Resveratrol chemosensitizes HER-2-overexpressing breast cancer cells to docetaxel chemoresistance by inhibiting docetaxel-mediated activation of HER-2-Akt axis.

As breast cancer cells often develop chemoresistance, better therapeutic options are in search to circumvent it. Here we demonstrate that human epidermal growth factor receptor-2 (HER-2)-overexpressing breast cancer cells resist docetaxel-induced cytotoxicity by upregulating HER-2 and its activity downstream, through Akt and mitogen-activated protein kinase (MAPK) pathways. We observed that introducing resveratrol as a chemosensitizer in docetaxel chemotherapy blocks upregulation and activation of HER-2 in addition to blocking downstream signaling pathways such as Akt. Resveratrol and docetaxel combination results in the synergistic induction of cell death in HER-2-overexpressing SK-BR-3 cells, whereas introduction of wild-type HER-2 in MDA-MD-231 cells increased the resistance to docetaxel. Dominant-negative HER-2 sensitizes SK-BR-3 cells to docetaxel. Our study identified a new synergistic therapeutic combination that targets HER-2-induced breast cancer resistance and might help to overcome therapeutic resistance during breast cancer therapy. The synergism of docetaxel and resveratrol was maximum in SK-BR-3, which is unique among the cell lines studied, due to its high expression status of HER-2, a receptor known to dictate the signaling environment of breast cancer cells. Docetaxel could further induce HER-2 activity in these cells, which was downregulated on resveratrol treatment. Transfection of DN-HER-2 in SK-BR-3 cells inhibits the synergism as the transfection itself sensitizes these cells to docetaxel, leaving no role for resveratrol, whereas ectopic expression of HER-2 introduces the synergism in MDA-MB-231, the triple-negative cell line, in which the synergism was minimum, attesting the crucial role of HER-2 in suppressing the sensitivity to docetaxel. Single-agent docetaxel induced HER-2-mediated resistance to cell death, which was blocked by resveratrol. Resveratrol also downregulated docetaxel-induced activation of MAPK and Akt, survival signaling pathways downstream of HER-2. In short, this study, for the first time, establishes the role of HER-2-Akt signaling axis in regulating the synergistic effect of docetaxel and resveratrol in breast cancer cells overexpressing HER-2.

Diclofenac sodium loaded gelatin magnetic microspheres for intra-arterial administration: formulation, characterization and in vitro release studies.

Gelatin magnetic microspheres loaded with diclofenac sodium were prepared by emulsification and crosslinking by glutaraldehyde. The microspheres were formulated with 23-30% theoretical diclofenac sodium and magnetite content. The formulated microspheres were characterized by drug loading, entrapment efficiency, encapsulation efficiency, magnetite content, FT-IR spectroscopy, particle size analysis, optical microscopy, scanning electron microscopy, and in vitro release studies. The data obtained from the in vitro release studies were applied to various kinetic models. The FT-IR revealed no drug/polymer interaction. The average particle size was between 36 to 61 microm depending on quantity of magnetite and gelatin used. Optical microscopy and SEM showed spherical and compact nature of microspheres. The formulated microspheres released the drug for a period of 42 to 78 hours depending on drug loading. The release was diffusion controlled at lower drug loading and dissolution/diffusion controlled at higher drug loading.

Retarding fluoride accumulation in Amaranthes viridis through liming and implications of phosphorous treatment.

With an objective to retard fluoride being taken up by the plants from soil, a study was carried out on Amaranthes viridis. Four groups of treatment were carried out vis-à-vis fluoride alone, fluoride and calcium, fluoride and phosphorous and fluoride, calcium and phosphorous together at three different concentration levels vis-à-vis 1, 10 and 25 mg/kg soil of each. Sampling was carried out first on day 45 and at the end of reproductive phase on leaf and seed for accumulation of fluoride in the plants. It was observed that fluoride accumulation in plants could be averted through soil amendment by calcium treatment in the form of calcium carbonate thereby reducing the risk of human and livestock exposure to abnormal levels of fluoride through food chain other than protecting plants from getting affected. At the same time, fertilizing the soil contaminated with fluoride by superphosphate would aggravate fluoride accumulation and exacerbate fluorosis problem in human and livestock through food chain. Therefore it is recommended to use acid water-soluble orthophosphate or anhydrous dicalcium phosphate or soluble pyrophosphate fertilizers as an alternative.

Low levels of p53 mutations in Indian patients with osteosarcoma and the correlation with fluoride levels in bone.

The pathogenesis of osteogenic sarcoma is not known. Recently, chronic fluoride exposure has been incriminated as having a possible etiologic role by causing a nonspecific osteoblast proliferation. We were interested in exploring the possible relationship between fluoride bone content and p53 mutations. We analyzed p53 mutations in various exons in tissue of osteosarcoma, and correlated the findings with the bone fluoride levels in Indian patients. We analyzed tissue samples from 20 osteosarcoma patients for possible genetic alterations including mutations, and we assessed the extent of fluoride accumulation in bone. Fragments displaying an altered electrophoretic mobility were confirmed as having mutated sequences. Mutation was observed in samples of two cases (10% incidence). Eighteen samples showed bone fluoride levels between 1000 and 27,000 ppm, whereas the 2 mutated samples showed fluoride levels of 64,000 and 89,000 ppm, respectively. The high levels of bone fluoride levels and the similarity of the mechanisms of action between fluoride-induced DNA damage and chemically-induced p53 mutations lead us to propose that high fluoride bone content might have been one of the major factors causing osteosarcoma.

Acute pulmonary toxicity of acrolein in rats--underlying mechanism.

Acute exposure of rats to acrolein (1 or 2 ppm) resulted in reduced levels of glutathione, ascorbic acid and alpha-tocopherol. The activities of catalase and glutathione peroxidase were reduced whereas an increase in the activities of superoxide dismutase was observed. This led to enhanced lipid peroxidation, which produced extensive lung damage as indicated by the elevated levels of the biochemical markers--angiotensin converting enzyme, lactate dehydrogenase, protein and lactate in the bronchoalveolar lavage.

Effect of subacute dosage of fluoride on male mice.

A sublethal concentration (one-tenth of the LD50) of fluoride (F) (5.2 mg F/kg body weight) was administered to Swiss albino mice (male) daily for 35 days. These mice showed a decrease in body weight gain, and food and water consumption. A significant decrease in red blood cell counts and an increase in white blood cell counts were seen in fluoride-administered mice. These animals also showed a decline in albumin, total protein, cholesterol, glucose and alkaline phosphatase activity in the serum. The fluoride content significantly increased in different organs of these animals. Sperm did not show any abnormalities due to fluoride toxicity.

The effect of fluoride on fertilized eggs of a freshwater fish, Catla catla (Hamilton).

The eggs of Catla catla were exposed to 2 fluoride media, (1) effluent dilutions containing 1.86, 3.21, 7.12, 9.56, and 16.23 ppm fluoride, and (2) fluoride (NaF) solutions containing 1.86, 3.56, 7.34, 10.01, and 16.68 ppm fluoride. The eggs exposed to 1.86 ppm fluoride (in both media) hatched at the end of 6 h, while in rest of the fluoride concentrations hatching was delayed by 1-2 h. The eggs showed decreases in water and protein and increase in fluoride contents. Toxicity of fluoride to eggs was more related to the availability of fluoride ions, than to the total fluoride in the media.