium(II) complex, [Pd 2 (μ ‑OAc‑ κ O,O) 2 (phpy‑ κ N,C) 2 ] (1), with 2‑phenylpyridine (H‑phpy) as a ligand was synthesized and characterized by IR, ESI-MS, single-crystal X-ray diffraction, and elemental analysis. By the MTT assay, the dinuclear palladium(II) complex 1 showed lower cytotoxic activity toward normal HL-7702 cells (IC 50 = 85.89 ± 0.89 μM). However, it displayed high cytotoxicity against SK-OV-3, NCI-H460, T-24, and HeLa cells, with IC 50 values of 5.50 ± 1.08, 0.46 ± 0.28, 7.93 ± 1.16 and 0.35 ± 0.29 μM, respectively. Importantly, we found that this Pd(II) complex exhibited lower toxicity and better anticancer activity than that of cisplatin. Further cellular assays, including Western blotting and flow cytometry, gave evidence that apoptosis after treatment with the dinuclear palladium(II) complex 1 may be induced by the intrinsic mitochondrial dysfunction pathway. Graphical abstract Apoptosis after treatment with the dinuclear palladium(II) complex 1 may be induced by the intrinsic mitochondrial dysfunction pathway. Unlabelled Image Highlights • Synthesis of the dinuclear palladium(II) complex 1 was reported. • The dinuclear palladium(II) complex 1 was more cytotoxic than cisplatin in all the cell lines tested. • The dinuclear palladium(II) complex 1 could induce mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Polyrhachis vicina Roger (P. vicina), a traditional Chinese medicinal animal, has been used to treat rheumatoid arthritis, hepatitis, cancer, and other conditions. Due to its anti-inflammatory properties, our previous pharmacological investigations have demonstrated that it is effective against cancer, depression, and hyperuricemia. Nevertheless, the key active components and targets of P. vicina in cancers are still unexplored. The study aimed to evaluate the pharmacological treatment mechanism of the active fraction of P. vicina (AFPR) in treating colorectal cancer (CRC) and to further reveal its active ingredients and key targets. To examine the inhibitory impact of AFPR on CRC growth, tumorigenesis assays, cck-8 assays, colony formation assays, and MMP detection were utilized. The primary components of AFPR were identified by GC-MS analysis. The network pharmacology, molecular docking, qRT-PCR, western blotting, CCK-8 assays, colony formation assay, Hoechst staining, Annexin V-FITC/PI double staining, and MMP detection were performed to pick out the active ingredients and potential key targets of AFPR. The function of Elaidic acid on necroptosis was investigated through siRNA interference and the utilization of inhibitors. Elaidic acid's effectiveness to suppress CRC growth in vivo was assessed using a tumorigenesis experiment. Studies confirmed that AFPR prevented CRC from growing and evoked cell death. Elaidic acid was the main bioactive ingredient in AFPR that targeted ERK. Elaidic acid greatly affected the ability of SW116 cells to form colonies, produce MMP, and undergo necroptosis. Additionally, Elaidic acid promoted necroptosis predominantly by activating ERK/RIPK1/RIPK3/MLKL. According to our findings, Elaidic acid is the main active component of AFPR, which induced necroptosis in CRC through the activation of ERK. It represents a promising alternative therapeutic option for CRC. This work provided experimental support for the therapeutic application of P. vicina Roger in the treatment of CRC. [Display omitted] • The active fraction of Polyrhachis vicina Roger (AFPR) inhibited CRC growth in vivo and in vitro. • Network pharmacology and molecular docking predicted ERK might be the key target of AFPR in antagonizing CRC. • Elaidic acid was a key active component of AFPR and induced necroptosis. • Elaidic acid induced necroptosis via ERK activation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Citri Reticulatae Pericarpium (Rutaceae, CRP), commonly called as Chenpi (陈皮) in Chinese, is most frequently used as a qi-regulating drug in thousands of Chinese medicine prescriptions. CRP is found mainly in major citrus-producing areas such as the Guangdong, Guangxi, Sichuan, Fujian, and Zhejiang Provinces of China. Since thousands of years in China, CRP has been used widely in clinical practice to treat nausea, vomiting, indigestion, anepithymia, diarrhea, cough, expectoration, and so on. Currently, CRP is listed in the Pharmacopoeia of the People's Republic of China. The present paper reviews the botany, ethnopharmacology, phytochemistry, pharmacology, quality control, and toxicology of CRP. Materials and methods Information on CRP was gathered from various sources including the books on traditional Chinese herbal medicine; scientific databases including Elsevier, PubMed, and ScienceDirect; Baidu Scholar; CNKI; and others and from different professional websites. Results Approximately 140 chemical compounds have been isolated and identified from CRP. Among them, volatile oils and flavonoids are generally considered as the main bioactive and characteristic ingredients. CRP possesses wide pharmacological effects such as having a beneficial effect on the cardiovascular, digestive, and respiratory systems, antitumor, antioxidant, and anti-inflammatory properties; and a protective effect on the liver and nerve. Moreover, hesperidin is chosen as an indicator in the quantitative determination of CRP, and the quantity of aflatoxin in CRP must not exceed the standard limit mentioned in the pharmacopoeia. Conclusions In brief, CRP has a warming nature, and hence, it can be used in harmony with a lot of medicines. CRP not only exhibits its effects individually but also aids other medicines exhibit a better effect. CRP can be consumed with tea, food, alcohol, and medicine. Irrespective of the form it is being consumed, CRP not only shows a synergistic effect but also has strengths on its own. Modern pharmacological studies have demonstrated that CRP has marked bioactivities, especially on the diseases of the digestive and respiratory systems. The bioactivities of CRP are useful for its clinical application and provide prospects for the development of drugs as well as food and health products for people. Although CRP is a commonly used drug in the traditional Chinese herbal prescription, there is an urgent need for further research on its synergistic effect with other herbs based on the compatibility theory of TCM, which would further increase our understanding on the compatibility theory of TCM. [ABSTRACT FROM AUTHOR]

There iridium(III) complexes, [Ir(3-MeO-Phtpy)Cl 3 ] ( 1 ), [Ir(2-MeO-Phtpy)Cl 3 ] ( 2 ) and [Ir(4-MeO-Phtpy)Cl 3 ] ( 3 ) with 4′-(3-methoxyphenyl)-2,2′:6′,2″-terpyridine (3-MeO-Phtpy), 4′-(2-methoxyphenyl)-2,2′:6′,2″-terpyridine (2-MeO-Phtpy) and 4′-(4-methoxyphenyl)-2,2′:6′,2″-terpyridine (4-MeO-Phtpy) as ligands, respectively, were synthesized and evaluated for their antiproliferative activities. In these complexes, the iridium(III) center adopts a six-coordinate distorted octahedral geometry. Among them, complex 1 exhibited the most potent activity, with IC 50 values of 3.19–27.77 μ M against four cancer cell lines (BEL-7404, Hep-G2, NCI-H460 and MGC80-3 cells). Cellular mechanism studies suggested that complexes 1 – 3 directly targeted c-myc promoter elements and inhibited the telomerase activity. In addition, complexes 1 – 3 may trigger cell apoptosis via a mitochondrial dysfunction pathway. We postulated that the difference in the in vitro antitumor activities of complexes 1 – 3 is mainly dependent on the position of the methoxy group on the phenyl ring of the iridium ligand. [ABSTRACT FROM AUTHOR]

The mechanism for improved therapeutic efficacy of the combination therapy with nanoparticle albumin-bound paclitaxel (nAb-PTX) and gemcitabine (gem) for pancreatic ductal adenocarcinoma (PDAC) has been ascribed to enhanced gem transport by nAb-PTX. Here, we used an orthotopic mouse model of gem-resistant human PDAC in which increasing gem transport would not improve the efficacy, thus revealing the importance of nAb-PTX transport. We aimed to evaluate therapeutic outcomes and transport of nAb-PTX to PDAC as a result of (1) encapsulating nAb-PTX in multistage nanovectors (MSV); (2) effect of gem on caveolin-1 expression. Treatment with MSV/nAb-PTX + gem was highly efficient in prolonging animal survival in comparison to other therapeutic regimens. MSV/nAb-PTX + gem also caused a substantial increase in tumor PTX accumulation, significantly reduced tumor growth and tumor cell proliferation, and increased apoptosis. Moreover, gem enhanced caveolin-1 expression in vitro and in vivo, thereby improving transport of nAb-PTX to PDAC. This data was confirmed by analysis of PDACs from patients who received gem-based neo-adjuvant chemotherapy. In conclusion, we found that nAb-PTX treatment of gem-resistant PDAC can be enhanced by (1) gem through up-regulation of caveolin-1 and (2) MSV through increasing accumulation of nAb-PTX in the tumor. [ABSTRACT FROM AUTHOR]

Ginsenoside Rg1 (Rg1) is one of the main active components in Panax ginseng C. A. Meyer (ginseng), which has been widely used to delay senescence or improve health conditions for more than 2000 years. Increasing studies have revealed that Rg1 could regulate cell proliferation and differentiation, as well as anti-inflammatory and anti-apoptotic effects, and might have protective effects on many chronic kidney diseases. Diabetic nephropathy (DN) is one of the most dangerous microvascular complications of diabetes and is the leading cause of end-stage renal disease worldwide. However, the role and mechanism of Rg1 against high-glucose and high-fat-induced glomerular fibrosis in DN are not clear. This study aimed to investigate the protective effect of Rg1 on DN and its possible mechanism. The type 2 diabetes mellitus (T2DM) mice models were established with a high-fat diet (HFD) combined with an intraperitoneal injection of streptozotocin (STZ). Urine protein and serum biochemical indexes were detected by corresponding kits. The kidney was stained with H&E, PAS, and Masson to observe the pathological morphology, glycogen deposition, and fibrosis. The expression of CD36 and p-PLC in the kidney cortex was detected by IHC. The expressions of FN and COL4 were detected by IF. Western blot and PCR were performed to examine protein and mRNA expressions of kidney fibrosis and TRPC6/NFAT2-related pathways in DN mice. Calcium imaging was used to examine the effect of Rg1 on [Ca2+] i in PA + HG-induced human mesangial cells (HMCs). Visualization of the interaction between Rg1 and CD36 was detected by molecular docking. Rg1 treatment for 8 weeks could prominently decrease urinary protein, serum creatinine, and urea nitrogen and downgrade blood lipid levels and renal lipid accumulation in T2DM mice. The pathological results indicated that Rg1 treatment attenuated renal pathological injury and glomerular fibrosis. The further results demonstrated that Rg1 treatment remarkably decreased the expressions of CD36, TRPC6, p-PLC, CN, NFAT2, TGF-β, p-Smad2/3, COL4, and FN in renal tissues from T2DM mice. Calcium imaging results found that Rg1 downgraded the base levels of [Ca2+] i and ΔRatioF340/F380 after BAPTA and CaCl 2 treatment. Molecular docking results showed that Rg1 could interact with CD36 with a good affinity. These results revealed that Rg1 could ameliorate renal lipid accumulation, pathological damage, and glomerular fibrosis in T2DM mice. The mechanism may be involved in reducing the overexpression of CD36 and inhibiting the TRPC6/NFAT2 signaling pathway in renal tissues of T2DM mice. [Display omitted] • Rg1 treatment ameliorates glomerular fibrosis and diabetic nephropathy in T2DM mice. • Rg1 treatment decreases the levels of blood lipids and renal DAG and IP3 in T2DM mice. • Rg1 treatment inhibits CD36 expression and PLC activation in T2DM mice. • Rg1 treatment inhibits TRPC6/CN/NFAT2 signaling in T2DM mice. [ABSTRACT FROM AUTHOR]

Two G-quadruplex ligands: [Co( H-L a ) 2 Cl 2 ] ( Co1 ) and [Co( L b ) 2 ][CoCl 4 ]⋅2H 2 O ( Co2 ) have been synthesized and characterized. Two cobalt oxoisoaporphine complexes exhibited selective cytotoxicity to SK-OV-3/DDP cells than for HL-7702 cells. Cytotoxic mechanism studies indicated that both Co1 and Co2 were telomerase inhibitor targeting c-myc, telomere, and bcl-2 G4s, and triggering cell senescence and apoptosis, which caused S phase arrest. They also induced mitochondrial dysfunction. The better antitumor activity of Co2 , which should be correlated with a moiety of 2-[5-(2-pyridinyl)-1 H -pyrrol-2-yl]pyridine in the L b . Importantly, Co2 at high doses showed at least the same level of tumor growth inhibition efficacy compared to that of cisplatin, and better in vivo safety profile. [ABSTRACT FROM AUTHOR]

The increasingly acquired resistance to vemurafenib and side effects of known inhibitors motivate the search for new and more effective anti-melanoma drugs. In this Letter, virtual screening and scaffold growth were combined together to achieve new molecules as BRAF V600E inhibitors. Along with docking simulation, a primary screen in vitro was performed to filter the modifications for the lead compound, which was then substituted, synthesized and evaluated for their inhibitory activity against BRAF V600E and several melanoma cell lines. Out of the obtained compounds, derivative 3l was identified as a potent BRAF V600E inhibitor and exerted an anticancer effect through BRAF V600E inhibition. The following biological evaluation assays confirmed that 3l could induce cell apoptosis and marked DNA fragmentation. Furthermore, 3l could arrest the cell cycle at the G0/G1 phase in melanoma cells. The docking simulation displayed that 3l could tightly bind with the crystal structure of BRAF V600E at the active site. Overall, the biological profile of 3l suggests that this compound may be developed as a potential anticancer agent. [ABSTRACT FROM AUTHOR]

Novel approaches to pre-transplant conditioning are needed to improve treatment of advanced T-cell malignancies. We investigated the synergism of fludarabine (Flu), clofarabine (Clo), busulfan (Bu), and romidepsin (Rom) in T-cell lines and patient-derived cell samples. [Flu + Clo + Bu + Rom] had combination indexes of 0.4–0.5 at ∼50% cytotoxicity in PEER and SUPT1 cells, suggesting synergism. Drug exposure resulted in histone modifications, DNA-damage response (DDR), increased reactive oxygen species (ROS), decreased glutathione (GSH) and mitochondrial membrane (MM) potential, and apoptosis. Similar activation of DDR and apoptosis was observed in patient samples. The PI3K-AKT-mTOR, NFκB, Raf-MEK-ERK, JAK-STAT and Wnt/β-catenin pro-survival pathways were inhibited by the 4-drug combination. The SAPK/JNK stress pathway was activated. A novel finding was the down-regulation of the drug transporter MRP1. We propose the following mechanisms of synergism: Flu, Clo and Rom induce histone modifications and chromatin remodeling, exposing DNA to Bu alkylation; the increased production of ROS, due to drug-mediated stress response and decreased GSH, damages the MM causing leakage of pro-apoptotic factors; down-regulation of MRP1 increases intracellular Bu concentration and exacerbates the DDR; and inhibition of multiple survival pathways. Our results provide the basis for a clinical trial to evaluate [Flu + Clo + Bu + Rom] as part of conditioning regimen for refractory T-cell malignancy patients undergoing stem cell transplantation. [ABSTRACT FROM AUTHOR]

G-quadruplex as a therapeutic target to develop novel anti-cancer agents has attracted a growing interest. Among all the ligands of G-quadruplexes, pyridostatin derivatives play a very important role. Here, we first reported the recognition of the fundamental skeleton pyridostatin I , which was simply synthesized. Compared to pyridostatin II comprising terminal amino groups, pyridostatin I selectively stabilized intramolecular anti-parallel telomeric G-quadruplex by raising the melting temperature about 20 °C at 295 nm of H22, while pyridostatin II preferred to stabilize intermolecular parallel telomeric G-quadruplex by raising the melting temperature about 25 °C at 265 nm of H7, maybe due to the suited size measurements between G-quadruplex hosts and pyridostatin guests. MTT assays indicated that pyridostatin II had better cytotoxic effects against HCT-8 and A549 cell lines obviously, indicating positively charged side chains may be required for improving the water solubility and cellular uptake of the apolar central skeleton. [ABSTRACT FROM AUTHOR]

A key problem in designing G-quadruplex ligand is how to discriminate quadruplex DNA specifically from other DNAs, searching ligands targeted at special G-quadruplex structure with high selectivity is a major challenge. Herein, a phenanthrolin-dicarboxylate ester (PD) is proved to exhibit selectivity toward parallel and hybrid G-quadruplex structures with propeller and edge-wise loops, over duplex DNA and antiparallel quadruplex structure with diagonal loop. Such preferred binding of PD to these special G-quadruplex structures is possibly resulted from steric hindrance of: (1) the four substituent groups in PD molecule which prevent close interaction with duplex DNA and (2) the diagonal loop above the G-tetrads in antiparallel G-quadruplex which hinder face-to-face stacking of planar phenanthrolin ring to G-tetrads. In line with its stabilizing ability of G-quadruplex, PD molecule exhibit a inhibitory ability telomerase activity, as well as the potent cytotoxic activity against several human cancer cell lines, which makes it an interesting anti-tumor drug lead. [ABSTRACT FROM AUTHOR]