published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Physiology / Doctoral / Doctor of Philosophy

published_or_final_version / Physiology / Master / Master of Philosophy

Parthenolide (PN), a major active component of the traditional herbal medicine feverfew, has been shown to have anti-inflammatory and anti-tumor properties. More remarkably, the cytotoxicity of PN seems selective to tumor cells but not their normal cell counterparts. In the present study, we investigate whether and how PN selectively enhances tumor sensitivity to radiation therapy by using prostate cancer cells LNCaP, DU145 and PC3, as well as normal prostate epithelial cells PrEC. Our study demonstrates that inhibition of NF-κB pathway and suppression of its downstream target MnSOD are common mechanisms for the radiosensitization effect of PN in prostate cancer cells. The differential susceptibility to PN in two radioresistant cancer cells, DU145 and PC3, is due, in part, to the fact that in addition to NF-κB inhibition, PN activates the PI3K/Akt pro-survival pathway in both cell lines. The presence of PTEN in DU145 cells enhances the radiosensitization effect of PN by suppression of the steady state level of activated p-Akt. We also demonstrate that PN selectively exhibits a radiosensitization effect on prostate cancer PC3 cells but not on normal prostate epithelial PrEC cells. PN causes oxidative stress in PC3 cells but not in PrEC cells, as determined by the oxidation of the ROS-sensitive probe H2DCFDA and intracellular reduced thiol and disulfide levels. In PC3 but not PrEC cells, PN activates NADPH oxidase leading to a decrease in the level of reduced thioredoxin, activation of PI3K/Akt and consequent FOXO3a phosphorylation, which results in the downregulation of FOXO3a targets, antioxidant enzyme MnSOD and catalase. Importantly, when combined with radiation, PN further increases ROS levels in PC3 cells, while it decreases radiation-induced oxidative stress in PrEC cells, possibly by increasing GSH level. Overall, our data support the concept that increasing oxidative stress in cancer cells, which are already under high constitutive oxidative stress, will lead to cell death, while the same stress may allow normal cells to maintain redox homeostasis through adaptive response. Thus, modulating cell redox status may be a novel approach to efficiently and selectively kill cancer cells.

The purpose of this study was to determine the factors related to young black men’s intention to screen for prostate cancer as well as their engagement in prostate cancer risk-reduction behaviors. The study tested the significance of the constructs – age, attitude (direct and indirect), social influence, comfortability, cues to action, health screening experiences and knowledge – in predicting young black men’s intention to screen for prostate cancer; as well as the significance of the constructs – age, cues to action, exercise and knowledge – in predicting engagement in prostate cancer risk-reduction behaviors. Demographic/personal factors were also explored in related to the model predictors. Web-based and paper-pencil surveys were administered to 279 black men aged between 18 – 40 years from the Austin area. Three focus groups were conducted to collect information regarding young black men’s behavioral beliefs toward prostate cancer screening as well as their comfortability with prostate examinations. The number of usable surveys was 267. Using direct and indirect measures, the combination of attitude, social influence, comfortability (indirect model), and knowledge explained 41.0 and 43.0 percent of the variance in intention to screen for prostate cancer, respectively; with social influence being the strongest predictor ([Beta]=0.41; p <0.01 for the direct model and [Beta]=0.47 for the indirect model). For the model with prostate cancer risk-reduction as the outcome variable, the model accounted for 10.0 percent of the variance in behavior with only knowledge ([Beta]=0.19; p=0.03) as significant predictor. Interventions that address young black men’s attitude, social influence, comfortability, and knowledge may be necessary to increase young men’s intention to screen for prostate cancer when it is recommended by a physician. Additionally, factors surrounding exercise and knowledge may be important in increasing young men’s engagement in prostate cancer risk-reduction behaviors. Future studies using intention as a predictor of young men’s behavior are needed to assess the influence of intention on prostate cancer screening. / text

Prostate cancer is the most commonly diagnosed cancer and second leading cause of death in American men. Patients with localized prostate cancer may experience unique and multidimensional symptoms that are distressful from treatment and thereafter. This cross-sectional correlational study aimed to investigate the relationships among stress, symptoms, symptom distress, and symptom self-management and identify the effective strategies of symptom self-management in men with localized prostate cancer following prostatectomy or radiation therapy.Eight saliva samples and 3 questionnaires (Perceived Stress Scale, Symptom Indexes, and Strategy and Effectiveness of Symptom Self-Management) were obtained from each participant between 1 and 3 months following their first prostate cancer treatment. The sample consisted of 53 men with localized prostate cancer. Mean salivary cortisol concentrations for the entire sample ranged from 0.3 to 0.08 ug/dL. Cortisol was secreted in a circadian rhythm with heightened activity in the early morning and lowered activity late in the day. The circadian pattern of cortisol secretion was similar in both the prostatectomy and radiation therapy groups, although the values were slightly different. Two areas Under the Curve (AUC) of salivary cortisol were calculated. Three cortisol circadian rhythms were identified, but the majority of the sample had a typical negative consistent circadian rhythm.Patients with localized prostate cancer who underwent radical prostatectomy or radiation therapy had low perceived stress. Perceived stress was positively correlated with AUCg, noon salivary cortisol concentrations, and afternoon salivary cortisol concentrations. Subjects reported a moderate degree of symptoms and symptom distress on urinary, bowel, and sexual dysfunction 1-3 months following treatments. The most effective strategies of urinary symptom management were pad and kegel exercise; the most effective strategy of bowel symptom management was rest or endure; the most effective strategies of sexual dysfunction management included express their feelings or find alternative ways to express their affection. The symptom self-management strategies were significantly and positively correlated with symptom self-management effectiveness.Symptom distress and AUCg were significant and strong predictors of symptom self-management. Findings can help health care providers develop effective strategies for symptom self-management that enhance health related quality of life among men with localized prostate cancer.

No description available.

Vinclozolin (VCZ), an antiandrogenic fungicide, is an endocrine disrupting chemical that is known to possess high affinity for the androgen receptor (AR) and modulate expression of critical androgen-dependant genes in the prostate. In this study, viability and expression of AR, NKX3.1 and CYP3A4 genes were measured in androgen-sensitive prostate cells LNCaP after exposure to VCZ and VCZ treated with S9 microsomes in a time and dose dependent manner. NKX3.1 is an androgen regulated gene that plays a vital role in prostate development. CYP3A4 is involved in xenobiotic metabolism. VCZ decreased the viability at high doses after 48 hours which was slightly mitigated by treatment with S9 metabolites. Expression of NKX3.1 and CYP3A4 was upregulated while an initial downregulation of AR was observed. NKX3.1 upregulation corroborates with possibility of antiandrogens to act as androgens in LNCaP. The results illustrate that VCZ can interfere with the expression of critical prostate genes.

Prostate cell lines were derived from two regions of prostate tissue from the same patient. The objective was to produce cell lines (as a useful in vitro model) from these two different regions which exhibit different properties for carcinoma development. The tissue was obtained from patients suffering from benign prostate hyperplasia undergoing trans-urethral resection. Tissue was taken from the deep (peripheral) and superficial (peri-urethral) areas. The cells were immortalised by transduction with constructs over expressing the cdk4 and hTERT genes. These cell lines were then characterised for their cellular phenotypes utilized for radiation transformation studies and utilized to investigate the role of plant derived polyphenols on normal and tumour cells. The cell line from the superficial region (P21s) was treated to fractionated doses of gamma radiation and a transformed cloned cell line was derived (P21s 40Gy (clone-a)). The cell line from the deep region (P21d) was found to consist of a mixed population of abnormal cells and a transformed cloned cell line was derived from it (P21d 0Gy (clone-a). In an attempt to obtain a normal P21d cell line cloned cell lines from early passage P21d cells were established. All seven cloned lines were abnormal with an average of 80 chromosomes per cell, invasive using a Matrigel assay and produced anchorage independent colonies. All cell lines were fully characterised with immunocytochemistry, chromosome analysis, invasion assays, and anchorage independent colony formation. P21s expressed basal cell markers (cytokeratin 5 (CK5) and 14), were positive for stem cell markers (prostate specific stem cell antigen PSCA, CK6), positive for p16, p63 and telomerase expression and negative for c-Myc expression. P21s was not invasive in a Matrigel assay and did not produce anchorage independent colony formation. P21d and P21d 0Gy (clone-a) also expressed CK5, CK14, PSCA, CK6, and telomerase but not p16 or p63 and showed an increase in expression of nuclear c-Myc, highly invasive and produced anchorage independent colonies. P21s 40Gy (clone-a) expressed CK5, CK14, PSCA, CK6, telomerase and p63, produced anchorage independent colonies, and was weakly positive for c-Myc expression. Spectral karyotyping analysis (SKY) showed P21s had a normal chromosome complement except an additional chromosome 20 whereas the P21s 40Gy (clone-a), P21d and P21d 0Gy (clone-a) cell lines had an abnormal chromosome complement with P21d and P21d 0Gy (clone-a) cell lines expressing multiple copies of every chromosome including loss of the Y chromosome. These results were echoed in the single nucleotide polymorphism chip (SNP) results which showed P21s as normal but P21d and P21d 0Gy (clone-a) to have large deletion and amplification regions that correlated with the SKY analysis. No differential cytotoxic response was noted between normal and abnormal cell lines including prostatic carcinoma cell lines LNCaP and PC-3 following treatment with strawberry polyphenol compounds. Most reports of a cytotoxic response to tumour cells in the literature did not compare the response to normal cells and used established cell lines. Human lymphocytes were also tested and all compounds were toxic in high doses. Polyphenol and ellagitannin rich polyphenol fractions were very cytotoxic and the anthocyanin rich fraction less toxic. In contrast to the lack of a direct differential cytotoxic effect, plant polyphenols did produce a protective effect to a carcinogenic insult. However a protective effect was noted via micronucleus assay with 3 hour incubation with the polyphenol rich fraction prior to radiation treatment. Finally, the expression and association of metabolic enzymes within the cells cytosol were investigated. The P21s cells were found to express both isoforms of LDH and so thought to be able to metabolise anaerobically and aerobically. P21d and P21d 0Gy (clone-a) cells were found to only express one isoform in the complex and so it was assumed that these cells favoured anaerobic metabolism of ATP in correlation to the Warburg effect. c-Myc association with compounds in the cell cytosol of P21s cells existed whereas, abnormal cells lost this association along with up-regulation of c-Myc expression and down stream targets of c-Myc in the nuclei. Thus these newly established human prostate cell lines provide a useful model system for investigating the biology of the prostate and prostate cancer.