curcumin and hydrazinocurcumin

Hydrazinocurcumin (HZC), a synthetic derivative of curcumin (CUR), has been documented to show anticancer potential in impeding tumor growth in several cancers, including hepatocellular carcinoma (HCC). However, the underlying molecular mechanisms remain unclear. This study aimed to explore the function and underlying mechanisms of HZC on HCC cells, which may involve the p38 mitogen activated protein kinase (MAPK) pathway. HZC was first purified and identified. HepG2 cells were then subjected to treatment with HZC or CUR of different concentrations and p38 MAPK signaling inhibitor (SB203580) to verify their effects on HCC cell apoptosis and proliferation. Furthermore, the functional relevance between HZC and the p38 MAPK pathway in HCC was examined. It was observed that 40 μM HZC exhibited the best pro-apoptosis effect in HCC cells. HZC was found to inhibit HCC cell proliferation and promote apoptosis, the effect of which was stronger than 5-fluorouracil (5-FU). More importantly, the anti-oncogenic effect of HZC and 5-FU was implicated with activation of the p38 MAPK pathway. In vivo experimental results showed that HZC inhibited tumor growth more effectively than 5-FU through the p38 MAPK pathway. These results provide evidence that HZC exerted anti-oncogenic and pro-apoptosis effects in HCC cells through activation of the p38 MAPK pathway.

Topics: Animals; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Hep G2 Cells; Humans; Hydrazines; Imidazoles; Liver Neoplasms; Male; MAP Kinase Signaling System; p38 Mitogen-Activated Protein Kinases; Pyridines; Rats; Toxicity Tests, Subacute; Xenograft Model Antitumor Assays

Curcumin, a natural polyphenol from Curcuma longa, is known to possess diversified pharmacological roles including anti-inflammatory, antioxidant, antiproliferative and antiangiogenic properties; however, its bioavailability is severely limited due to its poor solubility, poor absorption, rapid metabolism, and significant elimination. Hydrazinocurcumin (HZC), a novel analogue of curcumin has been reported to overcome the limitations of curcumin and also possesses multiple pharmacological activities. The present study aimed to evaluate the unexplored pharmacokinetic profile of this agent in experimental rats.. Drug formulations were administered to the experimental animals via oral, intravenous and intraperitoneal routes. Blood samples were collected at different pre-determined time intervals to determine the pharmacokinetic parameters. To understand the biodistribution profile of HCZ, tissue samples were isolated from different groups of Sprague-Dawley rats at different time points. The pharmacokinetic parameters of HZC were evaluated after administration through oral (100 mg/kg), intraperitoneal (100 mg/kg) and intravenous (10 mg/kg) routes.. Significantly (p < 0.05) higher total AUC along with maximum concentration were evident with intraperitoneal administration when compared to the results of oral administration at a similar dose. In addition, shorter time to peak was observed with intraperitoneal administration. These results revealed a faster rate and longer duration of absorption with intraperitoneal administration, which further resulted in enhanced absolute bioavailability of HZC (29.17%) when compared to 5.1% upon oral dosing. The obtained data from the pharmacokinetic study indicated that HZC was instantaneously distributed and moderately eliminated from body fluids.. Based on the findings, it could be concluded that absorption of HZC is much higher via intraperitoneal route of administration compared to the oral administration.

Topics: Administration, Intravenous; Administration, Oral; Animals; Antioxidants; Area Under Curve; Biological Availability; Curcumin; Hydrazines; Injections, Intraperitoneal; Rats; Rats, Sprague-Dawley; Tissue Distribution

Hydrazinocurcumin (HZC), a curcumin analogue, serves as a tumor suppressor in breast cancer and lung cancer. In this study, we investigate the role and mechanism of HZC in regulating HepG2 cell apoptosis and tumorigenicity, and its synergistic effects with 5-fluorouracil (5-Fu). HepG2 cells were treated with HZC and/or 5-Fu to analyze the possible synergistic effects on cell proliferation, apoptosis and cell cycle distribution in vitro using EdU staining, Hoechst staining and flow cytometry, respectively. For mechanistic investigation we used pic, a phosphatase and tensin homolog (PTEN) inhibitor, and in other studies assessed the expression pattern of PTEN and PI3K/Akt signaling pathway-related genes. Additionally, we tested in vivo effects of HZC and 5-Fu treatment on growth of HepG2 cell tumors in nude mice. We found that HZC or 5-Fu induced apoptosis and repressed proliferation of HepG2 cells by upregulating the expression of PTEN and disrupting the PI3K/Akt signaling pathway activation. Moreover, HZC had a higher pro-apoptotic effect than 5-Fu. HZC and 5-Fu induced HepG2 cell apoptosis and inhibited their tumorigenicity in vivo. Inhibition of PTEN expression activated the PI3K/Akt signaling pathway and reversed the protective effects of HZC or 5-Fu. Thus, HZC and 5-Fu increase PTEN, which blocks the PI3K/Akt signaling pathway, ultimately inducing HepG2 cell apoptosis. Importantly, the synergistic combination of HZC and 5-Fu may present promising strategy for the treatment of HCC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Hepatocellular; Cell Proliferation; Curcumin; Drug Synergism; Fluorouracil; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Hydrazines; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Phosphatidylinositol 3-Kinase; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Signal Transduction; Tumor Burden; Xenograft Model Antitumor Assays

Hydrazinocurcumin is a semi-synthetic analogue of curcumin with superior anticancer and anti-angiogenic activities. In the present work a simple and sensitive reverse phase high performance liquid chromatography (RP-HPLC) method for quantitative evaluation of hydrazinocurcumin in plasma and various organs of rats including liver, kidneys, brain, heart, lungs and spleen was developed. Hydrazinocurcumin was separated using octadecylsilane (Inertsil-ODS-3V) column in an isocratic mode using mobile phase consisting of methanol-acetonitrile- water (36:27:37 v/v) with flow rate of 1.0 ml/min. Ultra violet (UV) detection of hydrazinocurcumin and internal standard was carried out in dual-wavelength mode at 332 nm and 380 nm, respectively. The linearity of hydrazinocurcumin was found in the range 0.05-5 µg/ml with a correlation coefficient of r

Topics: Animals; Chromatography, High Pressure Liquid; Curcumin; Hydrazines; Limit of Detection; Linear Models; Male; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Spectrophotometry, Ultraviolet; Tissue Distribution

An efficient metal-free approach for the synthesis of N-coumaryl amino acids and the first one-step synthesis of 4-hydrazinocoumarin from 4-hydroxycoumarin was developed. The nucleophilic addition of amino acid methyl esters to 4-tosylcoumarins produced a series of 4-N-α-coumaryl amino acids in good to excellent yields without racemization. The antioxidant activities of the synthesized compounds were investigated using DPPH and FRAP methods. 4-Hydrazinocoumarin and N-coumaryl tyrosine had the best antioxidant activity. The antimicrobial activities of the compounds against Gram-positive was stronger than Gram-negative. 4-Hydrazinocoumarin showed the best antibacterial effect.

Topics: 4-Hydroxycoumarins; Amino Acids; Anti-Bacterial Agents; Antioxidants; Bacteria; Curcumin; Fluorescence; Hydrazines

Hypoxia enhances immortality and metastatic properties of solid tumors. Deregulation of histone acetylation has been associated with several metastatic cancers but its effect on hypoxic responses of cancer cells is not known. This study aimed at understanding the effectiveness of the hydrazinocurcumin, CTK7A, an inhibitor of p300 lysine/histone acetyltransferase (KAT/HAT) activity, in inducing apoptosis of gastric cancer cells (GCCs) exposed to cobalt chloride (CoCl

Topics: Acetylation; Antineoplastic Agents; Apoptosis; Cell Line, Transformed; Cell Line, Tumor; Cobalt; Curcumin; E1A-Associated p300 Protein; Enzyme Inhibitors; Gastric Mucosa; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Hydrogen Peroxide; MAP Kinase Signaling System; Neoplasm Invasiveness; Oxidative Stress; Reactive Oxygen Species; Solubility; Stomach Neoplasms; Tumor Hypoxia

The purpose of the present study was to evaluate the preventive effects of hydrazinocurcumin (HZC) on diethylnitrosamine (DEN)-induced hepatocarcinogenesis in a male Sprague Dawley (SD) rat model. One hundred and twenty male SD rats used in this study were divided into six groups. Those receiving DEN with curcumin (CUR) or HZC were studied compared with the DEN-alone group. The study demonstrated that DEN induced severe histological and immunohistochemical changes in liver tissues, significantly increasing the levels of liver marker enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT) and total bilirubin level (TBL)). The hepatocarcinoma incidences were 100.0%, 36.7% and 20.0% in the DEN-alone, DEN-CUR and DEN-HZC groups, respectively. Although macroscopic and microscopic features suggested that both CUR and HZC were effective in inhibiting DEN- induced hepatocarcinogenesis, HZC was exerted a stronger influence. Immunohistochemical analysis with PCNA demonstrated significantly differences among the groups (all P < 0.05). Taken together, the results suggested application of CUR and HZC could prevent the occurrence of carcinogenesis and HZC may be a more potent compound for prevention of DEN-induced hepatocarcinogenesis in rats than CUR.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Aspartate Aminotransferases; Carcinogenesis; Carcinoma, Hepatocellular; Curcumin; Diethylnitrosamine; gamma-Glutamyltransferase; Hydrazines; Liver; Liver Function Tests; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Rats; Rats, Sprague-Dawley

Tumor-associated macrophages (TAMs) are essential cellular components within tumor microenvironment (TME). TAMs are educated by TME to transform to M2 polarized population, showing a M2-like phenotype, IL-10(high), IL-12(low), TGF-β(high). STAT3 signaling triggers crosstalk between tumor cells and TAMs, and is crucial for the regulation of malignant progression. In our study, legumain-targeting liposomal nanoparticles (NPs) encapsulating HC were employed to suppress STAT3 activity and "re-educate" TAMs, and to investigate the effects of suppression of tumor progression in vivo. The results showed that TAMs treated by HC encapsuled NPs could switch to M1-like phenotype, IL-10(low), IL-12(high), TGF-β(low), and the "re-educated" macrophages (M1-like macrophages) considerably demonstrated opposite effect of M2-like macrophages, especially the induction of 4T1 cells migration and invasion in vitro, and suppression of tumor growth, angiogenesis and metastasis in vivo. These data indicated that inhibition of STAT3 activity of TAMs by HC-NPs was able to reverse their phenotype and could regulate their crosstalk between tumor cells and TAMs in order to suppress tumor progression.

Topics: Animals; Apoptosis; Blotting, Western; Breast Neoplasms; Cell Cycle; Cell Line; Cell Line, Tumor; Cell Survival; Curcumin; Female; Flow Cytometry; Hydrazines; Macrophages; Mice; Mice, Inbred BALB C; Nanoparticles; STAT3 Transcription Factor

Curcumin, the active component of turmeric, has been shown to protect against carcinogenesis and prevent tumor development in cancer. In our study, we tested the efficacy of a synthetic curcumin analogue, known as hydrazinocurcumin (HC), in breast cancer cells. The results demonstrated that compared to curcumin, HC was more effective in inhibiting STAT3 phosphorylation and downregulation of an array of STAT3 downstream targets which contributed to suppression of cell proliferation, loss of colony formation, depression of cell migration and invasion as well as induction of cell apoptosis. It was concluded that HC is a potent agent in the inhibition of STAT3 with more favorable pharmacological activity than curcumin, and HC may have translational potential as an effective cancer therapeutic or preventive agent for human breast carcinoma.

Topics: Apoptosis; Breast Neoplasms; Cell Adhesion; Cell Cycle Checkpoints; Cell Growth Processes; Cell Line, Tumor; Cell Movement; Cell Survival; Curcumin; Dose-Response Relationship, Drug; Female; Humans; Hydrazines; Phosphorylation; STAT3 Transcription Factor

Altered histone acetylation is associated with several diseases, including cancer. We report here that, unlike in most cancers, histones are found to be highly hyperacetylated in oral squamous cell carcinoma (OSCC; oral cancer) patient samples. Mechanistically, overexpression, as well as enhanced autoacetylation, of p300 induced by nucleophosmin (NPM1) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) causes the hyperacetylation, which is nitric oxide (NO) signal dependent. Inhibition of the histone acetyltransferase (HAT) activity of p300 by a water-soluble, small molecule inhibitor, Hydrazinocurcumin (CTK7A), substantially reduced the xenografted oral tumor growth in mice. These results, therefore, not only establish an epigenetic target for oral cancer, but also implicate a HAT inhibitor (HATi) as a potential therapeutic molecule.

Topics: Acetylation; Animals; Cell Proliferation; Cellular Senescence; Curcumin; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Glyceraldehyde-3-Phosphate Dehydrogenases; HeLa Cells; Histone Acetyltransferases; Histones; Humans; Hydrazines; Mice; Mice, Nude; Mouth Neoplasms; Nitric Oxide; Nuclear Proteins; Nucleophosmin; p300-CBP Transcription Factors; Solubility; Up-Regulation; Water

Hydrazinocurcumin (HZC) is a patented multiactivity compound and is a potent derivative of curcumin which is not yet explored for further development as formulation and requires the determination of biopharmaceutical suitability of the molecule. Intestinal permeability and logP of a compound are two vital biopharmaceutical properties by which, any "hit" molecule proceeds towards NCE (new chemical entity) and govern formulation design of bioactive molecules. In this report, a simple, precise and accurate isocratic reverse phase (RP) liquid chromatography method for simultaneous analysis of HZC and phenol red, for the application in rat in situ single-pass intestinal perfusion (SPIP) was developed and validated using FDA bioanalytical guidelines. RP-HPLC method was developed on C-18 column with UV detection at 332 nm for both the compounds. Isocratic run with the mobile phase consisting of organic phase (methanol:acetonitrile:: 50:20 v/v) and water in the ratio of 80:20 v/v provided a short run time of 7 min with resolution of more then two without interference of blank matrix. The working/expected concentration range for HZC and phenol red were 0.5-50 and 2-200 microg/ml. LOQs for HZC and phenol red of the method was found to be 0.167 and 0.271 microg/ml respectively. The validation parameters indicate that method was suitable for the intended purpose. Permeability, considering water flux with the help of non-permeable marker phenol red was calculated to be 0.34 x 10(-4)cm/s. Along with other descriptors, logP (1.78) and MW (<500) of HZC makes it a potential candidate for oral formulation.

Topics: Animals; Calibration; Chromatography, High Pressure Liquid; Curcumin; Hydrazines; Intestinal Absorption; Male; Phenolsulfonphthalein; Rats; Rats, Wistar; Reference Standards; Reproducibility of Results; Sensitivity and Specificity; Spectrophotometry, Ultraviolet

Hydrazinocurcumin (HC), a synthetic derivative of curcumin, has been reported to inhibit angiogenesis via unknown mechanisms. Understanding the molecular mechanisms of the drug's action is important for the development of improved compounds with better pharmacological properties. A genomewide drug-induced haploinsufficiency screening of fission yeast gene deletion mutants has been applied to identify drug targets of HC. As a first step, the 50% inhibition concentration (IC50) of HC was determined to be 2.2 microM. The initial screening of 4,158 mutants in 384-well plates using robotics was performed at concentrations of 2, 3, and 4 microM. A second screening was performed to detect sensitivity to HC on the plates. The first screening revealed 178 candidates, and the second screening resulted in 13 candidates, following the elimination of 165 false positives. Final filtering of the condition-dependent haploinsufficient genes gave eight target genes. Analysis of the specific targets of HC has shown that they are related to septum formation and the general transcription processes, which may be related to histone acetyl transferase. The target mutants showed 65% growth inhibition in response to HC compared with wild-type controls, as shown by liquid culture assay.

Topics: Curcumin; Drug Evaluation, Preclinical; Gene Deletion; Genome, Fungal; Haploidy; Heterozygote; Hydrazines; Inhibitory Concentration 50; Schizosaccharomyces; Schizosaccharomyces pombe Proteins

Curcumin and some of its derivatives were known as in vivo inhibitors of angiogenesis. In present study, a novel curcumin derivative, named hydrazinocurcumin (HC) was synthesized and examined for its biological activities. HC potently inhibited the proliferation of bovine aortic endothelial cells (BAECs) at a nanomolar concentration (IC(50)=520 nM) without cytotoxicity. In vivo and in vitro angiogenesis experiments showed HC as a new candidate for anti-angiogenic agent.

Topics: Angiogenesis Inhibitors; Animals; Cattle; Cell Division; Chick Embryo; Curcumin; Dose-Response Relationship, Drug; Endothelium, Vascular; Hydrazines; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Molecular Structure; Neovascularization, Physiologic

Curcumin and some of its derivatives were known as in vivo inhibitors of angiogenesis. In present study, a novel curcumin derivative, named hydrazinocurcumin (HC) was synthesized and examined for its biological activities. HC potently inhibited the proliferation of bovine aortic endothelial cells (BAECs) at a nanomolar concentration (IC(50)=520 nM) without cytotoxicity. In vivo and in vitro angiogenesis experiments showed HC as a new candidate for anti-angiogenic agent.

Topics: Angiogenesis Inhibitors; Animals; Cattle; Cell Division; Chick Embryo; Curcumin; Dose-Response Relationship, Drug; Endothelium, Vascular; Hydrazines; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Molecular Structure; Neovascularization, Physiologic