Cell Carcinoma Of Cervix Research Articles

Bispecific targeting of EGFR and uPAR in a mouse model of head and neck squamous cell carcinoma

To investigate the efficacy of the bispecific targeted toxin, dEGFATFKDEL, on head and neck carcinoma cell lines in vitro and in vivo. A deimmunized bispecific anti-cancer agent was constructed to simultaneously target both the overexpressed EGF receptor on carcinomas and the urokinase receptor (uPAR), that is found on the endothelial cells of the neovasculature within tumors. Flow cytometry assays were performed to determine the level of EGFR expressed on a variety of carcinoma lines. These lines were then tested in tritiated leucine incorporation assays to determine the efficacy of dEGFATFKDEL. Human vein endothelial primary cells were also tested to determine the effectiveness of the ATF portion of the molecule that binds uPAR. Furthermore, mouse studies were performed to determine whether dEGFATFKDEL was effective at inhibiting tumor growth in vivo. UMSCC-11B and NA, two head and neck squamous cell carcinomas, highly expressed EGFR. Both the carcinoma lines and the human vein endothelial cells were inhibited at sub-nanomolar concentrations by dEGFATFKDEL. The tumor studies showed that the tumors treated with dEGFATFKDEL were significantly inhibited whereas the negative control and untreated tumors progressed. In a separate in vivo study involving another carcinoma line, MDA-MB-231, the effectiveness of dEGFATFKDEL was confirmed. No toxicity was seen at the doses used in either of these mouse studies. This bispecific agent is effective in a mouse model of head and neck squamous cell carcinoma. Further study of this reagent for use in the treatment of carcinomas is warranted.

<i>In Vitro</i> Evaluation of Folate-Targeted Chitosan Nanoparticles Loaded with Hydroxycamptothecin

We prepared FA-targeted and 10-hydroxycamptothecin loaded chitosan nanoparticles (FA-HCPT-NPs) with a combination of emulsion-solvent evaporation and chemical crosslinking method. In vitro cytotoxicity test to the Human Cervix Carcinoma cells (HeLa) was evaluated by cell morphology and internalization observation. The specicity of the FA-HCPT-NPs targeting cancerous cells was demonstrated by comparative intracellular uptake of HCPT-NPs and commercial availible HCPT injection. Laser confocal scanning imaging proved that FA-HCPT-NPs could greatly enhance up-take by HeLa cells. The morphological changes of HeLa cells showed the FA-HCPT-NPs could inhibit HeLa cells more effectively than HCPT-NPs and HCPT. The results indicated that the novel FA-HCPT-NPs could be a potential drug delivery system for tumor cell-selective targeting therapy.

Synthesis and anticancer activity of 5,6,8,13-tetrahydro-7H-naphtho[2,3-a][3]-benzazepine-8,13-diones

A series of naphthoquinones fused benzazepines, 5,6,8,13-tetrahydro-7H-naphtho[2,3-a][3]-benzazepine-8,13-diones, were synthesized and evaluated for their anticancer activity against four cell lines; human breast carcinoma cell line, human cervix carcinoma cell line, human hepatocellular carcinoma cell line and human keratinocyte cell line. The results showed that 5,6,8,13-tetrahydro-2,3,4,9-tetramethoxy-7H-naphtho[2,3-a][3]benzazepine-8,13-dione 4g and 5,6,8,13-tetrahydro-2,3,9-trimethoxy-7H-naphtho[2,3-a][3]benzazepine-8,13-dione 4h have significant cytotoxicity against a hepatocellular carcinoma cell line with IC(50) = 3.5 μg/mL and 3.0 μg/mL, respectively.

Modulation of cellular S1P levels with a novel, potent and specific inhibitor of sphingosine kinase-1

SphK (sphingosine kinase) is the major source of the bioactive lipid and GPCR (G-protein-coupled receptor) agonist S1P (sphingosine 1-phosphate). S1P promotes cell growth, survival and migration, and is a key regulator of lymphocyte trafficking. Inhibition of S1P signalling has been proposed as a strategy for treatment of inflammatory diseases and cancer. In the present paper we describe the discovery and characterization of PF-543, a novel cell-permeant inhibitor of SphK1. PF-543 inhibits SphK1 with a K(i) of 3.6 nM, is sphingosine-competitive and is more than 100-fold selective for SphK1 over the SphK2 isoform. In 1483 head and neck carcinoma cells, which are characterized by high levels of SphK1 expression and an unusually high rate of S1P production, PF-543 decreased the level of endogenous S1P 10-fold with a proportional increase in the level of sphingosine. In contrast with past reports that show that the growth of many cancer cell lines is SphK1-dependent, specific inhibition of SphK1 had no effect on the proliferation and survival of 1483 cells, despite a dramatic change in the cellular S1P/sphingosine ratio. PF-543 was effective as a potent inhibitor of S1P formation in whole blood, indicating that the SphK1 isoform of sphingosine kinase is the major source of S1P in human blood. PF-543 is the most potent inhibitor of SphK1 described to date and it will be useful for dissecting specific roles of SphK1-driven S1P signalling.

Synthesis and antiviral evaluation of C5-substituted-(1,3-diyne)-2′-deoxyuridines

Starting from acetylated 5-ethynyl-2′-deoxyuridine (3), 14 hitherto unknown C5-substituted-(1,3-diyne)-2′-deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)phenyl and disubstituted-phenyl substituents) have been synthesized via a nickel-copper catalyzed C–H activation between two terminal alkynes, in yields ranging from 19% to 67%. Their antiviral activities were measured against a large number of DNA and RNA viruses including herpes simplex virus type 1 and type 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. The 5-[4-(4-trifluoromethoxyphenyl)buta-1,3-diynyl]-2′-deoxyuridine (26) is the most potent inhibitor of this series against VZV with an EC50 of ∼1 μM and a CC50 of 55 μM. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including influenza virus A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and vesicular stomatitis, coxsackie B4 and respiratory syncytial virus in HeLa cell cultures and against human immunodeficiency virus type 1 and 2 in CEM cell cultures, with no specific antiviral effect. This class of compounds could be of further interest for lead optimization as anti-infectious (i.e. herpetic) agents.

Abstract LB-371: Beneficial effect of combination therapy with radiation and MSC-based IL-12M gene vaccine, Gx-051, in allograft animal mode

Abstract PURPOSE: During the last decades, irradiation is one of the most well-known therapies in head and neck cancer. The combination of radiation with other treatment modalities has been researched to improve its therapeutic efficacy and reduce its side effects. Gx-051, that is mesenchymal stem cell (MSC) expressing modified interleukin-12 (MSCs/IL-12M), is recently reported as a novel component of human immune system to attack cancer cells by the recruitment of immune cells with a high specificity. We would like to evaluate the therapeutic benefits of combined radiation and immunotherapy, compared to the treatment with each single modality in allograft animal model. METHODS AND MATERIALS: AT-84 cells, one of murine head and neck carcinoma cells, were injected for allograft induction on C3H/HeN mice. All the mice were randomly divided into 4 groups; control (non-treated), radiation only-treated, Gx-051 only-treated, and irradiation with Gx-051-treated. Intra-tumoral injection of Gx-051 (adopted within 24hr after irradiation) as well as 8 Gy-local irradiation was carried out, totally 4 times (twice a week for 2 weeks). To clarify the anti-tumoral effect of radiation with Gx-051 administration, we provided reasonable evidences; tumor volume, levels of IL-12 and IFN-r, and the changes in signaling pathway related-protein expression level. RESULTS: In vivo allograft study using AT-84 cells and C3H/HeN mice showed that combined treatment with radiation and Gx-051 significantly enhanced the anti-tumor effect. The tumor volume markedly decreased in the combined treatment group compared to other groups (p<0.05). Both levels of IL-12 and IFN-r were significantly higher in the combined treatment group (p<0.05). The expression of Ki-67, p16, and vascular endothelial growth factor were suppressed and that of caspase-3 was enhanced in combined treatment group compared to others in immunostaining. In addition, The protein level of Ras and HIF-1α were reduced and that of cyclin B1 was increased compared to others in immunoblotting. CONCLUSIONS: Our results demonstrated the combined treatment with radiation and Gx-051 enhanced the responses to HNSCC by AT-84 via increasing cytokines’ levels (IL-12 and IFN-r) and mediating signaling pathways (apoptosis, cell cycle, and angiogenesis). Dual administration of radiation with Gx-051 showed significant anti-tumoral effects by inducing apoptosis and inhibiting angiogenesis of tumor cell and these evidences gave us the partial rationale to the further study about the combined therapy of radiation with Gx-051 for the advanced treatment of human HNSCC. This study was supported by grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare (A091205) and the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. 2011-0012555). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-371. doi:1538-7445.AM2012-LB-371

Abstract 3038: Delineating the role of Arid3B in normal and malignant differentiation of esophageal and cervical stratified squamous epithelia

Abstract ARID3B is DNA binding protein overexpressed in neuroblastoma and ovarian cancer. We have determined that ARID3B expression is also upregulated during squamous epithelial differentiation (cervix, skin, and esophagus). Therefore, we wanted to assess the role of ARID3B in development of squamous cell carcinomas of the esophagus and cervix. In addition to examining the expression of ARID3B, we also wanted to determine the mechanism for ARID3B regulation in cancer and normal squamous cell epithelia. Recent evidence suggests that p63, specifically the ΔNp63α isoform, transcriptionally regulates Arid3B. p63 is a member of the p53 transcription factor family and is essential for the proliferative potential of stem cells in stratified squamous epithelia. p63 is also involved in various cancers including skin cancer and esophageal cancer. In esophageal squamous cell carcinoma, p63 is ubiquitously expressed and low levels are associated with a poor prognosis. We hypothesize that p63 regulates Arid3B in normal and malignant differentiation of stratified squamous epithelium. To evaluate ARID3B expression in cancer we performed immunohistochemistry on tissue microarrays using two independent Arid3B antibodies. Loss of nuclear Arid3B appears to be common in squamous cell carcinoma of cervix and esophagus. We also examined expression of ARID3B in a normal and a squamous cell carcinoma esophageal cell line. We are also examining the coordinate expression of p63 and Arid3B in serial sections of normal and malignant tissue sections of esophagus, cervix, and skin. We are also investigating the regulation of ARID3B in 3D cell culture models of esophagus differentiation. Our data suggests that misregulation of ARID3B may contribute to the development of cancer in stratified epithelia specifically of the cervix and esophagus. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3038. doi:1538-7445.AM2012-3038

Use of cetuximab in combination with pulsed reduced dose-rate radiotherapy in a patient with recurrence of nasopharyngeal carcinoma in the neck

Reirradiation is a major therapeutic modality for patients with locally recurrent head and neck carcinoma. Due to normal tissue tolerances, reirradiation using conventional techniques has a narrow therapeutic ratio in the regional recurrence of nasopharyngeal carcinoma (NPC). Pulsed reduced dose-rate radiotherapy (PRDR), which delivers a series of 0.2 Gy pulses separated by 3 min intervals, is a new reirradiation technique. Head and neck carcinoma cells have high levels of epidermal growth factor receptor expression and cetuximab shows a clear benefit to locally advanced head and neck carcinoma. We report a 56-year-old male with a recurrent lesion of NPC in the neck following initial radical radiochemotherapy. The patient was retreated with PRDR and concurrent cetuximab. The total dose of PRDR was 70 Gy, using 35 daily fractions of 2.0 Gy. The recurrent lesion of this patient had a complete response with no apparent radiation-induced normal tissue complications. This is the first study concerning PRDR combined with cetuximab for the treatment of recurrent head and neck carcinoma following radiotherapy. The outcome of this patient reveals that treatment with PRDR and concurrent cetuximab is a promising therapeutic option for patients with recurrent head and neck carcinoma following radiotherapy.

Anti-Tumor Effect against Human Cancer Xenografts by a Fully Human Monoclonal Antibody to a Variant 8-Epitope of CD44R1 Expressed on Cancer Stem Cells

BackgroundCD44 is a major cellular receptor for hyaluronic acids. The stem structure of CD44 encoded by ten normal exons can be enlarged by ten variant exons (v1-v10) by alternative splicing. We have succeeded in preparing MV5 fully human IgM and its class-switched GV5 IgG monoclonal antibody (mAb) recognizing the extracellular domain of a CD44R1 isoform that contains the inserted region coded by variant (v8, v9 and v10) exons and is expressed on the surface of various human epithelial cancer cells.Methods and Principal FindingsWe demonstrated the growth inhibition of human cancer xenografts by a GV5 IgG mAb reshaped from an MV5 IgM. The epitope recognized by MV5 and GV5 was identified to a v8-coding region by the analysis of mAb binding to various recombinant CD44 proteins by enzyme-linked immunosorbent assay. GV5 showed preferential reactivity against various malignant human cells versus normal human cells assessed by flow cytometry and immunohistological analysis. When ME180 human uterine cervix carcinoma cells were subcutaneously inoculated to athymic mice with GV5, significant inhibition of tumor formation was observed. Furthermore, intraperitoneal injections of GV5markedly inhibited the growth of visible established tumors from HSC-3 human larynx carcinoma cells that had been subcutaneously transplanted one week before the first treatment with GV5. From in vitro experiments, antibody-dependent cellular cytotoxicity and internalization of CD44R1 seemed to be possible mechanisms for in vivo anti-tumor activity by GV5.ConclusionsCD44R1 is an excellent molecular target for mAb therapy of cancer, possibly superior to molecules targeted by existing therapeutic mAb, such as Trastuzumab and Cetuximab recognizing human epidermal growth factor receptor family.

Pro-inflammatory cytokines interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha alter the expression and function of ABCG2 in cervix and gastric cancer cells

The ATP-binding cassette sub-family G member 2 (ABCG2) is implicated as a member of multidrug resistant proteins in tumors, mediating efflux of a wide spectrum of anticancer drugs. Pro-inflammatory cytokines, which are present within the micro-environment of tumors and inflammation, are able to modulate the expressions and activities of different drug transporters. This study was aimed to evaluate the short-term (72-h treatment) effects of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) on the expression and function of ABCG2 in cervix carcinoma and gastric cancer cells. Effects of pro-inflammatory cytokines on mRNA, protein expression, and function of ABCG2 were studied using real time RT-PCR and flow cytometry methods, respectively. HeLa cells treated with IL-1β, IL-6, or TNF-α showed decrements in ABCG2 mRNA levels without any changes in protein expression and function of ABCG2. IL-6 and TNF-α had no effects on mRNA, protein expression, and function of ABCG2 in EPG85-257 cells. Although IL-1β did not alter ABCG2 at mRNA or protein levels in EPG85-257 cells, it augmented function of ABCG2 in these cells. Mitoxantrone accumulation was also amplified in IL-1β-, IL-6- or TNF-α-treated HeLa cells and in IL-1β-treated EPG85-257 cells. In conclusion, pro-inflammatory cytokines were able to modulate the expression of ABCG2 at transcriptional and post-transcriptional levels in human cervix and gastric cancer cells.

Synthesis, characterization and anticancer evaluation of novel tri-arm star shaped 1,3,5-triazine hydrazones

A series of novel trisubstituted triazine hydrazones [N3C3(single bondOC6H4-p-CHdouble bond; length as m-dashNsingle bondNHsingle bondC(O)single bondC6H4-p-X)3] (X = H, Br, Cl, F, OH, OCH3, CH3, NO2, NH2) were prepared by a three-fold condensation reaction of 2,4,6-tris(4-formylphenoxy)-1,3,5-triazine with p-substituted benzoic acid hydrazides [NH2single bondNHsingle bondC(O)single bondC6H4-p-X] with excellent yields. The structures were confirmed by elemental analysis, FT-IR, 1H, 13C, 2D-HSQC NMR and mass spectrometry (MALDI-TOF). These derivatives bearing hydrolysable hydrazone linkages were evaluated for their invitro antiproliferative activity against the human liver carcinoma cell line (HepG2) and human cervix carcinoma cell line (HeLa).

Present epidemiological status and clinical characteristics of cervical cancer in Beijing: a report of 1399 patients

To analyze the prevalence and clinical characteristics of hospitalized patients with cervical cancer over the last two decades in Beijing so as to provide scientific rationales for the management of cervical cancer. Stratified cluster sampling was employed to analyze a total of 1399 invasive cervical cancer cases from different class hospitals in Beijing during the period of 1990 - 2009. (1) The number of cervical cancer cases had been rising over the last 2 decades. (2) The age of onset ranged from 17 to 88 years old; the number of patients with stages I, II, III and IV was 772 (57.1%), 380 (28.1%), 182 (13.5%) and 18 (1.3%) respectively; 1135 (83.1%) patients were of squamous cell carcinoma while 182 (13.3%) adenocarcinoma. The last two decades was divided into 4 groups of 5 years each. The average age gradually decreased from 58.2 to 46.0 years old (P < 0.01). The proportion of patients with stages I and II also increased from 69.6% (16/23) to 89.4% (530/856); There was no significant change in histopathologic type of cervical cancer. And squamous cell carcinoma of cervix remained the predominant type (P > 0.05). (3) About 26.0% (364/1399) of cases received no vagino-recto-abdominal examination while 3.4% (48/1399) of cases were not staged. Over the last two decades, the number of newly diagnosed cervical cancer cases has showed a rising trend in Beijing. And the proportions of young patients and patients with early disease have both increased. Some irregularities still exist in the diagnosis of cervical cancer. So we should pay more attention to the screening program and standardize the diagnosis, therapy and follow-up of cervical cancer.

Interaction of antimony(III) chloride with thiourea, 2-mercapto-5-methyl-benzimidazole, 3-methyl-2-mercaptobenzothiazole, 2-mercaptopyrimidine, and 2-mercaptopyridine

New antimony(III) chloride complexes with heterocyclic thioamides, thiourea (TU), 2-mercapto-5-methyl-benzimidazole (MMBZIM), 3-methyl-2-mercaptobenzothiazole (MMBZT), 2-mercaptopyrimidine (PMT), 2-mercaptopyridine (PYT) of formulae [SbCl3(TU)2] (1), [SbCl3(MMBZIM)2] (2), [SbCl3(MMBZT)2] (3), [SbCl3(PMT)2] (4), [SbCl3(μ 2-S)(PYT)2] (5) were synthesized and characterized by elemental analysis, FT-IR and FT-Raman spectroscopies, and TG-DTA analysis. The crystal structure of 5 was also determined by X-ray diffraction. [C10H10Cl3N2S2Sb] (5) crystallizes in space group C2/c, with a = 25.0169(10) Å, b = 9.7952(3) Å, c = 12.9329(5) Å, β = 109.702(4)°, and Z = 8. Crystals of 5 grown from acetonitrile solutions adopt a square-pyramidal geometry. The equatorial plane is formed by three chlorides and one sulfur atom from the thione ligand while the second sulfur is axial. The complexes were evaluated for their biological activities and compared with [SbCl3(MMI)2] (6) (MMI = 2-mercapto-1-methylimidazole) and other isostructural ones. The complexes showed moderate cytostatic activity against murine leukemia cells (L1210), murine mammary carcinoma cells (FM3A), human T-lymphocyte (Molt4/C8, CEM), and human cervix carcinoma (HeLa) cells. The chloro and iodo derivatives show better cytostatic activity than the bromo ones.

Study on single crystal structure of the antimony(III) bromide complex with 3-methyl-2-mercaptobenzothiazole and biological activity of some antimony(III) bromide complexes with thioamides

Crystals of the [SbBr3(MMBZT)2] (1) complex (MMBZT = N-methyl-2-mercaptobenzothiazole) were grown from acetonitrile/methanol of the filtrate derived from the reaction between 3-methyl-2-mercaptobenzothiazole (MMBZT) in methanol, with antimony(III) bromide in acetonitrile. The crystal structure of 1 (C16H14Br3N2S4Sb) was determined by X-ray diffraction at 100(2) K, in space group P-1, with a = 10.738(2) A, b = 11.387(3) A, c = 11.439(3) A, α = 62.764°, β = 63.36(2)°, γ = 85.074(2)°, and Z = 2. The geometry around the metal center of complex 1 is square pyramidal, with two sulfur atoms from thione ligands and three bromide anions around Sb(III). Complex is monomer. The equatorial plane is formed by two sulfur and two bromide atoms in complex, in a cis-S, cis-Br arrangement. The in vitro cytotoxicity against leiomyosarcoma cells (LMS) of antimony(III) bromide complexes with thioamide ligands with formulae: [SbBr3(MMBZT)2] (1), [SbBr3(TU)2] (2), [SbBr3(MMI)2] (3), {[SbBr2(MBZIM)4]+·[Br]−·H2O} (4), {[SbBr2(μ 2-Br)(MMBZIM)2]2} (5), {[SbBr2(μ 2-Br)(EtMBZIM)2]2·MeOH} (6), {[SbBr3(μ 2-S-tHPMT)(tHPMT)] n } (7), {[SbBr2(μ 2-Br)(PYT)2) n } (8), {[SbBr2(μ 2-Br)(MTZD)2] n } (9), and {[SbBr5]2−[(PMTH2 +)2]} (10) (where TU = thiourea, MMI = methylimidazole, MBZIM = 2-mercaptobenzimidazole, MMBZIM = 2-mercapto-5-methyl-benzimidazole, EtMBZIM = 5-ethoxy-2-mercaptobenzimidazole, tHPMT = 2-mercapto-3,4,5,6-tetrahydro-pyrimidine, PYT = 2-mercaptopyridine, MTZD = 2-mercapto-thiazolidine, and PMTH = 2-mercaptopyrimidine) were evaluated. Complex 8 shows the strongest activity against LMS cells with IC50 value 1.7 ± 0.1 μΜ. The results are compared with their activity against human cervix carcinoma cell lines. Complexes 1, 6–9 were also tested for their inhibitory activity upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase. Computational studies using multivariate linear regression and considering biological results (50% inhibitory concentration, IC50) as dependent variables derived a theoretical equation for IC50 values of the complexes studied. The calculated IC50 values are compared adequately with the experimental inhibitory activity of the complexes measured.

Induction of G2/M phase arrest and apoptosis by potent antitumor APCA in human cervix carcinoma cells

3-(dimethylamino-ethylamino)-8-oxo-8H-acenaphthol[1, 2-b]pyrrole-9-carboxylic acid (APCA), as a potent antitumor compound, showed anticancer activity on a series of established cancer cells. Meanwhile, the cytotoxic effects of APCA were much smaller on normal human cells than that on cancer cells. This study investigated the molecular mechanisms underlying APCA-induced growth inhibition in HeLa cells. The results showed that the APCA-induced cell cycle arrest at G(2)/M phase correlated with cyclinB1 and cyclin-dependent kinase 1 expression downregulation in a p53-independent manner, and also caused an increase in apoptosis, which was confirmed by characteristic morphological changes and increased apoptotic sub-G(1) population. Furthermore, translocation inhibition of nuclear factor-κB, upregulation of Bax, and downregulation of Bcl-2, caspase-3 and caspase-9 activation, and poly-(ADP-ribose) polymerase cleavage were observed in HeLa cells treated with APCA, which indicated that the mitochondrial pathway was involved in the apoptosis signal pathway. In summary, APCA displayed an antitumor effect through cell cycle arrest and apoptotic induction in HeLa cells, which suggested that APCA might have therapeutic potential against cervix carcinoma as an effective lead compound.

Study of cytotoxic properties of Rosa damascena extract in human cervix carcinoma cell line

Objective: Cancer is a major health problem worldwide and current therapies for cancer are often limited by short-term efficacy due to drug resistance. There has been much interest in the use of naturally occurring compounds with chemo-preventive and chemotherapeutic properties in the treatment of cancers. Rose is one of the most important groups of ornamental plants which their fruits and flowers are used in a wide variety of foods, nutritional products and different traditional medicines. Material and methods: In this study cytotoxic effect of Rosa damascena extract was evaluated on HeLa cell line. HeLa cells were cultured in DMEM medium and incubated with different concentrations of Rosa damascene (R. damascene) extract. Cell viability was quantitated by MTT assay. Results: Rosa decreased cell viability in malignant cells in a concentration and time dependent manner. The IC50 values against HeLa were determined as 2135, 1540 and 305.1 µg.ml-1 after 24, 48 and 72h, respectively. Conclusion: It might be concluded that R. damascena could cause cell death in HeLa cells which could be also considered as a promising chemotherapeutic agent in cancer treatment in future.

Cytotoxic and antioxidant activities of selected Lamiales species from Mexico

Context: Methanol extracts obtained from eight species belonging to four families of the Lamiales order native to Mexico were investigated for biological action.Objective: Cytotoxicity and antioxidant activity of methanol extracts have been investigated.Materials and methods: Cytotoxic activity was evaluated by the sulphorhodamine B protein staining assay against KB (nasopharyngeal), HEp-2 (larynx), HF-6 (colon), MCF7 (breast), PC-3 (prostate), and Ca Ski (cervix) carcinoma cell lines. To analyze the antioxidant activity, common stable radicals chromogens, 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS·+) and DPPH (1,1-diphenyl-2-picrylhydrazyl) were used. The ferric reducing antioxidant power (FRAP) and the total phenolic content of the samples were also determined.Results: Some of the extracts, such as Limosella aquatica L. (Scrophulariaceae), Mimulus glabratus Kunth. (Phrymaceae), Pedicularis mexicana Zucc. ex Benth. (Orobanchaceae), and Penstemon campanulatus (Cav.) Willd. (Plantaginaceae) displayed remarkably selective cytotoxic activity. However, the extract from Veronica americana (Raf.) Schwein (Plantaginaceae) showed the highest activity with IC50 values of 1.46 and 0.169 μg/mL on PC-3 and HF-6 cells, respectively. With the exception of M. glabratus, all the extracts showed different degrees of antioxidant activity with IC50 values from 0.89 up to 1.8 in the ABTS assay; from 0.49 up to 1.25 mg/mL in the DPPH assay and with the FRAP evaluation, 36 to 68 equivalents in mM of FeSO4. V. americana also showed the highest antoxidant activity with IC50 values from 0.491 and 0.892 mg/mL, on DPPH and ABTS assays, respectively.Discussion and conclusion: These findings demonstrated that the species studied have great potential cytotoxic and antioxidant activity.

Essential role of caspase-8 in p53/p73-dependent apoptosis induced by etoposide in head and neck carcinoma cells

BackgroundCaspase-8 is a key upstream mediator in death receptor-mediated apoptosis and also participates in mitochondria-mediated apoptosis via cleavage of proapoptotic Bid. However, the role of caspase-8 in p53- and p73-dependent apoptosis induced by genotoxic drugs remains unclear. We recently reported that the reconstitution of procaspase-8 is sufficient for sensitizing cisplatin- but not etoposide-induced apoptosis, in chemoresistant and caspase-8 deficient HOC313 head and neck squamous cell carcinoma (HNSCC) cells.ResultsWe show that p53/p73-dependent caspase-8 activation is required for sensitizing etoposide-induced apoptosis by utilizing HOC313 cells carrying a temperature-sensitive p53G285K mutant. Restoration of wild-type p53 function under the permissive conditions, together with etoposide treatment, led to substantial transcriptional activation of proapoptotic Noxa and PUMA, but failed to induce apoptosis. In addition to p53 restoration, caspase-8 reconstitution was needed for sensitization to etoposide-induced apoptosis, mitochondria depolarization, and cleavage of the procaspases-3, and -9. In etoposide-sensitive Ca9-22 cells carrying a temperature-insensitive mutant p53, siRNA-based p73 knockdown blocked etoposide-induced apoptosis and procaspase-8 cleavage. However, induction of p73 protein and up-regulation of Noxa and PUMA, although observed in Ca9-22 cells, were hardly detected in etoposide-treated HOC313 cells under non-permissive conditions, suggesting a contribution of p73 reduction to etoposide resistance in HOC313 cells. Finally, the caspase-9 inhibitor Ac-LEHD-CHO or caspase-9 siRNA blocked etoposide-induced caspase-8 activation, Bid cleavage, and apoptosis in both cell lines, indicating that p53/p73-dependent caspase-8 activation lies downstream of mitochondria.Conclusionswe conclude that p53 and p73 can act as upstream regulators of caspase-8, and that caspase-8 is an essential mediator of the p53/p73-dependent apoptosis induced by etoposide in HNSCC cells. Our data suggest the importance of caspase-8-mediated positive feedback amplification in the p53/p73-dependent apoptosis induced by etoposide in HNSCC cells.

Synthesis and in vitro Cytotoxicity of Glycans-Capped Silver Nanoparticles

Silver nanostructures were successfully synthesized through a simple and “green” method using saccharides as reducing and capping agent. Transmission electron microscopy (TEM) and UV–Vis absorption were used to certify the quality of the silver nanoparticles obtained: firstly, size and dispersion. In this work Silver NanoParticles (AgNPs) cytotoxicity related to saccharides capping (Glucose and Glucose-Sucrose) was explored in human epitheloid cervix carcinoma cells (HeLa). The cells were incubated with increasing AgNPs number/cell and HeLa cells viability was monitored for a period of 48 h compared with the positive and negative controls. We observed that the toxicity increases with incubation time and with AgNPs number/cell. In particular, the different cytotoxic degree of the AgNPs, i.e. AgNP-G are more toxic than AgNP-GS, suggests that the cytotoxic effects are largely depended on the capping agent. The highest concentration of AgNP-G number/cell is able to induce extensive cell death of HeLa cells soon after 1 hr of incubation; conversely the lowest concentration of Ag NP-GS number/cell, surprisingly, is able to induce cell proliferation.

Correlation between structure, retention and activity of cholic acid derived cis–trans isomeric bis‐steroidal tetraoxanes

Both quantitative structure-retention (QSRR) and quantitative structure-activity relationship (QSAR) studies have been performed to correlate the molecular characteristics of seven pairs of cis-trans isomeric bis-steroidal tetraoxanes with their reversed-phase thin-layer chromatography (RPTLC) retention as well as with their antiproliferative activity. 2D and 3D molecular descriptors as whole molecule representations together with retention parameters as well as with biological activity data were subjected to the multivariate statistical analysis (principal component analysis--PCA and hierarchical cluster analysis--HCA) in order to determine the most influential factors governing the retention and activity against human cervix carcinoma (HeLa) and human malignant melanoma (Fem-X) cell lines. Both QSRR and QSAR models were built by means of the partial least-squares (PLS) statistical method. It was found that hydrogen bond donating (HBD), hydrogen bond accepting (HBAcc), hydrophilic surface percentage (%HS) and hydrophilic-lipophilic balance (HLB) exhibit the strongest influence on retention. The most prominent factors affecting antiproliferative activity of the investigated substances are those relating to the size and shape of a molecule such as: connectivity indices, refractivity (Ref), surface area (SA), molecular volume and weight, polarizability (Pol) and those regarding the ability of hydrogen bonding (HB).