Modulation of proteasome activity by curcumin and didemethylcurcumin.

Modulation of proteasome function by pharmacological interventions and molecular biology tools is an active area of research in cancer biology and neurodegenerative diseases. Curcumin (diferuloylmethane) is a naturally occurring polyphenol that affects multiple signaling pathways. Curcumin shows anti-inflammatory, antioxidant, anti-angiogenic, or anti-apoptotic properties. Recent research suggests that the therapeutic efficacy of curcumin may be due to its activity as a potent inhibitor of the proteasome. Using in vitro cell culture and molecular docking methods, here we show that both curcumin and its synthetic polyphenolic derivative (didemethylcurcumin, CUIII) modulated proteasome activity in a biphasic manner. Curcumin and CUIII increased proteasome activity at nanomolar concentrations, but inhibited proteasome activity at micromolar concentrations. Curcumin was more effective than CUIII in increasing relative proteasome activity at nanomolar concentrations. Also, curcumin was more effective than CUIII in inhibiting relative proteasome activity at micromolar concentrations. Docking simulations of curcumin and didemethylcurcumin binding to the 20S proteasome catalytic subunit estimated Kd values of 0.0054 µM and 1.3167 µM, respectively. These values correlate well with the results of the effectiveness of modulation by curcumin compared to CUIII. The small size of CUIII allows it to dock to the narrow cavity of the active site, but the binding interaction is not strong compared to curcumin. These results indicate that curcumin and its didemethyl derivative can be used to modulate proteasome activity and suggest that curcumin and its didemethyl derivative may be useful in treating two different disease classes: neurodegeneration and cancer.Communicated by Ramaswamy H. Sarma.

Unprecedented anticancer activities of organorhenium sulfonato and carboxylato complexes against hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells.

Cisplatin and other metal-based drugs often display side effects and tumor resistance after prolonged use. Because rhenium-based anticancer complexes are often less toxic, a novel series of organorhenium complexes were synthesized of the types: XRe(CO)3Z (X = α-diimines and Z = p-toluenesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, picolinate, nicotinate, aspirinate, naproxenate, flufenamate, ibuprofenate, mefenamate, tolfenamate, N-acetyl-tryptophanate), and their biological properties were examined. Specifically, in hormone-dependent MCF-7 and hormone-independent triple-negative MDA-MB-231 breast cancer cells, the p-toluenesulfonato, 1-naphthalenesulfonato, 2-naphthalenesulfonato, picolinato, nicotinato, acetylsalicylato, flufenamato, ibuprofenato, mefenamato, and N-acetyl-tryptophanato complexes were found to be far more potent than conventional drug cisplatin. DNA-binding studies were performed in each case via UV-Vis titrations, cyclic voltammetry, gel electrophoresis, and viscosity, which suggest DNA partial intercalation interaction, and the structure-activity relationship studies suggest that the anticancer activities increase with the increasing lipophilicities of the compounds, roughly consistent with their DNA-binding activities.

DNA-binding and cytotoxic efficacy studies of organorhenium pentylcarbonate compounds.

Seven organorhenium pentylcarbonate compounds (PC1-PC7) have been synthesized. DNA-binding studies of the PC-series compounds using electronic spectroscopy and gel electrophoresis suggest that the compounds presumably bind to DNA in an intercalative mode. The intrinsic binding constants for PC4, PC6, and PC7 were found to be 1.6 × 10(4), 3.9 × 10(4), and 4.2 × 10(4) M(-1), respectively. The X-ray structure determinations and density functional theory calculations indicate that the polypyridyl ligands in the compounds are nearly planar facilitating DNA binding through an intercalation mechanism. Cytotoxicity studies of 10 µM pentylcarbonate compounds against HTB-12 human astrocytoma brain cancer cells were studied for 48 h. It was observed that each of the pentylcarbonate compounds is active against the cancer cells. However, under analogous conditions, CRL-2005 rat astrocyte normal brain cells are not affected significantly.

Mathematical models for Enterococcus faecalis recovery after microwave water disinfection.

Microwave water disinfection is a rapid purification technique which can give billions of people access to clean drinking water. However, better understanding of bacterial recovery after microwave heating over time is necessary to determine parameters such as delayed bacterial growth rates and maximum bacterial yields. Mathematical models for Enterococcus faecalis recovery after microwave treatment in optimum growth conditions were developed for times up to 5 minutes using an optical absorbance method. Microwave times below 3 minutes (2,450 MHz, 130W) showed that bacterial recovery maintained a time-dependent sigmoidal form which included a maximum value. At microwave times greater than three minutes, bacterial recovery, with a time-dependent exponential form, significantly decreased and did not reach the maximum value within the interval of observance (0-8 hours). No bacterial growth was found after 6 minutes of microwave treatment. The prepared mathematical models were produced by transforming the given variables to the logistic or exponential functions. We found that time-dependent maximum growth rates and lag times could be approximated with second order polynomial functions. The determined models can be used as a template to illustrate bacterial survival during water purification using microwave irradiation, in both commercial and industrial processes.

A novel series of potent cytotoxic agents targeting G2/M phase of the cell cycle and demonstrating cell killing by apoptosis in human breast cancer cells.

Breast cancer, a leading cause of mortality in women, warrants the development and biological evaluation of new anticancer agents. A novel series of thiopyridine triazine derivatives was synthesized and investigated in the human breast cancer cell line, MDA-MB-468. SM40, the most potent derivative, induced a G2/M arrest and apoptosis with a possible involvement of p53. The cytotoxicity of SM40 was also examined against the NCI 60 cell line panel and its potency was rationalized using molecular modeling. Results suggest that SM40 is a promising cytotoxic agent.

A new platinum complex of triazine demonstrates G1 arrest with novel biological profile in human breast cancer cell line, MDA-MB-468.

A novel class of platinum(II) complexes of pyridine sulfide derivatives of triazine was synthesized, characterized, and investigated using the human breast cancer cell line, MDA-MB-468. S-30 was one of the most potent derivatives of its class (IC(50), 0.39 microM) eliciting the greatest biological response. S-30 induced arrest in the G1 phase and apoptosis (TUNEL assay) in a p53/p21(WAF1/CIP1)-consistent manner. Modeling and docking experiments were performed for three known targets for cisplatin, d(GpG), d(ApG), and a protein (Cu/Zn superoxide dismutase, SOD) from bovine origin. A Blast search of bovine SOD was performed to identify analogous human protein targets resulting in about 22 human proteins. A multi-sequence alignment of those targets showed >80% sequence identity and >88% similarity. One of them is SOD1 that is differentially expressed (based on global gene expression pattern) in various forms of cancer and other diseases. SOD1 controls apoptosis via p53/BAD/BAX/BCL2 in the amyotrophic lateral sclerosis (ALS) pathway and is also involved in various other KEGG's pathways. Results suggest that the S-30 is a potential cytotoxic agent.

Effects of oxalate on HK-2 cells, a line of proximal tubular epithelial cells from normal human kidney.

PURPOSE: Oxalate, a metabolic end product, is a major constituent of majority of renal stones. Previous studies with LLC-PK1 cells, a line of proximal renal epithelial cells of porcine origin, have shown that oxalate produces time and concentration dependent effects on the growth and viability of these cells. We assessed the possibility that oxalate may be toxic to HK-2 cells, a line of human proximal renal epithelial cells. MATERIALS AND METHODS: HK-2 cells were maintained in Dulbecco's modified Eagle's medium supplemented with fetal bovine serum and antibiotics. Cells were exposed to oxalate for various intervals. Trypan blue exclusion criteria were used to assess membrane integrity, cell morphology was assessed by hematoxylin and eosin staining and crystal violet staining was used to measure cell density. DNA synthesis was measured by [3H]-thymidine incorporation and superoxide production was measured by the nitroblue tetrazolium reduction method. RESULTS: Exposure of HK-2 cells to oxalate produced time and concentration dependent increase in the membrane permeability to trypan blue and changes in the light microscopic appearance of the cells. Long-term exposure to oxalate resulted in an increase in DNA synthesis and alterations in cell viability with net cell loss after exposure to high oxalate concentrations. CONCLUSIONS: To our knowledge the results provide the first direct demonstration of the toxic effects of oxalate in HK-2 cells, a line of human renal epithelial cells, and suggest that hyperoxaluria may contribute to renal tubular damage associated with calcium oxalate stone disease.