Human Solid Tumor Cell Research Articles

Enhancing the cytotoxicity of chemoradiation with radiation-guided delivery of anti-MGMT morpholino oligonucleotides in non-methylated solid tumors

The DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) is epigenetically silenced in some tumors by MGMT gene promoter methylation. MGMT-hypermethylated solid tumors have enhanced susceptibility to the cytotoxic effects of alkylating chemotherapy such as temozolomide, compared with non-methylated tumors. In glioblastoma, subjects with MGMT hypermethylation have significantly longer survival rates after chemoradiotherapy. We report the first successful use of a non-ablative dose of ionizing radiation to prime human cancer cells to enhance the uptake of unmodified anti-MGMT morpholino oligonucleotide (AMON) sequences. We demonstrate >40% reduction in the in vitro proliferation index and cell viability in radiation-primed MGMT-expressing human solid tumor cells treated with a single dose of AMONs and temozolomide. We further demonstrate the feasibility of using a non-ablative dose of radiation in vivo to guide and enhance the delivery of intravenously administered AMONs to achieve 50% MGMT knockdown only at radiation-primed tumor sites in a subcutaneous tumor model. Local upregulation of physiological endocytosis after radiation may have a role in radiation-guided uptake of AMONs. This approach holds direct translational significance in glioblastoma and brain metastases where radiation is part of the standard of care; our approach to silence MGMT could overcome the significant problem of MGMT-mediated chemoresistance.

Indium(III) complexes with 2-acetylpyridine-derived thiosemicarbazones exhibit cytotoxic activity against human leukemia and solid tumor cell lines

Complexes [In(2Ac4Ph)2]NO3·H2O (1), [In(2Ac4mClPh)2]NO3·1.5H2O (2), [In(2Ac4pClPh)2]NO3·2H2O (3) and [In(2Ac4pIPh)2]NO3·H2O (4) were obtained with N(4)-phenyl-2-acetylpyridine thiosemicarbazone (H2Ac4Ph), and its N(4)-meta-chlorophenyl-(H2Ac4mClPh), N(4)-para-chlorophenyl-(H2Ac4pClPh) and N(4)-para-iodophenyl-(H2Ac4pIPh) derivatives. The crystal structures of [In(2Ac4Ph)2]NO3·MeOH (1a), [In(2Ac4mClPh)2]NO3·EtOH·H2O (2a) and [In(2Ac4pClPh)2]·NO3 (3a) were determined. The cytotoxic effects of the thiosemicarbazone ligands and of complexes (1–4) were evaluated against HL-60, Jurkat and THP-1 leukemia cells and against MCF-7, MDA-MB-231 and HCT-116 solid tumor cells, as well as against mammalian healthy Vero cells. Upon coordination to indium(III) cytotoxicity increased in several cases. In addition, complex (1) was active in sub-micromolar doses against all tested cell lineages, with selectivity indexes (SI=IC50 Vero/IC50 tumor cell) ranging from 3 (against THP-1 cells) to 144 (against HCT-116 cells).

Abstract DDT01-03: ABBV-621: A best-in-class TRAIL-receptor agonist fusion protein that enhances optimal clustering for the treatment of solid and hematologic tumors

Abstract Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily of proteins that play diverse roles in the activation of several intracellular signaling pathways that control cell proliferation, survival, and apoptosis. Activation of the TRAIL pathway has been viewed as an attractive therapeutic approach for the treatment of cancer because of its distinct role in the induction of tumor cell apoptosis. TRAIL can bind as a trimer to membrane-bound or soluble receptors, and only the two closely related cell surface death receptors TRAIL-R1 (DR4) and TRAIL-R2 (DR5) can preferentially trigger the extrinsic pathway of tumor cells, leading to apoptotic cell death. The BCL-2 family member-driven mitochondrial apoptotic pathway can also serve to amplify the extrinsic pathway through further downstream activation of caspases. Given the crosstalk between the extrinsic and intrinsic cell death pathways, several resistance mechanisms have emerged to escape TRAIL-induced apoptosis. These include altered receptor regulation, overexpression of cellular FLICE-like inhibitory protein (cFLIP) that inhibits the proapoptotic activity of the DISC, overexpression of the prosurvival BCL-2 family member proteins, and the inhibitor of apoptosis proteins (IAPs) that directly inhibit caspases. In addition, TRAIL can induce non–cell death signaling pathways (e.g., NF-κB, MAPK, PI3K) to promote tumor cell growth as a potential resistance mechanism. Results of several clinical trials that targeted DR4 and DR5 with first-generation agonistic anti-TRAIL antibodies or human recombinant TRAIL indicated that these agents failed to demonstrate significant improvement in patient progression-free survival compared to standard-of-care therapy. The major contributing factor in this lack of clinical activity is believed to be the suboptimal TRAIL receptor clustering by these agonists. ABBV-621 is a novel, second-generation TRAIL receptor agonist comprising a human IgG1-Fc linked to native single-chain TRAIL-receptor binding domain (scTRAIL-RBD) monomers that are covalently connected by glycosylated linkers, resulting in two sets of trimeric RBDs. ABBV-621 is designed to maximize receptor clustering butdoes not require Fcγ-R-mediated crosslinking for optimal in vivo efficacy, which has been deemed an activity-limiting step for the competitor anti-DR4 and anti-DR5 antibodies in the clinic. In-house studies have demonstrated the requirement for enhanced caspase-8 aggregation into the death-inducing signaling complex (DISC) to induce potent tumor cell death, providing mechanistic insights as to why death receptor agonists originally failed and further distinguishing ABBV-621 from the first-generation agents. ABBV-621 induces dose-dependent apoptotic cell death at sub- to single-digit nanomolar potencies across a large panel (~100) of human hematologic and solid tumor cell lines in vitro. ABBV-621 activity is on-target and mechanism-based as demonstrated by a rapid activation of downstream apoptotic signaling events (cleavage of caspase-8, caspase-3, and PARP). In human tumor xenograft models, ABBV-621 exhibits potent antitumor activity in vivo as a monotherapy and in combination with targeted agents or chemotherapy using xenograft tumors derived from colorectal, lung, leukemia, and lymphoma cell lines. This activity is on-target, mechanism-based, and dose-dependent as indicated by rapid activation of tumor caspase-8 and caspase-3 after a single ascending dose of ABBV-621 in a colorectal carcinoma xenograft model. ABBV-621 exhibits a dose-proportional pharmacokinetic (PK) profile in mice and cynomolgus monkeys, and the projected human half-life is estimated to be ~2 days. PK/pharmacodynamic (PD) assessments estimate that achieving exposure above an efficacious concentration for 4-7 days is sufficient to maintain tumor regressions up to 4-7 weeks. Screens against 95 patient-derived xenograft (PDX) models consisting of 12 different solid tumor types uncovered single-agent activity (regressions) in >50% of all PDXs tested. PDX models can be more reflective of human disease by providing estimation of effects of tumor heterogeneity on ABBV-621 activity. Models that were partially sensitive or completely resistant to treatment were also identified, and collectively these responses are being utilized with associated pre- and post-treatment genomic/proteomic information to further inform potential patient stratification markers. To demonstrate on-target biologic activity in the clinic, proximal and distal target engagement markers will be pursued. In a GLP monkey toxicity study, ABBV-621 was well tolerated with no adverse test item–related findings. The first-in-human (FIH) phase 1/1b study with ABBV-621 will enroll subjects with previously treated advanced solid tumors and hematologic malignancies. The phase 1 objectives will be to establish the safety and tolerability of ABBV-621, as well as to understand the PK properties. Secondary objectives will be to explore target engagement and efficacy biomarkers and to evaluate clinical activity. Citation Format: Susan E. Morgan-Lappe. ABBV-621: A best-in-class TRAIL-receptor agonist fusion protein that enhances optimal clustering for the treatment of solid and hematologic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT01-03. doi:10.1158/1538-7445.AM2017-DDT01-03

Abstract 5127: In vitro and in vivo evaluation of FF-10502-01, a new pyrimidine nucleoside analogue

Abstract Introduction:FF-10502-01 is a synthetic pyrimidine nucleoside analogue structurally similar to gemcitabine (gem) with a substitution of sulfur for oxygen in the pentose ring. The anti-tumor effects of FF-10502-01 were studied in solid tumor cell lines and human tumor xenograft models. Methods:10 human solid tumor cell lines were studied and included the following: 4 pancreatic (PANC) (BxPC-3, SUIT-2, Capan-1 and MIA PaCa-2), colon (HCT116), lung (NCI-H460), ovary (SK-OV-3), prostate (LNCap.FGC), breast (MDA-MB231) and mantle cell lymphoma (MCL) (Jeko-1). The effect of FF-10502-01 on DNA synthesis versus gem was evaluated in a PANC cell line (Capan-1). Tumor growth suppression was evaluated in human PANC xenograft models, SUIT-2 and Capan-1. FF-10502-01 or gem was administered at 240 or 480 mg/kg once a week starting 7d after orthotopic transplantation for 18 weeks, n=20/grp. Animals were followed for 128d after transplantation. Capan-1 was transplanted SC into nude mice (n=8/grp). FF-10502-01 or gem was administered at 120, 240, 360 or 480 mg/kg once weekly x 4 weeks 7d after transplantation. Tumor growth inhibitory effects were evaluated for 27d after starting treatment. FF-10502-01 single-dose pharmacokinetics (PK) were investigated in the mouse, rat and dog. Results:FF-10502-01 demonstrated in vitro activity against the PANC, colon, lung, ovarian, prostate and MCL cell lines, with IC50s of 30 – 330 nM. The activity was 1.5 – 15-fold lower than gem, however, FF-10502-01 demonstrated a 23-fold higher inhibition of DNA α-polymerase-mediated synthesis over gem. In the SUIT-2 orthotropic implant model, both gem and FF-10502-01 improved survival over vehicle controls. Med survival was not reached for the 480 mg/kg gem grp or either the 240 or 480 mg/kg FF-10502-01 grps. The survival rate was 5%, 25%, 75% for the vehicle, 240 and 480 mg/kg gem grps (p<0.0001 versus vehicle), and 100% for the 240 and 480 mg/kg FF-10502-01 grps (p<0.0001 versus gem grps), respectively. In the Capan-1 xenograft model, both FF-10502-01 and gem demonstrated statistically significant tumor growth suppression versus vehicle control; FF-10502-01 demonstrated equivalent tumor growth suppression with less effect on body weight than gem at clinically achievable doses. PK following single bolus IV doses indicated a similar PK profile to other pyrimidine nucleoside analogues, including gem. Conclusions:FF-10502-01 is a new pyrimidine nucleoside analogue with demonstrated preclinical efficacy against solid tumors and a potentially more tolerable safety profile than gem. Citation Format: Shinji Mima, Hiroki Nishikawa, Shinichi Watanabe, Tamami Higuchi, Takeaki Suzuki, Hiroyuki Iwamura, Chihaya Kakinuma, Takaaki Nakamura, Yasuhiro Shimada. In vitro and in vivo evaluation of FF-10502-01, a new pyrimidine nucleoside analogue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5127. doi:10.1158/1538-7445.AM2017-5127

Comparison of a mouse and a novel human scFv-SNAP-auristatin F drug conjugate with potent activity against EGFR-overexpressing human solid tumor cells.

Antibody–drug conjugates (ADCs) can deliver toxins to specific targets such as tumor cells. They have shown promise in preclinical/clinical development but feature stoichiometrically undefined chemical linkages, and those based on full-size antibodies achieve only limited tumor penetration. SNAP-tag technology can overcome these challenges by conjugating benzylguanine-modified toxins to single-chain fragment variables (scFvs) with 1:1 stoichiometry while preserving antigen binding. Two (human and mouse) scFv-SNAP fusion proteins recognizing the epidermal growth factor receptor (EGFR) were expressed in HEK 293T cells. The purified fusion proteins were conjugated to auristatin F (AURIF). Binding activity was confirmed by flow cytometry/immunohistochemistry, and cytotoxic activity was confirmed by cell viability/apoptosis and cell cycle arrest assays, and a novel microtubule dynamics disassembly assay was performed. Both ADCs bound specifically to their target cells in vitro and ex vivo, indicating that the binding activity of the scFv-SNAP fusions was unaffected by conjugation to AURIF. Cytotoxic assays confirmed that the ADCs induced apoptosis and cell cycle arrest at nanomolar concentrations and microtubule disassembly. The SNAP-tag technology provides a platform for the development of novel ADCs with defined conjugation sites and stoichiometry. We achieved the stable and efficient linkage of AURIF to human or murine scFvs using the SNAP-tag technology, offering a strategy to improve the development of personalized medicines.

Antiproliferative Activity and Effect on GABAA Receptors of Callitrisic Acid Derivatives

AbstractThe semisynthesis and biological activity of the naturally occurring abietane diterpenoids callitrisic acid (4a; 4-epidehydroabietic acid) and callitrisinol (6) are reported. These compounds and jiadifenoic acid C (5) were obtained from methyl callitrisate (4b) isolated from Sandarac resin for biological evaluation and comparison with the biological activities of C4 epimers such as dehydroabietic acid (2a). In particular, the antiproliferative activity against a panel of six representative human solid tumor cell lines (A549, HBL-100, HeLa, SW1573, T-47D, WiDr) and the effect on GABAA receptors (α 1 β 2 γ 2s) were evaluated. The GI50 values were in the range of 3.4–61 µM and the potentiation of IGABA was 269–311% at 100 µM. Callitrisinol (6) was found to be 6.7-fold more potent than the reference etoposide in the WiDr (colon) cancer cell line. The role of the stereogenic center at C4 for antiproliferative and GABAA receptor modulating activities in the dehydroabietane scaffold has thus been revealed.

Indole carboxylic acid esters of melampomagnolide B are potent anticancer agents against both hematological and solid tumor cells

A series of novel, heteroaryl carboxylic acid conjugates of the sesquiterpene melampomagnolide-B (MMB, 3) has been evaluated as antitumor agents against an NCI panel of 64 human hematopoetic and solid tumor cell lines. The indole-3-acrylic acid conjugate 7j and the indole-3-carboxylic acid conjugate 7k were found to be the most potent analogs in the series. Compounds 7j and 7k exhibited remarkable growth inhibition, with GI50 values in the range 0.03–0.30 μM and 0.04–0.28 μM, respectively, against the cell lines in the leukemia sub-panel, and GI50 values of 0.05–0.40 μM and 0.04–0.61 μM, respectively, against 90% of the solid tumor cell lines in the NCI panel. Compound 7a was particularly effective against the sub-panel of breast cancer cell lines with GI50 values in the range <0.01–0.30 μM. Compounds 7j, 7a and its water soluble analog 7p also exhibited potent anticancer activity against rat 9L-SF gliosarcoma cells in culture. Compound 7j was the most potent compound in the series in the M9-ENL1 AML cell assay with a lethal dose concentration EC50 value of 720 nM, and exhibited the greatest cytotoxicity against a collection of primary AML stem cell specimens, which included a specimen that was unresponsive to PTL, affording EC50 values in the range 0.33–1.0 μM in three out of four specimens. The results from this study provide further evidence that analogs of the sesquiterpene MMB can be designed to afford molecules with significantly improved anticancer activity. Thus, both 7j and 7k are considered potential lead molecules in the search for new anticancer agents that can be used as treatments for both hematopoetic and solid tumors.

Efficient synthesis and biological evaluation of new benzopyran-annulated pyrano[2,3-c]pyrazole derivatives

A one-pot method has been described to synthesize benzopyran-annulated pyrano[2,3-c]pyrazoles, effectively by combining O-alkenyloxy/alkynyloxy-acetophenones with various pyrazolones in triethylammonium acetate (TEAA) under microwave irradiation. While combination of O-allyloxy- or O-prenyloxy-acetophenones with pyrazolones occurred efficiently, that of O-propargyloxy-acetophenones was found effective in the presence of ZnO catalyst, via a domino Knoevenagel-hetero-Diels-Alder (DKHDA) reaction. Aminobenzopyran frameworks were also synthesized, after nitro-containing products were reduced in tandem with iron(II) in an acidic medium. The in vitro antiproliferative activity of these compounds was measured and discussed against gram-positive, gram-negative and M. tuberculosis bacteria, fungi, and various representative human solid tumor cell lines, in addition to their ferric reducing antioxidant capability.

Different effect of resveratrol to induction of apoptosis depending on the type of human cancer cells

The effect of resveratrol on various human cancer cells was investigated with special focus on apoptotic cell death, in an attempt to further characterize its mechanism of action. There were great differences in the anti-viability effect of resveratrol between different types of human cancer cells. While the inhibition of cell viability by resveratrol was marked in U937 and MOLT-4 leukemia cells, resveratrol moderately inhibited cell viability in MCF-7 breast, HepG2 liver, and A549 lung cancer cells, and the effect was slight on cell viability in Caco-2, HCT116, and SW480 colon cancer cells. Following resveratrol treatment, U937 and MOLT-4 markedly increased the population of late apoptotic cells but MCF-7 and HepG2 underwent apoptosis with an increased population of early apoptosis, and resveratrol-induced DNA fragmentation was observed only in leukemic cells. Activation of sirtuin1 and adenosine-monophosphate-activated protein kinase was not responsible for resveratrol-induced cancer cell death. Instead, resveratrol significantly reduced Akt activation with the downregulation of H-Ras, resulting in facilitation of Bax translocation to mitochondria in leukemic cells. This study suggests that resveratrol can induce apoptotic cell death in human leukemic cells to a greater extent than in human solid tumor cells via reducing Akt activation due to Ras downregulation.

Cytotoxic and antimicrobial effects of indium(iii) complexes with 2-acetylpyridine-derived thiosemicarbazones.

Complexes [In(2Ac4oClPh)Cl2(MeOH)] (1), [In(2Ac4pFPh)Cl2(MeOH)] (2), [In(2Ac4pClPh)Cl2(MeOH)] (3) and [In(2Ac4pIPh)Cl2(MeOH)] (4) were obtained with N(4)-ortho-chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4oClPh), N(4)-para-fluorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pFPh), N(4)-para-chlorophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pClPh) and N(4)-para-iodophenyl-2-acetylpyridine thiosemicarbazone (H2Ac4pIPh). Theoretical studies suggested that the coordinated methanol molecule can be easily replaced by DMSO used in the preparation of stock solutions, with the formation of [In(L)Cl2(DMSO)] (HL = thiosemicarbazonate ligand), and that the replacement of DMSO by water is unfavorable. However, for all complexes the displacement of one or two chloride ligands by water in aqueous solution is extremely favorable. The cytotoxic activity of the compounds was evaluated against HL-60, Jurkat and THP-1 leukemia and against MDA-MB-231 and HCT-116 solid tumor cell lines, as well as against Vero non-malignant cells. The cytotoxicity and selectivity indexes (SI) increased in several cases for the indium(iii) complexes in comparison with the free thiosemicarbazones. The antimicrobial activity of the compounds was investigated against Candida albicans, Candida dubliniensis, Candida lusitaniae and Candida parapsilosis. In many cases complexation resulted in a substantial increase of the antifungal activity. Complexes (1-4) were revealed to be very active against C. lusitaniae and C. dubliniensis. Structure-activity relationship (SAR) studies were carried out to identify the physico-chemical properties that might be involved in the antifungal action, as well as in the cytotoxic effect of the compounds against HL-60 cells. In both cases, correlations between the bioactivity and physico-chemical properties did not appreciably change when the chloride ligands in [In(L)Cl2(DMSO)] were replaced by water molecules, suggesting [In(L)Cl(H2O)(DMSO)]+ or [In(L)(H2O)2(DMSO)]2+ to be the species that interact with the biological media.

Total Synthesis of the Proposed Structure for Aromin and Its Structural Revision.

This paper describes the first total synthesis of the proposed structure for aromin, an annonaceous acetogenin possessing an unusual bis-THF ring system, and its 4S,7R-isomer. The key steps involve an oxidative cyclization of a couple of terminal-diene alcohols and an intermolecular metathesis of an alkenyl tetrahydrofuran with an enone carrying a tetrahydrofuranyl lactone. The spectral data of both samples did not match those of aromin. Re-examination of the NMR data using the CAST/CNMR Structure Elucidator and chemical derivations suggested that the real structure of aromin should be revised to be a tetrahydropyran acetogenin, montanacin D. Cytotoxicities in human solid tumor cell lines for synthetic samples were also evaluated.

Cytotoxic activities of flavonoids from a traditional Mongolian medicinal herb Clematis aethusifolia Turcz.

In the course of our search for antitumour constituents from the traditional Mongolian medicinal herb Clematis aethusifolia Turcz., 11 flavonoids were isolated for the first time from the dried aerial parts of the plant by flash C18 column chromatography, Sephadex LH-20 and reversed phase preparative HPLC. The planar structures of these flavonoids were established based on 1D and 2D NMR and high-resolution mass spectrometry. Compounds 1, 2, 4 and 5 showed moderate cytotoxicity against a panel of five human solid tumour cell lines, including A-375, a human melanoma cell line; SK-OV-3, a human ovarian cancer cell line; A549, a human lung cancer cell line; HCT-15, a human colorectal adenocarcinoma cell line; and SH-SY5Y, a human neuroblastoma cell line (with IC50 values of 20–70 μM). The obtained cytotoxic apigenin and its derivatives may be useful as standard compounds for the quality control of the crude drug and its preparations.

Cytotoxic and Antitumor Activity of some Coumarin Derivatives

Several natural and synthetic coumarins were assayed against different cancer cell lines. Four of them have shown cytotoxicity against a panel of three human solid tumor cell lines (HeLa, T-47D, and WiDr) and a clearly activity/hydrophobicity relationship. Compound 13 proved to be the most active product in all cell lines tested, with values of 8.0 (±0.38) μM against HeLa cells and also able to inhibit Taq DNA polymerase. This dual activity of 13 makes it a candidate to be considered as a "lead" compound in the search for novel antitumor drugs.

Biological responses of human solid tumor cells to X-ray irradiation within a 1.5-Tesla magnetic field generated by a magnetic resonance imaging-linear accelerator.

Devices that combine magnetic resonance imaging with linear accelerators (MRL) represent a novel tool for MR-guided radiotherapy. However, whether magnetic fields (MFs) generated by these devices affect the radiosensitivity of tumors is unknown. We investigated the influence of a 1.5-T MF on cell viability and radioresponse of human solid tumors. Human head/neck cancer and lung cancer cells were exposed to single or fractionated 6-MV X-ray radiation; effects of the MF on cell viability were determined by cell plating efficiency and on radioresponsiveness by clonogenic cell survival. Doses needed to reduce the fraction of surviving cells to 37% of the initial value (D0s) were calculated for multiple exposures to MF and radiation. Results were analyzed using Student's t-tests. Cell viability was no different after single or multiple exposures to MRL than after exposure to a conventional linear accelerator (Linac, without MR-generated MF) in 12 of 15 experiments (all P > 0.05). Single or multiple exposures to MF had no influence on cell radioresponse (all P > 0.05). Cells treated up to four times with an MRL or a Linac further showed no changes in D0s with MF versus without MF (all P > 0.05). In conclusion, MF within the MRL does not seem to affect in vitro tumor radioresponsiveness as compared with a conventional Linac. Bioelectromagnetics. 37:471-480, 2016. © 2016 Wiley Periodicals, Inc.

Synthesis, characterization, and antitumor evaluation of 4-aminoximidofurazan derivatives

ABSTRACTReactions of 3-amino-4-aminoximidofurazan (AAOF) with Wittig–Horner reagents, trialkylphosphites, trisdialkylaminophosphines as well as the thiating Lawesson and Japanese reagents were studied. Elemental analysis and spectroscopic measurements were in good accord with the structures postulated for the new products. The antitumor activities of certain selected new compounds were screened, in vitro, against a panel of five (liver; HepG2; breast; MCF-7; lung; A549; colon; HCT116; and prostate PC3) human solid tumor cell lines.

Bismuth(III) complexes with 2-acetylpyridine- and 2-benzoylpyridine-derived hydrazones: Antimicrobial and cytotoxic activities and effects on the clonogenic survival of human solid tumor cells

Complexes [Bi(2AcPh)Cl2]·0.5H2O (1), [Bi(2AcpClPh)Cl2] (2), [Bi(2AcpNO2Ph)Cl2] (3), [Bi(2AcpOHPh)Cl2]·2H2O (4), [Bi(H2BzPh)Cl3]·2H2O (5), [Bi(H2BzpClPh)Cl3] (6), [Bi(2BzpNO2Ph)Cl2]·2H2O (7) and [Bi(H2BzpOHPh)Cl3]·2H2O (8) were obtained with 2-acetylpyridine phenylhydrazone (H2AcPh), its -para-chloro-phenyl- (H2AcpClPh), -para-nitro-phenyl (H2AcpNO2Ph) and -para-hydroxy-phenyl (H2AcpOHPh) derivatives, as well as with the 2-benzoylpyridine phenylhydrazone analogues (H2BzPh, H2BzpClPh, H2BzpNO2Ph, H2BzpOHPh).Upon coordination to bismuth(III) antibacterial activity against Gram-positive and Gram-negative bacterial strains significantly improved except for complex (4).The cytotoxic effects of the compounds under study were evaluated on HL-60, Jurkat and THP-1 leukemia, and on MCF-7 and HCT-116 solid tumor cells, as well as on non-malignant Vero cells. In general, 2-acetylpyridine-derived hydrazones proved to be more potent and more selective as cytotoxic agents than the corresponding 2-benzoylpyridine-derived counterparts.Exposure of HCT-116 cells to H2AcpClPh, H2AcpNO2Ph and complex (3) led to 99% decrease of the clonogenic survival. The IC50 values of these compounds were three-fold smaller when cells were cultured in soft-agar (3D) than when cells were cultured in monolayer (2D), suggesting that they constitute interesting scaffolds, which should be considered in further studies aiming to develop new drug candidates for the treatment of colon cancer.

Antiproliferative effect of extract from endophytic fungus Curvularia trifolii isolated from the “Veracruz Reef System” in Mexico

Context: It is well known that marine fungi are an excellent source of biologically active secondary metabolites, and by 2011, it was reported that over 400 bioactive metabolites were derived from marine fungi.Objective: This study establishes the basis for future research on antiproliferative compounds of marine endophytes inhabited in the Veracruz Reef System.Materials and methods: Isolation of the 34 fungal strains was carried out by microbiological method from samples of sponges, corals, and other biological material from the Veracruz Reef System. The fungal biomass and broth were separated and extracted with a mixture of solvents MeOH:CHCl3. Characterization and molecular identification of the fungal strains were performed through microbiological methods and the analysis of the ITS-rDNA regions. Antiproliferative activity was tested at a dose of 250 μg/mL on human solid tumor cell lines HBL-100, HeLa, SW1573, T-47D, and WiDr by the SRB assay after 48 h-exposure to the fungal extracts.Results: The extracts from five isolates showed an antiproliferative effect against one or more of the tested cell lines (percentage growth < 50%). The mycelial extract from the isolate LAEE 03 manifested the highest activity against the five cell lines (% PG of 17 HBL-100, 19 HeLa, 23 SW1573, -6 T-47D, and 10 WiDr) and the strain was identified as Curvularia trifolii (Kauffman) Boedijn (Pleosporaceae).Discussion and conclusion: The results obtained indicate that the extract from a marine derived C. trifolii has the antiproliferative effect, thus suggesting that this organism is a good candidate for further analysis of its metabolites.

Ent-Labdane Diterpenoids from the Aerial Parts of Eupatorium obtusissmum.

Six new ent-labdane diterpenoids, uasdlabdanes A-F (1-6), were isolated from the aerial parts of Eupatorium obtusissmum. The new structures were elucidated through spectroscopic and spectrometric data analyses. The absolute configurations of compounds 1 and 2 were established by X-ray crystallography, and those of 3-6, by comparison of experimental and calculated electronic circular dichroism spectra. The antiproliferative activity of the compounds was studied in a panel of six representative human solid tumor cell lines and showed GI50 values ranging from 19 to >100 μM.

Long Non-Coding RNA CCAT1 Acts as a Competing Endogenous RNA to Regulate Cell Growth and Differentiation in Acute Myeloid Leukemia.

Long non-coding RNAs (lncRNAs) are involved in multiple cellular events, as well as in tumorigenesis. Colon cancer-associated transcript-1 (CCAT1) gene encodes an lncRNA whose over-activation was observed in an expanding list of primary human solid tumors and tumor cell lines, however its biological roles in acute myeloid leukaemia (AML) has not been reported yet at present. In this study, the aberrant upregulation of CCAT1 was detected in French-American-British M4 and M5 subtypes of adult AML patients. By gain- and loss-of-function analysis, we determined that CCAT1 repressed monocytic differentiation and promoted cell growth of HL-60 by sequestering tumor suppressive miR-155. Accordingly, a significant decrease in miR-155 level was detected in AML patients. Re-introduction of miR-155 into HL-60 cells restored monocytic maturation and repressed cell proliferation. Furthermore, CCAT1 could up-regulated c-Myc via its competing endogenous RNA (ceRNA) activity on miR-155. In conclusion, these results revealed new mechanism of lncRNA CCAT1 in AML development, and suggested that the manipulation of CCAT1 expression could serve as a potential strategy in AML therapy.

Study on the cytotoxic activity of platinum(II) complexes of (1R,2R)-N(1)-cyclopentyl-1,2-cyclohexanediamine with substituted malonate derivatives.

Three platinum(II) complexes of (1R,2R)-N(1)-cyclopentyl-1,2-cyclohexanediamine with malonate derivatives were designed, synthesized and spectrally characterized. MTT assay showed that the complexes possessed positive cytotoxic effect on the four human solid tumor cell lines. Among the complexes, complex 2 demonstrated the strongest cytotoxic activity compared to cisplatin and oxaliplatin against HepG2 cell line (IC50=3.04μM). Furthermore, the results of gel electrophoresis revealed that complex 2 interacted with DNA in a different mode from that of cisplatin. Mechanism studies of cell proliferation inhibition and cellular uptake indicated that complex 2 entered HepG2 cell more efficiently than cisplatin, exhibited massive G2 accumulation and then induced apoptosis.