Cytotoxic Activity of Peripheral Blood Mononuclear Leukocytes, Activated by Interleukin-2/β-Cyclodextrin Nanocomposition against Androgen Receptor-Negative Prostate Cancers

Nanocomposition comprised of interleukin-2 in suboptimal noneffective concentration and β-cyclodextrin was studied in vitro. This preparation as well as interleukin-2 in optimal concentration was shown to increase natural killer activity to K-562 cells and cytotoxicity of activated peripheral blood mononuclear cells (PBMCs) against PC-3 and DU 145 cells. At the same time β-cyclodextrin or interleukin-2 in equimolar concentrations did not influence the spontaneous killer activity of PBMC. This combination of cyclodextrin + interleukin-2 led to the decrease of interleukin-2 effective concentration by an order. This phenomenon could be explained by cyclodextrins ability to promote the formation of nanoparticles with drugs, which results in enhancing their water solubility and bioavailability. Besides, interleukine-2/β-cyclodextrin nanocomposition as opposed to interleukin-2 alone led to increasing the number of not only lymphocytes, but also macrophages contained in activated PBMC population. Application of low concentration of interleukin-2 allowing for good clinical efficiency may significantly mitigate the side effects of the drug and enable to develop adoption of immunotherapy for patients with androgen-resistant prostate cancer

hypoxia immunity metabolism and hyperthermia

Hypoxia is common in solid tumors and in many other disease states such as myocardial infarction, stroke, bone fracture, and pneumonitis. Once hypoxia has developed, the undernourished and hypoxic cells trigger signals in order to obtain new blood vessels to satisfy their increasing demands and to resolve hypoxia. The principal signal activated is an ancestral oxygen sensor, the hypoxia inducible factor (HIF). After its nuclear translocation, HIF triggers a series of mediators that recruit, into the hypoxic milieu, several immature myeloid, mesenchymal, and endothelial progenitors cells. Resident and recruited cells participate in the processes of neoangiogenesis, for resolving the hypoxia, while at the same time trigger an inflammatory reaction. The inflammatory reaction has as primary end point, the repair of the damaged area, but if an insufficient production of resolvins is produced, the inflammatory reaction becomes chronic and is unable to repair the damaged tissue. In this brief overview, we will show the differences and the similar events present in cancer, myocardial infarction, and stroke. Furthermore, the metabolic alterations produced in the tumor by hypoxia/HIF axis and the consequences on hyperthermic treatment are also discussed

Trans-, cis-, and dihydro-resveratrol: a comparative study

BACKGROUND: Recent studies showed that moderate consumption of red or white wines increased the chances of breast cancer, while similar consumption of red wines, rich in trans-resveratrol (trans-R), decreased the rate of prostate cancer. This prompted us to explore the role of various forms of R in cancer proliferation. RESULTS: Trans-R was found to be the most potent antiproliferative agent. Cis-R demonstrated somewhat less potency compared to trans-R. Unlike cis-R and trans-R, dihydro-R exhibits moderate proliferative effect on androgen-independent prostate cancer cell lines PC-3 and DU-145 at picomolar concentrations. At higher concentrations, dihydro-R caused proliferation inhibition, similar to cis-R and trans-R. The proliferative effect of dihydro-R at low concentrations can be reversed by trans-R which acts as a partial antagonist in the presence of dihydro-R. Mixtures of dihydro-R and trans-R demonstrated complex non-monotonic cross-modulation activity patterns. CONCLUSIONS: Dihydro-R exhibits proliferative effects in androgen-independent prostate cancer cells at picomolar and nanomolar concentrations. While the exact mechanism of these effects requires further evaluation, our preliminary results point to hormone receptor modulation activity. We also observed strong cross modulation between trans-R and dihydro-R at sub-picomolar concentrations. The role of dihydro-R in cancer proliferation related to moderate consumption of red wine remains an open question because dihydro-R has a very complex activity pattern in the presence of trans-R

Influence of Flavonoids on the Cytotoxic Activity of Mononuclear Blood Cells in Model Tests

BACKGROUND: The spread of phytocomplex application and justification of its selective effects on tumour cells (mainly due to the presence of flavonoids) require research of its cytotoxic and immunomodulatory activity. AIM: The goal was to study the direct cytotoxic effect of the phytocomplex and its modulating effect on the cytotoxic activity of the donor's mononuclear blood cells in in vitro experiments. METHODS: The phytocomplex was a dry extract from marsh cinquefoil, creeping alfalfa and common hop; its main active ingredients were flavonoids. Transplantable monolayer cultures of lung adenocarcinoma, colorectal cancer, erythroblastic leukaemia, and fibroblasts were used as target cells. The cytotoxic activity was assessed using a cytotoxic test based on the selective ability to live cells to reduce MTT (3-[4, 5-dimethyltriazol-2-yl]-2, 5 diphenyltetrazolium bromide) to formazan in mitochondria. Quantitative determination of formazan was performed using spectrophotometry. RESULTS: A direct cytotoxic effect of the phytocomplex in concentrations of at least 2.5 mg/ml on tumour cells has been established. Its modulating effect on the cytotoxic activity of mononuclear blood cells at a concentration of 0.05 mg/ml was shown. The phytocomplex in doses of 0.25 and 0.5 mg/ml increased the killer activity of the mononuclear cells in a diseased person's blood, but did not affect these blood cells in a healthy donor. Incubation of lymphocytes with a phytocomplex for 24 hours increased the cytotoxic activity of mononuclear cells by 20-25%. CONCLUSION: The direct cytotoxic effect of the phytocomplex and its modulating effect on the cytotoxic activity of mononuclear blood cells in model experiments in vitro have been established

Hypoxia Immunity, Metabolism, and Hyperthermia

Hypoxia is common in solid tumors and in many other disease states such as myocardial infarction, stroke, bone fracture, and pneumonitis. Once hypoxia has developed, the undernourished and hypoxic cells trigger signals in order to obtain new blood vessels to satisfy their increasing demands and to resolve hypoxia. The principal signal activated is an ancestral oxygen sensor, the hypoxia inducible factor (HIF). After its nuclear translocation, HIF triggers a series of mediators that recruit, into the hypoxic milieu, several immature myeloid, mesenchymal, and endothelial progenitors cells. Resident and recruited cells participate in the processes of neoangiogenesis, for resolving the hypoxia, while at the same time trigger an inflammatory reaction. The inflammatory reaction has as primary end point, the repair of the damaged area, but if an insufficient production of resolvins is produced, the inflammatory reaction becomes chronic and is unable to repair the damaged tissue. In this brief overview, we will show the differences and the similar events present in cancer, myocardial infarction, and stroke. Furthermore, the metabolic alterations produced in the tumor by hypoxia/HIF axis and the consequences on hyperthermic treatment are also discussed

<it>Trans</it>-, <it>cis</it>-, and <it>dihydro</it>-resveratrol: a comparative study

Abstract Background Recent studies showed that moderate consumption of red or white wines increased the chances of breast cancer, while similar consumption of red wines, rich in trans-resveratrol (trans-R), decreased the rate of prostate cancer. This prompted us to explore the role of various forms of R in cancer proliferation. Results Trans-R was found to be the most potent antiproliferative agent. Cis-R demonstrated somewhat less potency compared to trans-R. Unlike cis-R and trans-R, dihydro-R exhibits moderate proliferative effect on androgen-independent prostate cancer cell lines PC-3 and DU-145 at picomolar concentrations. At higher concentrations, dihydro-R caused proliferation inhibition, similar to cis-R and trans-R. The proliferative effect of dihydro-R at low concentrations can be reversed by trans-R which acts as a partial antagonist in the presence of dihydro-R. Mixtures of dihydro-R and trans-R demonstrated complex non-monotonic cross-modulation activity patterns. Conclusions Dihydro-R exhibits proliferative effects in androgen-independent prostate cancer cells at picomolar and nanomolar concentrations. While the exact mechanism of these effects requires further evaluation, our preliminary results point to hormone receptor modulation activity. We also observed strong cross modulation between trans-R and dihydro-R at sub-picomolar concentrations. The role of dihydro-R in cancer proliferation related to moderate consumption of red wine remains an open question because dihydro-R has a very complex activity pattern in the presence of trans-R.</p