HL-60 Tumor Cell Research Articles

Bioassays to Assess the Safety of Potassium and Sodium Nitrates and Nitrites

(1) Background: Advances in food processing practices and health care are some of the most significant advances in modern daily life. The goal of this study is to evaluate the safety of potassium and sodium nitrates and nitrites when they are used as fertilizers in agriculture and food additives, as well as the known conversion of nitrate to nitrite in humans. (2) Methods: Various bioassays were conducted to investigate the effects of nitrates and nitrites in the Drosophila melanogaster genetic tester system. These assays focused on the modulation of degenerative processes at the molecular, cellular, individual, and population levels. Additionally, we assessed the chemopreventive potential and the ability to induce DNA strand breaks in HL-60 tumour cells. (3) Results: All nitrate and nitrite concentrations tested were shown to not be toxic or genotoxic in Drosophila since none of the compounds reached the LD50 and significant genetic mutation. A positive or null protective capacity against a toxic agent was found for nitrates, not for nitrites, showing that sodium nitrite has a synergistic effect when combined with the oxidant toxin hydrogen peroxide; and a nutraceutical potential in the lifespan only for sodium nitrate to improve the quality of life in 5 days at ADI concentration. The in vitro results in human leukemia cells showed a chemopreventive potential only for potassium nitrate and sodium nitrite due to reducing the viability of HL-60 cells growth to 18% and 29%, respectively, compared to the controls at ADI (acceptable daily intake) concentrations. However, neither of these showed DNA damage or methylation modifications. (4) Conclusions: The tested compounds were shown to be safe to use during in vivo and in vitro tests when used at the extrapolated ADI concentrations.

In Vivo and In Vitro Studies Assessing the Safety of Monosodium Glutamate.

The controversial results of research on monosodium glutamate demand a new data corpus for the overall safety evaluation. Both animal and cellular model systems have been used to add a multilevel scope on its biological effects. The Drosophila melanogaster animal model has been used to test a wide range of concentrations for safety purposes: toxicity, genotoxicity, longevity and health span. Medium concentrations corresponding to the human acceptable daily intake (ADI) (0.06 mg/mL) were not toxic nor genotoxic for Drosophila and safe for the lifespan parameters. Once safety was determined, the possible nutraceutical effects of monosodium glutamate was monitored in terms of antitoxicity, antigenotoxicity assays and health span. The results for protective activity against hydrogen peroxide were positive in terms of the medium concentration, antitoxic and antigenotoxic in terms of inhibiting the genotoxicity induced by the oxidative toxin up to 43.7% and increasing the health span expectancy by 32% in terms of days. Monosodium glutamate has been demonstrated to be cytotoxic against the model tumour cell line HL-60, not only in a necrotic way but through internucleosomal DNA fragmentation antitumour activity. The significant LINE1 DNA sequence methylation of HL-60 tumour cells induced by monosodium glutamate is a molecular marker for chemoprevention. Conclusions: the slight or non-significant positive nutraceutical and chemo preventive potential showed by monosodium glutamate at its ADI concentration can be considered as a safe dose for a moderate consumption.

Preparation, Characterization, and Biological Assessment of Heterocyclic Schiff Base Metal Complexes

MIIMC, MMIIMC, and CMIIMC are biologically significant Schiff bases formed by the condensation of 3-amino-5-methyl isoxazole with formyl chromone. Substituted formyl chromones and metal chelates containing Cu(II), Ni(II), Co(II), and Zn(II) are prepared. These were studied utilising elemental analysis, FTIR, UV-VIS, 1H, 13C, mass spectra, magnetic susceptibility, conductance tests, and thermogravimetric techniques. The data revealed that the ligands display neutral, bidentate coordination through carbonyl oxygen and azomethine nitrogen. The antibacterial activity of the ligands and metal complexes is determined in vitro against bacteria and fungus using the paper disc method. Metal chelates have significantly higher MIC values against bacteria than ligands. The DNA binding properties of Cu(II) complexes were examined. MTT is used to determine the complexes' anticancer efficacy against HL60 tumour cells. The researchers discovered that the complexes prevented apparent morphological alterations. The inhibition ratio was hastened by increasing the dosage, and it had a strong positive association with the medicine dosage. Thermal analysis of complexes showed initial mass loss due to moisture and hydrated water molecules, followed by weight loss at 220oC due to coordinated water molecules, indicating metal oxide breakdown.

The Activity, Composition and Molecular Mechanism of Bothriospermum zeylanicum (Hornem.) Fisch. Et Mey Alleviation of Nonsmall Cell Lung Cancer

Objective: To study the effect of the ethyl acetate extract of Bothriospermum zeylanicum (Hornem.) Fisch., the active ingredients and mechanism of Et Mey (EAF) in nonsmall cell lung cancer (NSCLC) were explored. Methods: 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay was used to measure the effect of EAF on the proliferation of A549, HL-60, SMMC-7721, MDA-MB-231, and SW480 tumor cells. The components were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS), and the blood components were retrieved from the constituents absorbed into the blood and metabolites of traditional Chinese medicine (DCABM-TCM) database. The mechanism was determined by network pharmacology and verified by molecular docking. Results: The IC50 values for the proliferation of tumor cell strains were 41.13, 56.72, 36.69, 48.63, and 44.48 μg/mL, respectively. A concentration of 100 μg/mL had the strongest inhibitory effect on A549 cells. A total of 33 chemical components were identified by LC-MS, 7 of which have been reported to have certain anti-NSCLC effects, and a total of 6 blood components were identified using the DCABM-TCM database. Network pharmacology analysis revealed that anti-NSCLC activity mainly involves EGFR tyrosine kinase inhibitor resistance, the PI3K-Akt signaling pathway, the AGE-RAGE signaling pathway in diabetic complications, the HIF-1 signaling pathway and the VEGF signaling pathway. The molecular docking results verified that hesperetin, luteolin, and pinocembrin bind well to the AKT1, IL6, EGFR, BCL2, and CASP3 target proteins. Conclusion: The ethyl acetate fraction of B. zeylanicum (Hornem.) Fisch. Et Mey had obvious ant-non NSCLC activity, which may be related to resistance to EGFR tyrosine kinase inhibitors and the PI3K-Akt signaling pathway in diabetic complications, and its active ingredients may be hesperetin, luteolin, and pinocembrin.

Phytochemical Characterization, Antioxidant, and Anti-Proliferative Activities of Wild and Cultivated Nigella damascena Species Collected in Sicily (Italy).

The use of Nigella damascena seeds in the culinary field or as aerial parts infusions in the pharmaceutical and cosmetic fields is widely reported. The biological activity of this plant, as demonstrated over the years, is closely related to its phytochemical content. This investigation focused on the comparative study of the same plants of N. damascena, one totally wild (WND), while the other two, one with white flowers (CWND) and the other with blue flowers (CBND), were subject to cultivation, irrigation, and manual weeding. Using the potential of 1D and 2D-NMR spectroscopy, coupled with MS/MS spectrometric studies, the three methanolic extracts of N. damascena were investigated. Chemical studies have highlighted the presence of triterpene saponin compounds and various glycosylated flavonoids. Finally, the in vitro antiproliferative and antioxidant activities of the three individual extracts were evaluated. The antiproliferative activity performed on U-937, HL-60, and MCF-7 tumor cell lines highlighted a greater anticancer effect of the CBND and CWND extracts compared to the data obtained using WND. The antioxidant activity, however, performed to quantify ROS generation is comparable among the extracts used.

Design, Synthesis, and Antiproliferative Activity of Selective Histone Deacetylases 6 Inhibitors Containing a Tetrahydropyridopyrimidine Scaffold

The development of selective histone deacetylase 6 inhibitors (sHDAC6is) is being recognized as a therapeutic approach for cancers. In this paper, we designed a series of novel tetrahydropyridopyrimidine derivatives as sHDAC6 inhibitors. The most potent compound, 8-(2, 4-bis(3-methoxyphenyl)-5, 8-dihydropyrido [3, 4-d]pyrimidin-7(6H)-yl)-N-hydroxy-8-oxooctanamide (8f), inhibited HDAC6 with IC50 of 6.4 nM, and showed > 48-fold selectivity over other subtypes. In Western blot assay, 8f elevated the levels of acetylated α-tubulin in a dose-dependent manner. In vitro, 8f inhibited RPMI-8226, HL60, and HCT116 tumor cells with IC50 of 2.8, 3.20, and 3.25 μM, respectively. Moreover, 8f showed good antiproliferative activity against a panel of tumor cells.

Abstract 3500: AUR103 an oral small molecule CD47 antagonist in combination with azacytidine and bortezomib exhibits potent anti-tumor activity in myeloma and leukemia models in vitro and in vivo

Abstract The CD47/signal regulatory protein alpha axis is a critical regulator of myeloid cell activation and serves as an immune checkpoint for macrophage mediated phagocytosis. Targeting CD47-SIRPα axis is emerging as one of the promising new immunotherapy approaches that targets innate immune response. Number of clinical trials are in progress to evaluate CD47/SIRPα blocking therapies. Most of these molecules are either anti-CD47 antibodies or SIRPα-Fc recombinant proteins. We have developed a novel small molecule CD47 antagonist, AUR103 as a therapeutic agent for solid and hematological cancers. AUR103 is efficacious as a single agent in tumors with high expression of “eat-me” signals and synergizes well in combination with tumor-targeting antibodies. We hypothesized that agents capable of inducing “eat-me” signals such as calreticulin (CRT) a pro-phagocytic signal, will synergize with AUR103 to enhance phagocytosis and antitumor activity. Here, we report the anti-tumor efficacy of AUR103 in combination with azacytidine and bortezomib in acute myeloid leukemia and multiple myeloma model of cancer, respectively.In the phagocytosis assay, HL-60 human myeloid leukemia or NCI-H929 human multiple myeloma cells were treated with azacytidine or bortezomib for 48 hours. Cells were stained with CFSE and were further treated with AUR103. Cells were then added to human macrophages and allowed to undergo phagocytosis. Phagocytosis of target cells was measured by detecting cells that were double positive for APC and CFSE by FACS. HL-60 cells were orthotopically implanted in NOD SCID mice while NCI-H929 multiple myeloma cells were sub-cutaneously implanted in NOD SCID mice. Tumor bearing mice were treated with AUR103 (10 and 30 mg/kg, b.i.d, and po) as a single agent or in combination with azacytidine (5 mg/kg i.p., twice weekly) or bortezomib (0.4 mg/kg i.v., twice weekly). AUR103 in combination with azacytidine and bortezomib significantly enhanced phagocytosis of HL-60 and NCI-H929 tumor cells, respectively when compared to individual treatments. In the combination efficacy studies, AUR103 combination treatments with azacytidine and bortezomib were well tolerated without any signs of toxicity. In the HL-60 orthotopic model, AUR103 combination with azacytidine significantly reduced the engraftment of HL-60 tumor cells. AUR103 combination with bortezomib resulted in enhanced tumor growth inhibition in NCI-H929 tumor model when compared to individual treatments. These results demonstrate the therapeutic potential of AUR103 in combination with agents that are capable of inducing “eat-me” or pro-phagocytic signals. Citation Format: Girish C. Daginakatte, Sasikumar Pottayil, Sudarshan Naremaddepalli, Gundala Chennakrishnareddy, Prasad Bilugudi, Sai Krishna Tangella, Sandeep Patil, Nagesh Gowda, Kiran Aithal, Wesley Roy Balasubramanian, Amit Dhudashiya, Samiulla Dodheri, Kavitha Nellore, Susanta Samajdar, Murali Ramachandra. AUR103 an oral small molecule CD47 antagonist in combination with azacytidine and bortezomib exhibits potent anti-tumor activity in myeloma and leukemia models in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3500.

Design, synthesis and biological evaluation of chromone derivatives as novel protein kinase CK2 inhibitors

Protein kinase CK2 is a potential target for the discovery of anticancer drugs. Flavonoids are reported to be effective CK2 inhibitors. Herein, based on structural trimming of flavonoids, a series of chromone-2-aminothiazole derivatives (1a-d, 2a-g, 4a-j, 5a-k) were designed and synthesized by hybridizing the chromone skeleton with 2-aminothiazole scaffold. Among these compounds, compound 5i was the most effective CK2 inhibitor (IC50 = 0.08 μM) and possessed potent anti-proliferative activity against HL-60 tumor cells (IC50 = 0.25 μM). Cellular thermal shift assay (CESTA) confirmed that 5i directly bound to the CK2, and the possible binding mode of 5i toward CK2 was also simulated. Further studies showed that 5i induced the apoptosis of HL-60 cells and arrested the cell cycle. Finally, western-blot analysis showed that 5i could inhibit the downstream of CK2, including α-catenin/Akt pathway and PARP/Survivin pathway.

Discovery of tight-binding competitive inhibitors of dipeptidyl peptidase IV

Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) is an abundant serine aminopeptidase that preferentially cleaves N-terminal Xaa-Pro or Xaa-Ala dipeptides from oligopeptides. Inhibitors of DPP-IV activity are used for treating type 2 diabetes mellitus and other diseases. DPP-IV is also involved in tumor progression. We identified four new non-peptide tight-binding competitive inhibitors of porcine DPP-IV by virtual screening and enzymatic assays. Molecular docking simulations supported the competitive behavior, and the selectivity of one of the compounds in the DPP-IV family. Since three of these inhibitors are also aminopeptidase N (APN) inhibitors, we tested their impact on APN+/DPP-IV+ and DPP-IV+ human tumor cells' viability. Using kinetic assays, we determined that HL-60 tumor cells express both APN and DPP-IV activities and that MDA-MB-231 tumor cells express DPP-IV activity. The inhibitors had a slight inhibitory effect on human HEK-293 cell viability but reduced the viability of APN+/DPP-IV+ and DPP-IV+ human tumor cells more potently. Remarkably, the intraperitoneal injection of these compounds inhibited DPP-IV activity in rat brain, liver, and pancreas. In silico studies suggested inhibitors binding to serum albumin contribute to blood-brain barrier crossing. The spectrum of action of some of these compounds may be useful for niche applications.

Influence of ligand lipophilicity in Pt(II) complexes on their antiproliferative and apoptotic activities in tumour cell lines

One of the most widely used strategies for drug development is the coordination of bioactive ligands to transition metals, which could improve biological activity. Moreover, the incorporation of aromatic groups to ligands may allow an enhanced lipophilicity that can influence the cellular uptake and accumulation of the metallodrugs, thus increasing their activity. Herein, we have reported the synthesis and characterization of four Pt(II) complexes [PtCl2(L)], where L = 2-(1-pyrazolyl)-2-thiazoline (PzTn), 2-(1-pyrazolyl)-1,3-thiazine (PzTz), 2-(3,5-diphenyl-1-pyrazolyl)-2-thiazoline (DPhPzTn) or 2-(3,5-diphenyl-1-pyrazolyl)-1,3-thiazine (DPhPzTz). The study was aimed at analysing their potential anticarcinogenic ability in epithelial cervix carcinoma HeLa, human promyelocytic leukemia HL-60 and human histiocytic lymphoma U-937 tumour cell lines as well as checking whether the structural factors of the organic ligand may influence their biological activity. Our findings showed that PtDPhPzTn and PtDPhPzTz were far more effective in terms of cytotoxicity than their less lipophilic counterparts (PtPzTn and PtPzTz), especially in cells derived from solid cervical tumours, thereby suggesting that modulating the lipophilicity of the ligands can help improve the cytotoxic effect of the metal complexes.

Synthesis and anticancer activity of Pt(II) complexes of spiro-5-substituted 2,4-dithiohydantoins

Despite the widely studied anticancer activity of metal complexes of various hydantoin derivatives, reports on biological properties of dithiohydantoin complexes are limited to only few. Main challenge is determination of their structure, since no crystallographic data are available for metal complexes of dithiohydantoins. Herein, we describe the synthesis and structure of Pt(II) complexes of two spiro-5-(2,4-dihiohydantoins) with large and potentially intercalating aromatic rings, namely 3′,4′-dihydro-2H,2′H,5H-spiro[imidazolidine-4,1′-naphthalene]-2,5-dithione and spiro-(fluorene-9,4′-imidazolidine)-2′,5′-dithione. The anticancer activity of all compounds were tested against HL-60, BV-173, and K-562 tumor cell lines. Single-crystal X-ray analysis was performed for the spiro-(benzocyclohexane-4′-imidazolidine)-2′,5′-dithione, whereas all other compounds were characterized by integrated approach of spectroscopic (IR and solid-state NMR) and theoretical (DFT) studies. The analysis of the data suggested Pt2L4 composition of the complexes with bridging N^S coordination of four ligand molecules and two Pt(II) centers of square planar geometry. Polymeric structure in the solid state was also presumed. The complexes showed modest to moderate anticancer activity as compared to cisplatin and the chronic myeloid leukemia derived BV-173 proved to be the most responsive tumor model.

Isoprenoid pterocarpans, isoflavonoids and flavonoids from Erythrina stricta

• Three new isoprenoid pterocarpans, erystrictins A-C, were isolated from Erythrina stricta . • Alkaloid 22 was isolated from Erythrina genus for the first time. • Several compounds exhibited certain degrees of cytotoxic activity. A pair of diastereoisomeric pterocarpans, erystrictins A/B (1a/1b), possessing a highly oxidized 3-hydroxy-2-(1-hydroxy-1-methylethyl)- 2,3-dihydro furan substituent, and erystrictin C (2), along with seven known pterocarpans ( 3 - 9 ), eleven known flavonoids ( 10 - 20 ), and two known alkaloids ( 21 - 22 ) were isolated from Erythrina stricta. Their structures were established by extensive spectroscopic analyses, including HRESIMS, 1D and 2D NMR, and electronic circular dichroism (ECD) calculations. Using the MTS method, compounds 1 - 12 were tested for their cytotoxicity against the HL-60, SMMC-7721, A-549, MCF-7 and SW-480 human tumor cell lines, compounds 4, 10 and 12 showed moderated cytotoxicity. All the compounds, except for 10 and 12 were isolated from this plant for the first time. Compound 21 was isolated from Erythrina genus for the first time.

Synthesis, antineoplastic activity and in silico studies of (S)-N-(1-hydroxy-3-methylbutan-2-yl)-3-(p-tolyl)-1,2,4-oxadiazole-5-carboxamide

The development of chemotherapy agents without side effects is a major challenge, since traditional medicines usually have undesirable properties such as high toxicity, resistance and low bioavailability. In this sense, computational methods play a crucial role in the discovery and optimization of new drugs, as they combine speed and efficiency with low cost. The 1,2,4-oxadiazoles are one of the main classes of heterocyclics due to their numerous biological applications. In this work, we report the synthesis, antineoplastic evaluation and in silico study of a new 1,2,4-oxadiazole. The (S)-N-(1-hydroxy-3-methylbutan-2-yl)-3-(p-toluyl)-1,2,4-oxadiazole-5-carboxamide was obtained after two reaction steps in excellent yield. Although it has shown low activity in relation to the MCF-7, HCT116 and HL60 tumor cell lines, the molecular docking study indicates that this compound acts in the colchicine site and can inhibit tubulin polymerization. From the calculation of pharmacokinetic properties by the SwissADME and Osiris Property Explorer programs, it is possible to infer that the compound meets the Lipinski rules presenting good oral bioavailability and low toxicity.

Analysis of Peganum harmala, Melia azedarach and Morus alba extracts against six lethal human cancer cells and oxidative stress along with chemical characterization through advance Fourier Transform and Nuclear Magnetic Resonance spectroscopic methods towards green chemotherapeutic agents

Traditional medicines implicate consumption of plant crude extracts, which may consist of extensive phytochemical diversity. Overall, the most biologically active extract of Peganum harmala (seeds) exhibited significant cytotoxic activity on Artemia salina with LC50 value of 61.547 µg/mL, while P. harmala (roots) [LC50 = 124.229 µg/mL] and M. azedarach (fruits) [LC50 = 147.813 µg/mL] showed moderate cytotoxic potential. P. harmala (seeds) extract also showed the maximum antitumor potential with 52.278 µg/mL LC50. Branches of P. harmala and Morus alba were not active in both bioassays. These outcomes were further reinforced by the levels of phenolics and flavonoids checked against gallic acid and quercetin equivalents, respectively, by standard curves. Current study aims to isolate, structurally characterize and analyze the bioactive compound from plant extracts by using chromatographic and spectrophotometric techniques. Bioactivity guided isolation of extracts led to the isolation of PH-HM-16 from ethyl acetate fraction P. harmala seeds. Chemical structure of PH-HM-16 was elucidated by ESI-MS, 1H NMR, 13C NMR, HSQC and IR spectrum. The results demonstrated significant positive anticancer activities against six human cancer cell lines assessed through MTT cancer cell growth inhibition assay. PH-HM-16 was most effective against prostate cancer cell lines [IC50 = 17.63 µg/mL] followed by breast cancer cell line MCF7 [IC50 value of 41.81 µg/mL]. IC50 value of PH-HM-16 against human myeloid leukemia cell line HL-60 and human colorectal tumor cells HCT-116 was observed as 68.77 µg/mL and 71.54 µg/mL respectively. The IC 50 value of PH-HM-16 compound was not significant against human gastric cancer SGC-7901 (111.89 µg/mL) and human lung adenocarcinoma epithelial cell line A549 (176.04 µg/mL). Isolated bioactive metabolite PH-HM-16 possesses significant antitumor potential so this could be the first step to develop an effective anticancer agent. Hence, this compound represents a promising potential to be chemically standardized or developed into pharmaceuticals for the chemoprevention and/or the treatment of certain types of cancer, especially as adjuvant phytotherapeutics in conventional chemotherapy.

Inhibitory Activity of Brown Propolis Extracts on a Norfloxacin-Resistant Strain of Staphylococcus aureus

Brown propolis from northern Ceara, Brazil, was found to contain predominantly sesquiterpenes in its volatile profile. The ethanolic propolis extract yielded a substantial apolar fraction (80.07 ± 1.47%) after liquid–liquid partitioning, which explains the low phenolic content (41.33 ± 1.68 mgGAE gEXT−1). Phenolics, such as p-coumaric (0.13 ± 0.04 mg gEPE−1), ferulic (1.07 ± 0.09 mg gEPE−1), and trans-cinnamic (0.41 ± 0.02 mg gEPE−1) acids, were detected in the EtOH-soluble extract. The apolar fraction was rich in triterpenes such as cycloartenol (12.85 ± 2.80%), α-amyrenyl acetate (4.37 ± 0.69%), and α-amyrin (3.89 ± 0.62%). Despite the lack of a direct antibacterial activity against Staphylococcus aureus 1199-B, both fractions exhibited potentiating effects in combination with norfloxacin; these effects could be attributed to efflux pump inhibition. The apolar fraction was more effective than the EtOH-soluble one at reducing the minimum inhibitory concentration, producing similar results to chlorpromazine and ethidium bromide. The EtOH-soluble fraction exhibited cytostatic properties at lower concentrations, while the apolar fraction demonstrated better selectivity for PC3 and HL60 tumor cells. The findings highlight the biological potential of Brazilian brown propolis for application as a complementary agent in the treatment of S. aureus infections and as an alternative therapy for cancer treatment.

Inhibitory Effect of PKC412 Against Human Acute Leukemia Cell Line HL-60 Cells

To explore the effects and mechanisms of PKC412 inhibitor on proliferation and apoptosis of HL-60 cell line. CCK-8 assay was used to detect the effect of PKC412 on the proliferation of HL-60 cells at different concentrations; Wright-Giemsa staining was used to estimated the effect of PKC412 on the apoptosis of HL-60 cells; the mRNA expression of BCL-2 and P53 genes was detected by qRT-PCR, the expression of BCL-2 and P53 proteins was detected by Western blot. HL-60 cells were injected into mouse caudal vein to construct acute myeloid leukemia model, PKC412 was administered to tail vein for 31.25 nmol/kg, normal saline was injected into the same site of the mice as control group, and the inhibitory effect of PKC412 on HL-60 cells in mice was observed. ELISA assay was used to detect the effect of PKC412 on the inflammatory factors of TNF-α and TGF-β in tumor mice. PKC412 could inhibit the proliferation of HL-60 cell, which was in a dose dependent manner(r=0.9973) (IC50 was 0.31 μmol/L), and induce apoptosis of HL-60 cells. After HL-60 cell was treated by PKC412 for 48 h the expression of BCL-2 gene was down regulated(0.417±0.044 vs 0.933±0.033, t=9.347, P<0.001), the expression of P53 gene was up regulated(1.533±0.145 vs 1.050±0.161, t=2.231, P>0.05) as compared with control group. And the expression of BCL-2 protein was decreased, while the expression of P53 protein was increased. PKC412 could inhibited the growth of HL-60 tumor cells in vivo, the survival rate of mice after administration was 50% and the weight was increased as compared with that in control group(18.02±0.403 g vs 16.44±0.562 g, t=2.272, P=0.0356). The secretion of TNF-α and TGF-β cytokine in serum and spleen cells in PKC412 group was significantly lower than that in control group (P<0.05). PKC412 can induce apoptosis of HL-60 cells by inhibiting the expression level of BCL-2 gene, PKC412 administration in vivo can inhibit the growth of the tumors.

Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers

Novel tolmetin derivatives 5a–f to 8a–c were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The cytotoxic activity of the most active tolmetin derivatives 5b and 5c was examined against HL-60, HCT-15, and UO-31 tumour cell lines. Compound 5b was found to be the most potent derivative against HL-60, HCT-15, and UO-31 cell lines with IC50 values of 10.32 ± 0.55, 6.62 ± 0.35, and 7.69 ± 0.41 µM, respectively. Molecular modelling studies of derivative 5b towards the VEGFR-2 active site were performed. Compound 5b displayed high inhibitory activity against VEGFR-2 (IC50 = 0.20 µM). It extremely reduced the HUVECs migration potential exhibiting deeply reduced wound healing patterns after 72 h. It induced apoptosis in HCT-15 cells (52.72-fold). This evidence was supported by an increase in the level of apoptotic caspases-3, -8, and -9 by 7.808-, 1.867-, and 7.622-fold, respectively. Compound 5b arrested the cell cycle in the G0/G1 phase. Furthermore, the ADME studies showed that compound 5b possessed promising pharmacokinetic properties.

Synthesis and cytotoxic activity of unsaturated macrolides and their hybrid molecules with a C60 fullerene.

Previously unreported macrodiolides containing a 1Z,5Z-diene fragment in the structure have been synthesized with high yields and stereoselectivity by our research group, using the intermolecular esterification of malonic acid with α,ω-diols containing bis-methylene-separated Z-double bonds, catalyzed by Hf(OTf)4 hafnium triflate. Under Bingel-Hirsch conditions, the synthesized macrodiolides were chemically bonded with a C60 fullerene to produce the corresponding methanofullerenes. The cytotoxic activity of macrodiolides and methanofullerenes in relation to Jurkat, K562, U937, HL60 tumor cell lines and normal fibroblasts was studied. Covalent binding of macrodiolides to the C60 fullerene molecule was found to significantly increase the cytotoxic effect (from 5 to 170 times) of the hybrid molecule as compared to the initial macrodiolide. Moreover, the synthesized hybrid molecules initiate apoptosis by uncoupling oxidation and phosphorylation of the mitochondrial membrane of tumor cells.

A New Prenylated Flavanonol from the Roots of Sophora flavescens

A new prenylated flavanonol, (2R,3R)-8-isopentenyl-5-methoxy-7,2′,4′-trihydroxyflavanonol (1) was isolated from the roots of Sophora flavescens. The structure was elucidated on the basis of spectroscopic data. Compound 1 exhibited moderate inhibition towards HeLa, HepG2, and HL-60 tumor cell lines at 14.3, 19.2, 31.5 μg/mL, respectively.

Phytochemical profile of Anacardium occidentale L. (cashew tree) and the cytotoxic and toxicological evaluation of its bark and leaf extracts

Anacardium occidentale (Anacardiaceae), popularly known as cashews, is a vegetable native to South America, consumed worldwide in the food sector. Its leaves and bark are used in the preparation of teas for health maintenance, being indicated in ethnobotanical studies for the treatment of cancer, which is considered a serious public health problem worldwide. The objective of this study was to evaluate the cytotoxicity of the A. occidentale leaf and bark extracts over tumor and normal cells, as well as their in vivo toxicity using the Drosophila melanogaster fruit fly. Cytotoxicity was evaluated using the MTT method [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol bromide] in five cell lines (HL-60, NCI-H292, HCT-116, P815 and L929). Toxicity was evaluated by fly mortality rate and negative geotaxis, as well as by oxidative stress markers (Fe2+ quantification, protein and non-protein thiols) in the D. melanogaster model. The chromatographic study was performed by UPLC-QTOF/MS. As a result, 11 compounds present in the A. occidentale leaf extract (LEAo) and 6 compounds in the bark extract (BEAo) were identified, with gallic acid and galloyl hexoside being present in both samples. The bark extract presented a greater cytotoxic activity for HCT-116, HL60 and P815 tumor cells. The extracts also presented a low cytotoxicity with the normal cell line, L929. No changes in the levels of protein and non-protein thiols (NPSH) were observed, whereas a considerable increase in Fe2+ levels was observed in the Fe2+ quantification assays from homogenized flies exposed to the leaf extract in the D. melanogaster assays. However, further in-depth studies need to be carried out to elucidate the mechanisms of action of the extracts and to assess their pharmacological safety.