benzofurans and Uterine-Cervical-Neoplasms

Design and synthesis of a new series of benzofuran derivatives has been performed.

Topics: Antineoplastic Agents; Benzofurans; Breast Neoplasms; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; Female; Humans; MCF-7 Cells; Molecular Docking Simulation; Molecular Structure; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Sorafenib; Structure-Activity Relationship; Uterine Cervical Neoplasms; Vascular Endothelial Growth Factor Receptor-2

Eukaryotic translation initiation factor 4E (eIF4E) is activated in cancers in response to stress. This is regulated by MAP kinase interacting serine/threonine kinase (MNK) in cancerous but not normal cells. Chemoresistance causes treatment failure in advanced cervical cancer. In this study, we addressed chemotherapy effects on eIF4E for cervical cancer and reversal effects by MNK inhibitor cercosporamide for chemo-resistance mitigation.. Cell assays and mouse tumour models were used to determine the efficacy of cercosporamide. Western blotting was applied to understand the affected cell signaling after cercosporamide treatment.. Cercosporamide spared normal cervical epithelial cells. On cervical cancer cell lines, it showed inhibition of cell growth and migration, and induced apoptosis. Cercosporamide was effective on chemoresistant cancer cells and augmented the efficiency of doxorubicin and cisplatin both in vitro and in vivo. Cercosporamide suppressed eIF4E signaling. Of note, chemotherapy increased p-eIF4E. Cercosporamide abolished chemotherapy-induced eIF4E activation. The higher level of p-eIF4E in cancer cells compared with normal cervical epithelial cells explains the preferential toxicity of cercosporamide.. This work demonstrates the ability of cercosporamide to overcome chemoresistance and highlight preferential inhibition of eIF4E via MNK inhibition in cervical cancer.

Topics: Animals; Antineoplastic Agents; Benzofurans; Cell Line, Tumor; Drug Resistance, Neoplasm; Eukaryotic Initiation Factor-4E; Female; Humans; Intracellular Signaling Peptides and Proteins; Mice, Nude; Molecular Targeted Therapy; Protein Serine-Threonine Kinases; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

This study represents the synthetic approaches of a new set of 2-(((3-(benzofuran-2-yl)-1-phenyl-1H-pyrazol-4-yl)methylene)hydrazono)-5-(aryl)thiazolidin-4-one derivatives 4-22 aiming to obtain new antiproliferative candidates against human cervix carcinoma cells (Hela) of EGFR PK inhibiting potency. The cancer cells represented promising sensitivity towards the compounds 6, 7, 11, 13, 14, 16, 17 more than or equal to that against the reference drug doxorubicin. In addition, the latter compounds were tested as EGFR protein kinase inhibitors. The results revealed that compound 14 showed more significant EGFR PK inhibitory activity than the reference drug erlotinib (IC50; 0.07, 0.08 µM, respectively). Moreover, cell cycle analysis and apoptosis assay were performed for compound 14 proving its ability to cause G1/S phase arrest and apoptosis in Hela cancer cells, in addition to its activation of the caspases-7 and -3. In addition, derivative 14 increased the expression level of p53 and the ratio of Bax/Bcl-2 which confirmed its mode of action. Molecular docking study of 14 was performed to investigate its binding mode of interaction with EGFR PK in the active site with the aim of rationalizing its promising inhibitory activity. Accordingly, compound 14 might be considered as a promising scaffold anticervical cancer chemotherapeutic and deserves further optimization and in-depth biological studies.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; ErbB Receptors; Female; HeLa Cells; Humans; Hydrazones; Molecular Docking Simulation; Molecular Structure; Protein Kinase Inhibitors; Pyrazoles; Structure-Activity Relationship; Thiazolidinediones; Uterine Cervical Neoplasms

Topics: Antineoplastic Agents; Benzofurans; Cell Cycle Checkpoints; Cell Proliferation; Cell Survival; Colonic Neoplasms; Depsides; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HeLa Cells; Humans; Hydroxybenzoates; Lactones; Lichens; Molecular Structure; Poly(ADP-ribose) Polymerases; Proto-Oncogene Proteins c-bcl-2; Salicylates; Uterine Cervical Neoplasms

7-hydroxy-5,4'-dimethoxy-2-arylbenzofuran (Ary) is purified from Livistona. It has been demonstrated to have anticancer activity to various tumors in including cervical cancer, but its mechanism is still unclear. In the present, we show that Ary induces cervical cancer cells apoptosis through mitochondria degradation and mediates cervical cancer cell arrest. Further, Ary-inducing cell cycle G1/S-phase arrest is associated with increased cyclin A2 and cyclin dependent kinase 2 (Cdk2) proteins. Knockdown of cyclin A2 using small interfering RNA (siRNA), and inhibiting Cdk2 activity with flavopiridol, strikingly reduced G1/S-phase arrest. Moreover, Ary sustainedly induced phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). And ERK1/2 phosphorylation inhibition using specific inhibitor U0126 effectively suppressed cyclin A2 expression, and reduced G1/S-phase arrest induced by Ary. All the experiments in vitro and in vivo verified that Ary has an anticancer effect on cervical cancer. These data provide novel evidences that Ary induces cervical cancer cells apoptosis through mitochondria degradation and cell G1/S-phase arrest. These findings also suggest that ERK-mediated Cdk2/cyclin A signaling pathway is involved in Ary-induced G1/S-phase arrest.

Topics: Animals; Apoptosis; Benzofurans; Cell Line, Tumor; Cyclin A2; Cyclin-Dependent Kinase 2; Female; G1 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Molecular Structure; Phytotherapy; Plant Extracts; Protein Kinases; Signal Transduction; Tumor Burden; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays

A series of (E,Z)-1-(dihydrobenzofuran-5-yl)-3-phenyl-2-(1,2,4-triazol-1-yl)-2-propen-1-ones (C1-C35) were designed and synthesized, and the structures of compounds (Z)-C27 and (Z)-C29 were confirmed by single-crystal X-ray diffraction. The antitumor activities of these novel compounds against cervical cancer (HeLa), lung cancer (A549), and breast cancer (MCF-7) cell lines were evaluated in vitro. Majority of the title compounds exhibited strong antitumor activities and were much more promising than the positive control Taxol, which were also accompanied by lower cytotoxicity to normal cells. In particular, compounds (E,Z)-C24 exhibited the most consistent potent activities against three neoplastic cells with IC50 values ranging from 3.2 to 7.1 μm. Further researches demonstrated that compounds (E,Z)-C24 could induce cell apoptosis and arrest cell cycle at the G2/M and S phases. Meanwhile, the structure-activity relationship between the configurations and cytotoxicity of the compounds was also investigated.

Topics: Antineoplastic Agents; Apoptosis; Benzofurans; Breast Neoplasms; Cell Cycle; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Drug Screening Assays, Antitumor; Female; HEK293 Cells; HeLa Cells; Humans; Lung Neoplasms; MCF-7 Cells; Neoplasms; Structure-Activity Relationship; Uterine Cervical Neoplasms

4-(3',3'-Dimethylallyloxy)-5-methyl-6-methoxy-phthalide (DMMP) has previously been isolated from the endophytic fungus Pestalotiopsis photiniae. Although the cytotoxic activities of DMMP have been reported, little is known concerning the molecular mechanism of its cytotoxic effect. In the present study, we investigated the effect of DMMP on the growth of several types of cancer cell lines and investigated the mechanism of its antiproliferative effect. DMMP caused the growth inhibition of human cancer lines HeLa, MCF7 and MDA-MB-231, but had little antiproliferative effect on MRC5 normal lung cells. DMMP also significantly caused cell cycle arrest in the G1 phase and upregulated the cyclin-dependent kinase inhibitor p27KIPI protein in the HeLa cells. Moreover DMMP was able to induce marked nuclear apoptotic morphology in HeLa cells. DMMP induced apoptosis and loss of mitochondrial membrane potential (ΔΨm) in the HeLa cells. Although the activated forms of caspase-9 and -3 in HeLa cells were detected, pretreatment with caspase inhibitors (Ac-DEVD-CHO and Z-VAD-FMK) failed to attenuate DMMP-induced cell death. In addition, protein levels of the p53 family members, p53 and p73, were upregulated, and DMMP significantly increased the mRNA expression of pro-apoptotic Bcl-2 family genes (PUMA, NOXA, Bax, Bad and Bim). HPV E6-E7 mRNA levels were reduced. In conclusion, DMMP demonstrates potential for use in the treatment of cervical cancer.

Topics: Amino Acid Chloromethyl Ketones; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; bcl-2-Associated X Protein; Bcl-2-Like Protein 11; bcl-Associated Death Protein; Benzofurans; Caspase 3; Caspase 9; Caspase Inhibitors; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase Inhibitor p27; DNA-Binding Proteins; Female; G1 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; MCF-7 Cells; Membrane Potential, Mitochondrial; Membrane Proteins; Mitochondria; Nuclear Proteins; Oligopeptides; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; RNA, Messenger; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins; Up-Regulation; Uterine Cervical Neoplasms; Xylariales

U-73,975 (U-73), U-77,779 (U-77), and U-80,244 (U-80) are analogs of the potent antitumor compound CC-1065. This class of drugs act as alkylating agents binding to DNA preferentially. Using the ATP-chemosensitivity assay, this study was designed to compare the potencies of U-73, U-77, and U-80 with cisplatin (DDP) or adriamycin (DXR) in 10 gynecologic cancer cell lines. The mean IC50s were: U-73, 0.173 +/- 0.115 ng/ml; U-77, 0.650 +/- 0.209 ng/ml; U-80, 3.0 +/- 3.0 ng/ml; DDP, 4.40 +/- 2.83 micrograms/ml; and DXR, 0.286 +/- 0.040 micrograms/ml. U-73 appears the most potent analog, being 10(3) to 10(4) times more cytotoxic than DDP and DXR. U-77 and U-80 were somewhat comparable, demonstrating approximately 10(2) to 10(3) greater potency than DDP and DXR. All the cervical, endometrial, and ovarian cell lines were sensitive to U-73, with decreasing sensitivity to U-77, U-80, DXR, and DDP in that order. U-73 as well as the other analogs appear promising chemotherapeutic agents.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Benzofurans; Cisplatin; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Doxorubicin; Drug Screening Assays, Antitumor; Duocarmycins; Endometrial Neoplasms; Female; Humans; In Vitro Techniques; Indoles; Ovarian Neoplasms; Tumor Cells, Cultured; Urea; Uterine Cervical Neoplasms

U-73,975 (U-73), a closely related synthetic analogue of the antitumor agent CC-1065, acts by binding tightly in the minor groove of DNA. A comparison was made between the cytotoxicity of U-73 and cisplatin (DDP) on 11 fresh cervical and 7 fresh ovarian carcinoma specimens. The ATP-chemosensitivity assay as previously described (Sevin et al. Gynecol. Oncol. 31, 191-204, 1988) was used to determine the cytotoxic effect of U-73 and DDP. IC 50s were calculated using regression analysis. The mean IC 50s for U-73 and DDP were 519 pg/ml and 2918 ng/ml, respectively, for the cervical carcinoma specimens and 324 pg/ml and 2649 ng/ml, respectively, for the ovarian carcinoma specimens. Significance comparing U-73 and DDP for cervical and ovarian tissue was demonstrated with P < 0.001. U-73 was 4000 times as cytotoxic per unit of mass as DDP on cervical carcinoma compared to over 8000 times for ovarian carcinoma. Based on these in vitro data, U-73 appears to be a very promising antitumor agent for cervical and ovarian carcinoma.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Benzofurans; Cisplatin; Cyclohexanecarboxylic Acids; Cyclohexenes; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Duocarmycins; Female; Humans; In Vitro Techniques; Indoles; Ovarian Neoplasms; Regression Analysis; Uterine Cervical Neoplasms