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Background: Epstein–Barr virus (EBV) is well known to be associated with a lot of tumors, including lymphoma, nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and some other carcinomas with similar lymphoepithelioma-like features. However, the association between EBV and thymic epithelial tumors (TETs) is inconclusive as reports in this regard are not entirely consistent and the methods employed are of different sensitivity and specificity. The geographical difference of the patients is also one of the reasons for the different points of view. Methods: In our study, we examined 72 thymomas, including 3 cases of type A thymomas, 27 cases of type AB, 6 cases of type B1, 26 cases of type B2 and 10 cases of type B3 thymomas, and 15 thymic carcinomas to detect the viral genome at both DNA and RNA levels. The genome DNA of fresh tissues was first screened by nested polymerase chain reaction (PCR), which could be regarded as the most sensitive method to detect small amounts of DNA. Then all the tissue blocks were further submitted for viral localization by Epstein–Barr-encoded RNA (EBER) ISH. Group parameters were assessed using the chi-square test at a significance level of p < 0.05. Results: Nested PCR results showed that none of type A, eight (29.6%) type AB, one (16.7%) type B1, fifteen (57.7%) type B2, and four (40.0%) type B3 were positive for EBV genome. However, none of them detected EBER expression except for one case of type B2 thymoma. Fourteen (93.3%) thymic carcinomas were positive for EBV by nested PCR, of which three displayed weak nuclear signals within the tumor cells by EBER ISH. Conclusions: These results showed that nested PCR was a sensitive method for screening the EBV genome in thymic epithelial tumors. As the malignancy of thymoma increases, the rate of EBV infection became higher. Thymic carcinomas were well associated with the Epstein–Barr virus.There was significant association between the EBV infection rate and thymoma type (p < 0.05). We further analyzed the association between EBV infection and myasthenia gravis. However, it showed no significant difference(p = 0.2754), although the EBV infection rate was higher in the thymomas with myasthenia gravis. [ABSTRACT FROM AUTHOR]

(–)-5-Methylmellein (1) and its new dimer (2) were isolated from cultures of the basidiomycete Inonotus sinensis. Their structures were elucidated on the basis of extensive spectroscopic methods including UV, IR, HR-EI-MS, 1D NMR and 2D NMR. The structure of Compound 2 was determined by single-crystal X-ray crystallographic analysis. Compound 2 was tested for the cytotoxicities against five human cancer cell lines. [ABSTRACT FROM AUTHOR]

Two new tremulane-type sesquiterpenes, irlactin L (1) and irlactin M (2) were isolated from cultures of the fungus Irpex lacteus, together with one known compound, 6-hydroxy-2,6-dimethyloct-7-enoic acid (3). Their structures were elucidated by spectroscopic data analysis. Compounds 1–2 were tested for their cytotoxicities against five human cancer cell lines and for their inhibitory activities against isozymes of 11β-hydroxysteroid dehydrogenases (11β-HSD). [ABSTRACT FROM AUTHOR]

Two new compounds, daedatrin K (1) and 2-hydroxy-1-(5-(hydroxymethyl)furan-2-yl)propan-1-one (2), were isolated from cultures of the basidiomycetes Daedaleopsis tricolor. The new structures were elucidated on the basis of extensive spectroscopic methods. At the same time, two compounds were tested for their cytotoxicities against five human cancer cell lines. [ABSTRACT FROM AUTHOR]

Background: Developing the natural medicine that allow for the specific targeting cytotoxicity is a very important research area in the development of anti-tumor drugs.Aims and Objectives: This study was conducted to determine the targeted inhibitory effects of luteolin-loaded Her-2-poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) on gastric cancer cells and to delineate the mechanism underlying the inhibition of tumors by luteolin.Materials and Methods: Luteolin-loaded Her-2-PLGA NPs (Her-2-NPs) were prepared, physically and chemically characterized, and their effects on gastric cancer cells were investigated. The rate of NP uptake by cells and the cell morphology were observed using confocal microscopy; the rates of cell proliferation and apoptosis were identified using the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay and flow cytometry, respectively; and the mRNA and protein expression levels of forkhead box protein O1 (FOXO1) were determined using quantitative polymerase chain reaction and Western blotting, respectively.Results: Compared with nontargeted microspheres, Her-2-NPs led to significantly enhanced uptake of luteolin by SGC-7901 cells. Luteolin-loaded Her-2-NPs also significantly inhibited the proliferation of gastric cancer cells, weakened their migratory ability, and increased both the mRNA and protein expression levels of FOXO1.Conclusion: Luteolin-loading of Her-2-NPs could potentially be used as a novel anti-cancer drugs for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Chemical study on the ethanolic extract generated from the aerial parts of Croton kongensis led to the isolation of three new 8,9-seco-ent-kaurane diterpenoids, kongeniods A‒C (1‒3), together with seven known analogs (4-10). The structures of these compounds were assigned by spectroscopic data analysis. The vitro cytotoxic tests showed that compounds 1-3 exhibited strong activities against HL-60 cell lines with IC50 values of 0.47, 0.58, and 1.27 μM, respectively. [ABSTRACT FROM AUTHOR]

A new isopimarane diterpenoid, inonotolide D (1), was isolated from cultures of the basidiomycetes Inonotus sinensis. The new structure was elucidated on the basis of extensive spectroscopic studies. The compound was evaluated for its cytotoxicities against five human cancer cell lines. [ABSTRACT FROM AUTHOR]

A new tremulane sesquiterpene lactone, named irlactin K (1), was isolated from the culture broth of the basidiomycete Irpex lacteus. The structure of the new compound was established through extensive spectroscopic analyses. The compound was tested for its cytotoxicity against five human cancer cell lines and for its inhibitory activity against isozymes of 11β-hydroxysteroid dehydrogenases. [ABSTRACT FROM AUTHOR]

Three new drimane sesquiterpenoids, 12-hydroxyalbrassitriol (1), drim-8(12)-en-6β,7α, 9α,11-tetraol (2), and drim-68(12)-dien-9α,11-diol (3), along with one known analog albrassitriol (4), were isolated from cultures of the tin mine tailings-associated fungusPenicillium sp.The new structures were determined on the basis of extensive spectroscopic analyses. All compounds were tested for their cytotoxicities against five human cancer cell lines. [ABSTRACT FROM PUBLISHER]

Three new isopimarane diterpenoid lactones, named inonotolides A–C ( 1–3 ), were isolated from cultures of the basidiomycete Inonotus sinensis. Their structures were elucidated on the basis of extensive spectroscopic studies and the structure of inonotolide A ( 1 ) was confirmed by single-crystal X-ray crystallographic analysis. All compounds were evaluated for their cytotoxicities against five human cancer cell lines. [ABSTRACT FROM AUTHOR]

BACKGROUND The 14-3-3ζ protein has been identified as a putative oncoprotein in several cancers, including non-small cell lung cancer (NSCLC). However, the mechanisms underlying its functions have not been well defined. METHODS Proteins that interact with 14-3-3ζ were identified through coimmunoprecipitation and mass spectrometry in NSCLC cells. The interaction of 14-3-3ζ with these molecular partners and their roles in the invasiveness and metastasis of NSCLC cells were assayed through specific disruptions in the 14-3-3ζ signaling network. In addition, the clinical implications of this 14-3-3ζ complex were examined in samples from patients with NSCLC. RESULTS Among the identified proteins that interacted with 14-3-3ζ, there were 230 proteins in 95-D cells, 181 proteins in 95-C cells, and 203 proteins in A549 cells; and 16 interacting proteins were identified that overlapped between all cell lines. Further studies revealed 14-3-3ζ complexes within the heat shock protein 27 (Hsp27) protein and demonstrated that the interference of Hsp27 or 14-3-3ζ inhibited the invasion and metastasis of NSCLC cells. The invasive and metastatic capabilities of cells with both Hsp27 and 14-3-3ζ interference could be completely restored only by Hsp27 and 14-3-3ζ complementary DNA transfection and not by either agent alone. Clinically, the postoperative 5-year overall survival (OS) in patients who had high expression of both 14-3-3ζ and Hsp27 was significantly lower than the 5-year OS in patients who had low expression of both 14-3-3ζ and Hsp27 (26.5% vs 59.7%, respectively). Multivariate analysis revealed that the combined expression of 14-3-3ζ and Hsp27 was an independent prognostic indicator of OS ( P = .036). CONCLUSIONS The current data suggest that the combined expression of 14-3-3ζ and Hsp27 may be a biomarker for predicting survival in patients with NSCLC, and this combination may have potential as a therapeutic target for NSCLC. Cancer 2014;120:652-663. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

Two new sesquiterpenoids, vernobockolides A (1) and B (2), along with five known ones, piptocarphin C (3), piptocarphin F (4), piptocarphin A (5), hirsutolide (6), and β-d-glucopyranosyl taraxinic ester (7), were isolated from the aerial part of Vernonia bockiana. Their structures were determined by spectroscopic analysis, especially 2D NMR. Among them, compounds 2-6 showed strong cytotoxic activities against mouse lymphoid tumor cell line P388 with the IC50 values of 1.81, 1.32, 0.77, and 0.73 μM, respectively. [ABSTRACT FROM AUTHOR]

Phosphatidylinositol 3-kinase (PI3K) δ-specific inhibitors have been approved for the therapy of certain types of B cell lymphoma (BCL). However, their clinical use is limited by the substantial toxicity and lack of efficacy in other types of BCL. Emerging evidence indicates that PI3Kα plays important roles in the progression of B cell lymphoma. In this study, we revealed that PI3Kα was important for the PI3K signaling and proliferation in BCL cells. A novel clinical PI3Kα-selective inhibitor CYH33 possessed superior activity against BCL compared to the marketed PI3Kα-selective inhibitor Alpelisib and PI3Kδ-selective inhibitor Idelalisib. Though CYH33 was able to inhibit PI3K/AKT signaling in tested BCL cells, differential activity against proliferation was observed. Transcriptome profiling revealed that CYH33 down-regulated "MYC-targets" gene set in sensitive but not resistant cells. CYH33 inhibited c-MYC transcription in sensitive cells, which was attributed to a decrease in acetylated H3 bound to the promoter and super-enhancer region of c-MYC. Accordingly, CYH33 treatment resulted in phosphorylation and proteasomal degradation of the histone acetyltransferase p300. An unbiased screening with drugs approved or in clinical trials for the therapy of BCL identified that the clinical BET (Bromodomain and Extra Terminal domain) inhibitor OTX015 significantly potentiated the activity of CYH33 against BCL in vitro and in vivo, which was associated with enhanced inhibition on c-MYC expression and induction of cell cycle arrest and apoptosis. Our findings provide the rationale of combined CYH33 with BET inhibitors for the therapy of B cell lymphoma. [ABSTRACT FROM AUTHOR]

Phenanthroindolizidine alkaloids that possess profound anti-proliferative activity and unique mode of action have recently attracted much attention as potential anti-cancer drug candidates. To intensively study the structure-activity-relationship, we designed, synthesized, and evaluated a series of derivatives of 6-desmethylantofine at C-6 position. Most of the derivatives exhibited potent anti-proliferative activity in BEL-7402 and HL60cells. Compound R-12 , the cyanomethyl ether of 6-desmethylantofine, exhibited significant anti-cancer activity and inhibited the proliferation of a panel of 30 cancer cell lines including 2 multi-drug-resistant cell lines with an average IC 50 value of 18.7 nM, which suggests that R-12 is a promising new anti-cancer agent. Our studies suggest that R-12 displayed potent inhibitory effect on cell growth and colony formation, which is associated with delaying S phase progression by inhibiting DNA synthesis in human hepatoma cancer BEL-7402, SMMC-7721 and ZIP-177 cells. [ABSTRACT FROM AUTHOR]

Poly(ADP-ribose)polymerase (PARP)1/2 inhibitors have been proved to be clinically effective anticancer drugs. Here we report a new PARP1/2 inhibitor, simmiparib, displaying apparently improved preclinical anticancer activities relative to the first approved inhibitor olaparib. Simmiparib inhibited PARP1/2 approximately 2-fold more potently than olaparib, with more than 90-fold selectivity over the other tested PARP family members. Simmiparib and olaparib caused similar cellular PARP1-DNA trapping. Simmiparib selectively induced the accumulation of DNA double-strand breaks, G2/M arrest and apoptosis in homologous recombination repair (HR)-deficient cells. Consistently, simmiparib showed 26- to 235-fold selectivity in its antiproliferative activity against HR-deficient cells over the corresponding isogenic HR-proficient cells. Notably, its antiproliferative activity was 43.8-fold more potent than that of olaparib in 11 HR-deficient cancer cell lines. Simmiparib also potentiated the proliferative inhibition of several conventional anticancer drugs. Simmiparib reduced the poly(ADP-ribose) formation in HR-deficient cancer cells and xenografts. When orally administered to nude mice bearing xenografts, simmiparib revealed excellent pharmacokinetic properties. Simmiparib caused approximately 10-fold greater growth inhibition than olaparib against HR-deficient human cancer cell- or tissue-derived xenografts in nude mice. Collectively, these findings support the undergoing clinical trials of simmiparib. [ABSTRACT FROM AUTHOR]

Although anti-programmed cell death 1 (PD1) treatment has become a first-line therapy for advanced non-small cell lung cancer (NSCLC), most NSCLC patients are refractory to anti-PD1. Here, we aimed to investigate the mechanism of dysregulated circular RNAs (circRNAs) related to anti-PD1 resistance in NSCLC. The expression of circASCC3 (hsa_circ_0077,495) in NSCLC tissues and cell lines was evaluated by fluorescence in situ hybridization and quantitative reverse transcription-polymerase chain reaction. The functions and mechanisms of circASCC3 in NSCLC progression and anti-PD1 resistance were uncovered in vitro and in vivo. The circASCC3 level was upregulated in NSCLC compared with that in paired normal tissues. Specifically, circASCC3 expression was higher in tissues from NSCLC patients with anti-PD1 refractory than in those from patients who sensitive to anti-PD1. Overexpression of circASCC3 enhanced the malignant phenotype of NSCLC cells and led to an immunosuppressive microenvironment. Mechanistically, circASCC3 sponged miR-432-5p to increase complement C5a levels, which enhanced the progression and dysfunctional immune status of NSCLC. Thus, circASCC3 overexpression reshapes the tumor microenvironment by impacting the complement system in NSCLC and provides a potential strategy to overcome anti-PD1 resistance. [ABSTRACT FROM AUTHOR]

Highlights: [•] Four dinorditerpenoids and eight known triterpenoids from Drypetes perreticulata. [•] Two dinorditerpenoids showed strong inhibition against HL-60 tumor cell line. [•] The structure–activity relationship of cytotoxic compounds was briefly discussed. [ABSTRACT FROM AUTHOR]

Abstract: Fourteen apotirucallane-type triterpenoids, named brujavanones A–N, were isolated from the twigs of Brucea javanica, along with four known quassinoids and seven known lignans from the seeds of B. javanica. Their structures were elucidated on the basis of extensive spectroscopic data analysis. The structure of a previously reported triterpenoid, bruceajavanin C, was revised as its C-21 epimer. The cytotoxic activities of triterpenoids and quassinoids against two human tumor cell lines, HL-60 and A-549, were evaluated, but all the compounds were inactive (IC50 >10μM). [Copyright &y& Elsevier]

Among a large number of HIV-1 integrase (IN) inhibitors,the 8-hydroxy-[1,6]naphthyridines (i.e., L-870,810) were one of thepromising class of antiretroviral drugs developed by Merck Laboratories.In spite of its remarkable potency and efficacy, unfortunately uponcompletion of phase I clinical studies, development of L-870,810 washalted. Because of its desirable pharmacological and pharmaceuticalproperties we were intrigued to design novel analogues of L-870,810with goals to (1) improve upon limitations of naphthyridine-7-carboxamidesas antiviral agents and (2) to reposition their use as innovativecytotoxic agents for cancer therapeutics. Herein, we report on thedesign and synthesis of a series of 1,6-naphthyridine-7-carboxamideswith various substitutions at the 5- and 8-positions. All the new5-substituted-8-hydroxy-[1,6]naphthyridines were potent IN inhibitorsand the 5-substituted-8-amino-[1,6]naphthyridines were significantlycytotoxic. Further optimization of the 5,8-disubstituted-[1,6]naphthyridineswith structural variation on 7-carboxamide delivered novel compoundswith significant cytotoxicity in a panel of cancer cell lines andeffective inhibition against select oncogenic kinases. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 11H-benzo[a]carbazole-5-carboxamide derivatives were designed, synthesized and evaluated for their antitumor activity against human cancer A549 and HCT-116 cell lines. Most of the compounds showed potent antitumor activities, and compound 8 displayed remarkable in vitro and in vivo anticancer activity comparable to that of amonafide. [Copyright &y& Elsevier]

Abstract: Six new highly oxygenated daphnane-type diterpenoids, trigochinins D–I (1–6), were isolated from the twigs and leaves of Trigonostemon chinensis. Their structures with the absolute configuration were established on the basis of spectroscopic method and CD analysis. Trigochinins D–F (1–3) possessed a rare 4,6-oxetane moiety in this compound class. Trigochinins E and F exhibited significant inhibiting activity against HL-60 tumor cell line. [Copyright &y& Elsevier]

Abstract: Five novel prenylated polyketides, harrisotones A–E (1–5) representing a rare spirocyclic skeleton, along with a new hydroperoxypolyketide harrisonol A (6), were isolated from the stems and leaves of Harrisonia perforata. The structures of harrisotones A–E (1–5) were extensively elucidated on the basis of spectroscopic analysis, especially 2D NMR and CD spectra. A plausible origin of compounds 1–5 was rationalized biogenetically, and traced back to harrisonol A (6). Harrisotones A–C (1–3) and harrisonol A (6) exhibited significant cytotoxicity against P-388 and/or A-549 tumor cell lines. [Copyright &y& Elsevier]

Abstract: A series of triaminotriazine derivatives (compounds 5a–f, 6a–x, and 7a–g) was designed, synthesized, and evaluated for their inhibition activities to colorectal cancer (CRC) cell lines (HCT-116 and HT-29). Most of the synthesized compounds demonstrated moderate anti-proliferatory effects on both HCT-116 and HT-29 cell lines at the concentration of 10μM. The inhibitory activities against HCT-116 and HT-29 cell lines were discussed to develop the structure–activity relationships of this new series. Compounds 6l and 6o exhibited prominent inhibition activities toward HCT-116, with IC50s of 0.76 and 0.92μM, respectively. The in vivo antitumor studies and pharmacokinetics of compound 6l showed that it might be a promising new hit for further development of antitumor agents. [Copyright &y& Elsevier]

Abstract: Thymopentin (Arg–Lys–Asp–Val–Tyr, TP5) has shown immuno-regulatory activities in humans. In the present study, we investigated the effects of TP5 on the proliferation and differentiation of a human promyelocyte leukemia cell line, HL-60. It is noteworthy that TP5 displayed concentration-dependent inhibitory effects on the proliferation and colony formation of HL-60 cells. Furthermore, the decrease or even disappearance of AgNORs from nucleoli was observed in HL-60 cells after the treatment with TP5. The suppression induced by TP5 was accompanied by an accumulation of cell cycle in the G0/G1 phase. Moreover, TP5 significantly increased the NBT-reduction activity of HL-60 cells. Cytofluorometric and morphologic analysis indicated that TP5 had induced differentiation along the granulocytes lineage in HL-60 cells. d-tubocurarine (TUB) significantly antagonized the inhibitory effects induced by TP5, whereas atropine did not exhibit such effect. All the results indicated that TP5 was able to significantly inhibit proliferation and induce differentiation in HL-60 cells. Our observations also implied that TP5 not only acted as an immunomodulatory factor in cancer chemotherapy, but is also a potential chemotherapeutic agent in the human leukemia therapy. [Copyright &y& Elsevier]

Abstract: A series of new camptothecin derivatives, as topoisomerase I inhibitor, were synthesized to identify potent antitumor agents. The synthesis method was based on the Claisen rearrangement of 10-allyloxy-7-ethylcamptothecin. All of the compounds were assayed for cytotoxicity against two human tumor cell lines, Bel7402, HCT116, and showed good potency in vitro. Compounds 2, 4, 9, were assessed for the stability of lactone in human plasma. And then compound 2 was tested for antitumor activity in vitro against mouse tumor sarcoma-180. The results suggested that the small alkyl groups in the both 7- and 9-positions of camptothecin could promote liposolubility, antitumor activity in vitro and vivo, though did not bring much increase of the stability of lactone. [Copyright &y& Elsevier]

Abstract: A novel ternary copper(II) complex, [Cu(phen)(l-Thr)(H2O)](ClO4) (phen=1,10-phenanthroline, l-Thr=l-threonine), has been synthesized and structurally characterized. The complex crystallized in a triclinic system with space group , a=7.526(15) Å, b=11.651(2) Å, c=12.127(2) Å, α=115.41(3)°, β=102.34(3)° and γ=91.33(3)°. The copper(II) center is situated in a distorted square-pyramidal geometry. At a concentration of 10−6 mol L−1, the complex exhibited potent cytotoxic effects against human leukemia cell line HL-60 and human stomach cancer cell line SGC-7901 with inhibition rates of over 90%, however, less pronounced effects were observed for human liver carcinoma cell line BEL-7402 and human non-small-cell lung cancer cell line A-549. The complex was shown to bind DNA by intercalation and cleave pBR322 DNA in the presence of ascorbate. [Copyright &y& Elsevier]

Abstract: A series of shikonin analogues with side chain variants have been synthesized and evaluated for antitumor activity. These novel analogues show a broad spectrum of in vitro cytotoxicity against various cancer cell lines. Additionally, some analogues were also found to have the ability to decrease the expression level of HIF-1α in breast cancer cells MDA-MB-231 under hypoxia. The features of these analogues suggest their potential in cancer therapy. [Copyright &y& Elsevier]