The Effects of Combination Treatment Using Phenoxodiol and Docetaxel, and Phenoxodiol and Secreted Frizzled-related Protein 4 on Prostate Cancer Cell Lines

Although much progress has been made for the treatment of prostate cancer, patients with advanced prostate cancer still have a poor 5 year survival rate. Current practices for hormone-refractory/castrate resistant, metastatic prostate cancer involve the use of taxanes. Docetaxel, in particular, is being incorporated in numerous current clinical trials either as a single or combination agent against androgen-independent prostate cancer. Combination therapies have the potential to increase the effectiveness of drug treatments while simultaneously increasing quality of life by reducing side effects, lowering effective dosage rates, or by increasing effectiveness of one compound once combined with another. Using three diverse human prostate cancer cell lines, LNCap, DU145, and PC3, we studied the effect of the novel prostate cancer drug phenoxodiol in combination with docetaxel by utilizing isobolograms, and found that docetaxelinduced cell death was attenuated by co-treatment or pre-treatment of cells with phenoxodiol. This attenuation is associated with the prevention of cells from entering the G2/M phase of the cell cycle where docetaxel is functional in damaging the spindle fibers, and potentially due to p21WAF1 mediated cell survival after docetaxel treatment.We also investigated the use of the Wnt signaling pathway antagonist secreted frizzled-related protein 4 (sFRP4) to increase the effectiveness of phenoxodiol treatment. We found that, through stabilization of the GSK3β molecule, sFRP4 induces degradation of active β-catenin, which causes an increased sensitivity to isoflavone cytotoxic induction by increasing p21WAF1 expression and decreasing expression of c-Myc, Cyclin-D1, and other potent oncogenes. Phenoxodiol induces significant cytotoxicity when combined with a Wnt/β-catenin receptor blocker such as sFRP4. This promotes the concept that combination therapy of a Wnt inhibitor with phenoxodiol might increase the effectiveness of phenoxodiol and give a subset population of prostate cancer sufferers a more effective treatment regime

The Role of Secreted Frizzled Related Protein 4 (sFRP-4) in Regulating Oestradiol-Induced Growth of the MCF-7 Breast Cancer Cell Line

The Wnt signalling pathway is involved in regulating cellular proliferation and differentiation, and aberrant activation has been described in several cancers including breast. Oestradiol up regulates Wnt pathway gene expression, and thereby activates the Wnt signalling pathway. We used the oestrogen-responsive breast cancer cell line MCF-7 to examine the effects of secreted frizzled related protein 4 (sFRP-4) on oestradiol-induced growth, including gene expression of the Wnt signalling pathway genes Frizzled Receptor, Wnt-10b, and β-catenin. We demonstrate here that sFRP-4 inhibits oestradiol-induced cell growth in the MCF-7 cell line and also down regulates oestradiol-induced expression of selected Wnt signalling genes including β-catenin. We propose that sFRP-4 is a potent inhibitor of the Wnt signalling pathway and may negatively regulate oestradiol-mediated proliferation in human breast cancer cells

Pharmacological utilization of bergamottin, derived from grapefruits, in cancer prevention and therapy

In spite of significant advances in treatment options and the advent of novel targeted therapies, there still remains an unmet need for the identification of novel pharmacological agents for cancer therapy. This has led to several studies evaluating the possible application of natural agents found in vegetables, fruits, or plant-derived products that may be useful for cancer treatment. Bergamottin is a furanocoumarin derived from grapefruits and is also a well-known cytochrome P450 inhibitor. Recent studies have demonstrated potent anti-oxidative, anti-inflammatory, and anti-cancer properties of grapefruit furanocoumarin both in vitro and in vivo. The present review focuses on the potential anti-neoplastic effects of bergamottin in different tumor models and briefly describes the molecular targets affected by this agent

Secreted Frizzled-Related Protein 4 expression is positively associated with responsiveness to Cisplatin of ovarian cancer cell lines in vitro and with lower tumour grade in mucinous ovarian cancers

Ovarian cancer is one of the most lethal malignancies in women, as it is frequently detected at an advanced stage, and cancers often become refractory to chemotherapy. Evidence suggests that dysregulation of pro-apoptotic genes plays a key role in the onset of chemoresistance. The secreted Frizzled-Related Protein (sFRP) family is pro-apoptotic and also a negative modulator of the Wnt signalling cascade. Studies have demonstrated that the re-expression of sFRPs, in particular sFRP4, is associated with a better prognosis, and that experimentally induced expression results in cell death

The expression of tumor necrosis factor-alpha, its receptors and steroidogenic acute regulatory protein during corpus luteum regression

Background: Corpus luteum (CL) regression is known to occur as two parts; functional regression when steroidogenesis declines and structural regression when apoptosis is induced. Previous studies suggest this process occurs by the production of luteolytic factors, such as tumour necrosis factor-alpha (TNF-alpha). Methods: We examined TNF-alpha, TNF-alpha receptors (TNFR1 and 2) and steroidogenic acute regulatory (StAR) protein expression during CL regression in albino Wistar rats. CL from Days 16 and 22 of pregnancy and Day 3 post-partum were examined, in addition CL from Day 16 of pregnancy were cultured in vitro to induce apoptosis. mRNA was quantitated by kinetic RT-PCR and protein expression examined by immunohistochemistry and Western blot analyses. Results: TNF-alpha mRNA increased on Day 3 post-partum. TNFR were immunolocalized to luteal cells, and an increase in TNFR2 mRNA observed on Day 3 post-partum whilst no change was detected in TNFR1 mRNA relative to Day 16. StAR protein decreased on Day 3 post-partum and following trophic withdrawal but no change was observed following exogenous TNF-alpha treatment. StAR mRNA decreased on Day 3 post-partum; however, it increased following trophic withdrawal and TNF-alpha treatment in vitro. Conclusion: These results demonstrate the existence of TNFR1 and TNFR2 in rat CL and suggest the involvement of TNF-alpha in rat CL regression following parturition. Furthermore, decreased StAR expression over the same time points was consistent with the functional regression of the CL. © 2008 Abdo et al; licensee BioMed Central Ltd

Physiological differences between twin and single-born lambs and kids during the first month of life

Abstract. The effects of time after birth and of twinning on rectal temperature (RT), heart rate (HR), respiratory rate (RR) and body weight (BW) values were evaluated in five singleton Comisana lambs (three males and two females), five singleton Maltese Kids (three males and two females), four couples of twin Comisana lambs (four males and four females) and four couples of twin Maltese kids (four males and four females) during the first month of life. For all kids and lambs, RT, HR, RR and BW were recorded after 1 and 24 h from birth and every 2 days until the 30th day of life. The application of two-way repeated measures analysis of variance (ANOVA) showed a statistically significant effect of time (P  0.05) on all studied parameters was found in lambs, whereas statistically significant differences in BW, RT and HR values (P < 0.01) were found between twin and singleton kids throughout the first month of life. The results obtained in this study make a contribution to the knowledge of homeostatic, cardiorespiratory and thermoregulatory adaptations occurring in singleton lambs and kids and in twin lambs and kids during the first 30 days of life. Our findings indicate that the BW, RT, HR and RR values, whose homeostasis is still evolving in newborn, should be interpreted dynamically as a function of the period of postnatal adaptation and also of twinning

Increase in erythrocyte osmotic resistance following polyunsaturated fatty acids (PUFA) supplementation in show jumper horses

Osmotic fragility test has been used to study the influence of different factors on the osmotic properties of cell membranes. Considering the importance of polyunsaturated fatty acids (PUFA) in biological functions we aimed to investigate the effects of dietary PUFA supplementation on erythrocyte osmotic fragility (EOF), blood lactate (BL), hematocrit (Hct), red blood cell (RBC), hemoglobin (Hb), and mean cell volume (MCV) in 10 jumper horses. Two events occurred prior to start supplementing horse's diet and two events occurred after 4 weeks PUFA supplementation. Five horses received the PUFA supplementation (Group A), and five served as controls (Group B). Blood samples were taken before and after each course. The statistical analysis revealed significant increase in BL, Hct, RBC and Hb following exercise (P<0.0001). However, the interaction between exercise and PUFA supplementation (P=0.0083) showed PUFA-supplemented horses having a smaller rise in BL levels (P=0.0107) following exercise. Significant interactions between exercise and PUFA treatment were also found on EOF levels (P<0.05). The hemolysis curves showed PUFA-supplemented horses exhibiting a reduction in EOF compared to controls (P<0.05). Although hemolysis never occurred at 0.9% NaCl concentration, jumping exercise determined an increase in EOF (P=0.0014) at 0.8% NaCl solution. A significant interaction between exercise and PUFA treatment (P=0.0022) was found showing PUFA-supplemented horses having lower EOF (P=0.0015) following exercise. The assessment of EOF is a suitable indicator of athletic performance. The results showed that PUFA supplementation might exert beneficial effects on the horse body system by enhancing the performance in high-level show jumpers

Molecular targets modulated by fangchinoline in tumor cells and preclinical models

© 2018 MDPI AG. All rights reserved. Despite tremendous progress made during the last few decades in the treatment options for cancer, compounds isolated from Mother Nature remain the mainstay for therapy of various malignancies. Fangchinoline, initially isolated from the dried root of Stephaniae tetrandrine, has been found to exhibit diverse pharmacological effects including significant anticancer activities both in tumor cell lines and selected preclinical models. This alkaloid appears to act by modulating the activation of various important oncogenic molecules involved in tumorigenesis leading to a significant decrease in aberrant proliferation, survival and metastasis of tumor cells. This mini-review briefly describes the potential effects of fangchinoline on important hallmarks of cancer and highlights the molecular targets modulated by this alkaloid in various tumor cell lines and preclinical models

RT-qPCR Expression Profiles of Selected Oncogenic and Oncosuppressor miRNAs in Formalin-Fixed, Paraffin-Embedded Canine Mammary Tumors

MicroRNAs (miRNAs) can act as oncogenes or oncosuppressor genes, and their involvement in nearly all cancer-associated processes makes these small molecules promising diagnostic and prognostic biomarkers in cancer, as well as specific targets for cancer therapy. This study aimed to investigate the expression of 7 miRNAs (miR-18a, miR-18b, miR-22, miR-124, miR-145, miR-21, miR-146b) in formalin-fixed, paraffin-embedded canine mammary tumors (CMTs) by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Twenty-six mammary samples were selected, including 22 CMTs (7 benign; 15 malignant) and 4 control samples (3 normal mammary gland and 1 case of lobular hyperplasia). Oncogenic miR-18a, miR-18b and miR-21 were significantly upregulated in malignant tumors compared with control tissues (p &lt; 0.05). Conversely, oncosuppressor miR-146b was significantly downregulated in benign and malignant mammary tumors compared with control samples (p &lt; 0.05) while, no group-related differences in the expression levels of miR-22, miR-124 and miR-145 were found (p &gt; 0.05). Upregulated miRNAs found here, may regulate genes involved in receptor-mediated carcinogenesis and proteoglycan remodeling in cancer; while miRNA with reduced expression can regulate genes involved in Toll-like receptor and MAPK signaling pathways. According to the results obtained in the current study, the oncogenic and oncosuppressor miRNAs analyzed here are dysregulated in CMTs and the dysregulation of miRNA targets may lead to specific altered cellular processes and key pathways involved in carcinogenesis. Of note, since oncogenic miRNAs predicted to regulate neoplastic cell proliferation and hormonal activities, they may play an active role in neoplastic transformation and/or progression, having mechanistic and prognostic relevance in CMTs

The role of signal transducer and activator of transcription 3 (STAT3) and its targeted inhibition in hematological malignancies

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Signal transducer and activator of transcription 3 (STAT3), a member of the STAT protein family, can be phosphorylated by receptor-associated Janus kinases (JAKs) in response to stimulation by cytokines and growth factors. It forms homo-or heterodimers that can translocate to the cell nucleus where they act as transcription activators. Constitutive activation of STAT3 has been found to be associated with initiation and progression of various cancers. It can exert proliferative as well as anti-apoptotic effects. This review focuses on the role of STAT3 in pathogenesis i.e., proliferation, differentiation, migration, and apoptosis of hematological malignancies viz. leukemia, lymphoma and myeloma, and briefly highlights the potential therapeutic approaches developed against STAT3 activation pathway