Medical Sciences Commons^™

Crippling Rapid Evolution Of Metastasis And Drug Resistance In A549 Non-Small Cell Lung Cancer Cells With The Clinically Relevant Hsp90 Inhibitor Auy922, Nickolas Anthony Bacon

Theses, Dissertations and Capstones

The ability for species to evolve new features in response to changing circumstances in order to survive and propagate is a ubiquitous observation on both the macroscopic and microscopic levels of living systems. It should be no surprise, then, that diseases such as cancer utilize their own forms of adaptation to perpetuate themselves when exposed to external threats. Indeed, concepts drawn from Darwinian evolution are now widely accepted to help explain certain aspects of carcinogenesis and malignant progression, the sum of which have come to be known as the theory of tumor evolution. Since metastasis and drug resistance are features …

The Epigenetic Effects Of Omega-3 Fatty Acids In Diffuse Large B-Cell Lymphoma, Tanner Jeffrey Bakhshi

Theses, Dissertations and Capstones

Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma. It is an aggressive cancer, with 50-70% of patients diagnosed at an advanced stage and 30-50% of patients not cured by chemoimmunotherapy. DLBCL is almost always caused by genetic damage sustained during the germinal center (GC) reaction. The mechanisms that govern the GC reaction bear a striking resemblance to those that drive DLBCL. Genomic studies have shown that some of its most common mutations occur in genes that encode epigenetic modifiers, including the lysine (histone) acetyltransferases CREBBP and p300. These mutations prevent the acetylation of multiple histone residues, …

Potential Applications Of Capsaicinoids In Small Cell Lung Cancer Therapy, Jamie Rae Friedman

Theses, Dissertations and Capstones

Lung cancer continues to be the leading cause of cancer related mortality worldwide. Lung cancer is not a single disease but an umbrella that encompasses two major classifications, nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). SCLC represents about 15- 20% of all lung cancer cases and is almost exclusively diagnosed in smokers. Typically, patients will respond very well to first line treatment, but face inevitable relapse. The fact that SCLC still carries a grim 5-year survival rate of less than 5% highlights the lack of advancement in treatment options to effectively improve patient response and survival. …

Exploring The Regulatory Mechanism Of The Notch Ligand Receptor Jagged1 Via The Aryl Hydrocarbon Receptor In Breast Cancer, Sean Alan Piwarski

Theses, Dissertations and Capstones

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that binds pollutants, therapeutic drugs and endogenous ligands. AHR is of particular interest in cancer and has been shown to play roles in both tumor progression and tumor suppression. As a result, it has received growing attention as a possible chemotherapeutic target. AHR is expressed in all breast cancer subtypes and can promote or inhibit breast cancer depending on the ligand it binds. The Notch signaling pathway is a highly conserved evolutionary pathway that plays extremely vital roles during development by regulating cell fate and differentiation. Notch signaling has increasingly …

Employing The Enzyme Cofactor Function Of Ascorbic Acid To Affect Oncogenic Pathways In Human Melanoma: Modulating Hypoxia Inducible Factor-1Α And Dna Demethylation To Reduce Malignant Potential, Adam Patrick Fischer

Theses, Dissertations and Capstones

Dioxygenase enzymes such as the HIF hydroxylases (PHD1-3, FIH) and the Ten-eleven translocation (TET1-3) enzymes regulate the activity of the hypoxia inducible factor-1_a (HIF1_a) transcription factor and the DNA methylation status of cells, respectively. Aberrant accumulation and activation of HIF-1_a can allow malignant cells to acquire attributes that promote progression, chemotherapy resistance, and survival, while aberrant hypermethylation of gene promoters can silence the expression of tumor suppressor genes essential to preventing tumorigenesis. Inadequate levels of intracellular ascorbic acid (AA), a necessary cofactor for optimal dioxygenase enzyme function, could potentiate these tumorigenic conditions. In fact, plasma levels …

Doxorubicin Cytotoxicity In A Human Proximal Tubular Epithelial Cell Line Was Attenuated By The Natural Product Resveratrol, Morghan Schuyler Getty

Theses, Dissertations and Capstones

The cancer chemotherapeutic agent doxorubicin (DOX), Adriamycin, is part of the treatment regimen for breast, ovarian, small cell lung cancer and acute/chronic lymphoid leukemia. Adverse effects associated with DOX are cardiotoxicity and nephrotoxicity. Interventions are needed to reduce DOX nephrotoxicity. Resveratrol (RES) is a phytochemical contained in grapes, berries and nuts, which possesses antioxidant and anticancer properties. This study tested the hypothesis that RES will attenuate DOX renal cytotoxicity in human noncancerous renal proximal tubular epithelial (HK-2) cells and that RES will reduce DOX mediated changes in mitochondrial function. HK-2 cells were plated and grown for 48 hours (h). Cells …

Cancer Stem Cells In The Screening Of Anticancer Drugs For Central Nervous System Tumors, Sarah Elizabeth Daron-Mathis

Theses, Dissertations and Capstones

There is a growing need (in the medical field) to design personalized therapy for cancer patients. Decades of cancer research have found no silver bullet that can cure all or even most patients. This study evaluated four patients affected by central nervous system (CNS) tumors (Ependymoma and Glioblastoma), and found that tumors with the same histology had unique responses to treatment. Each sample presented different levels of heterogeneity in expressed biomarkers and responded to drugs at varying levels.

Oncologists conventionally treat cancer patients with drugs tested in large clinical trials. However, often patients do not experience positive outcomes following treatments …

Investigation Of Ultrasound Targeted Microbubbles As A Therapeutic Gene Delivery System For Prostate Cancer, Rounak Paramjeet Nande

Theses, Dissertations and Capstones

A major challenge for effective gene therapy is systemic delivery of viruses carrying therapeutic genes into affected tissue. The immunogenic nature of human adenoviruses (Ads) limits their use for intratumoral (IT) injection in gene therapy. Ads transfection is further hampered by the fluctuating presence of Coxsackie and Adenovirus Receptor (CAR) and integrins on the cells’ surface. To circumvent these limitations we developed a novel approach wherein Ads are encapsulated inside the shell of lyophilized, lipid-encapsulated, perfluorocarbon microbubbles (MBs)/ultrasound (US) contrast agents, which act as delivery vehicles for a sitespecific gene transfer system.

We performed infection studies with Ad.GFP (Green Fluorescent …

Benzyl Isothiocyanate As An Adjuvant Chemotherapy Option For Head And Neck Squamous Cell Carcinoma, Mary Allison Wolf

Theses, Dissertations and Capstones

Isothiocyanates (ITCs) are natural phytochemicals produced by cruciferous vegetables. Recent evidence supports that, in addition to cancer prevention, ITCs can use various mechanisms to target malignant cells. Current therapies for cancer often provoke detrimental side effects, however clinical evidence supports that ITCs have little to no side effects in patients. Consequently, ITCs may be a promising treatment option for cancer patients, especially patients suffering from head and neck squamous cell carcinoma (HNSCC).

Despite recent improvements in cancer treatment, overall survival of advanced HNSCC has not improved in the past three decades. Metastasis and chemoresistance represent two detrimental events that greatly …

The Role Of Ptip In Breast Cancer, Lina Niu

Theses, Dissertations and Capstones

In the U.S., breast cancer comprises about 30% of all cancer cases (excluding skin cancer) in women. Such a high incidence makes breast cancer a significant health concern, but our understanding of the molecular and cellular mechanisms of this disease is still limited. Growing evidence suggests that the development of human breast cancer may involve epigenetics, which attributes changes in phenotype to mechanisms other than changes in the DNA sequence itself. Histones as the chief proteins of chromatin work on gene expression, and methylation of histone 3 lysine 4 (H3K4) results in transcriptional activation. Lately, Paired box (Pax) trans-activation domain-interacting …

Redox Regulation Of Differentiation In Neuroblastoma, Anne Marie Silvis

Theses, Dissertations and Capstones

Neuroblastoma is the most common extracranial solid tumor in childhood, ranking third in prevalence among infant cancers. Despite intensive therapy with surgery, radiation and chemotherapy, there is a high chance of tumor recurrence. These children are therefore given retinoids in the maintenance phase to differentiate the tumor cells and to avoid/lessen this incidence. Although 13-cis retinoic acid (13-cis RA) is currently used to treat neuroblastoma, there is much evidence supporting the prevalence of its metabolite, all-trans retinoic acid (ATRA), to be the main signaling retinoid in vivo.

The SK-N-SH neuroblastoma cell line, which is composed of three sub-types: sympatheoadrenal neuroblasts …

Pitx2 Is Overexpressed In Follicular Cell-Derived Thyroid Cancer And Promotes Thyroid Cancer Proliferation By Regulating Cell Cycle, Yue Huang

Theses, Dissertations and Capstones

Thyroid cancer is the most prevailing malignancy of the endocrine system. Its incidence is rapidly rising at the second fastest rate of all malignancies in the United States, making it a significant health problem. Although the majority of thyroid cancer is slowly-growing and well-differentiated, available treatment options are very limited, and most of them require complete removal of the thyroid gland and surrounding tissues. Patients who have undergone thyroid removal have to take life-long hormone replacement therapy, which is very inconvenient and costly. Therefore, there is an urgent need to develop new treatments for this disease. As a prerequisite for …

Treatment Strategies In Acute Myelogenous Leukemia : Investigating Hsp90 And P53 As Targets, Jennifer M. Napper

Theses, Dissertations and Capstones

Acute myelogenous leukemia (AML) is the deadliest of the lymphatic and bone marrow cancers. Patients diagnosed with AML have a five year survival rate of 23.4%. AML is characterized by an accumulation of undifferentiated and functionless myeloid precursors in the bone marrow and blood. Heat shock protein 90 (Hsp90) inhibitors, such as 17-AAG, an analog of geldanamycin (GM), are currently undergoing phase I, and II and III clinical trials for various cancers with mixed results. I found distinct responses to 17-AAG treatment among the AML cell lines tested. I also discovered two mutant TP53 alleles in Kasumi-3 cells, an AML …

Genetic And Environmental Factors Suggest That Dietary Fatty Acid Content, Lipid Metabolism, And Bone Properties Are Key Regulators Of Myeloid Progenitor Cell Frequency, Melinda E. Varney

Theses, Dissertations and Capstones

Acute myelogenous leukemia (AML) and its precursors are the result of the dysregulation of hematopoiesis. Hematopoiesis proceeds in a stepwise manner, beginning with hematopoietic stem cells, continuing to develop into various stages of progenitor cells, and finally becoming fully functional blood cells. As this process goes awry, immature, functionless cells of the myeloid lineage proliferate out of control. Discerning how myeloid progenitor frequency is regulated allows for a better understanding of how the process may lose control. Hematopoiesis has been shown to depend on genetic and environmental factors. In this work, I have added to this knowledge base by providing …

The Expression And Function Of Hypoxia Inducible Factor-1Α In Human Melanoma, Sandeep S. Joshi

Theses, Dissertations and Capstones

Hypoxia inducible factor-1α (HIF-1α) protein, a key regulator of oxygen homeostasis, is stabilized under hypoxia and degraded under normal oxygen tension. Here, the human melanoma cells were found to express an elevated amount of HIF-1α mRNA and protein relative to normal human melanocytes under normoxic conditions. The amount of HIF-1α expressed is roughly correlated with the stage of melanoma from which the cell line was established. In addition, a splice variant mRNA of HIF-1α785 is expressed at higher levels than full-length HIF-1α mRNA in the more aggressive melanoma cells. This splice variant lacks part of the oxygen regulation domain. Ectopic …

Loss Of Ski Expression In Testicular Cancer Leads To An Enhanced Invasive Phenotype Through Both Bmp-Dependent And Bmp-Independent Pathways, Amy N. Nash

Theses, Dissertations and Capstones

The proto-oncogene SKI is a transcription factor and a co-repressor of the TGFβ superfamily, including TGF

β and BMP. However, additional data suggests that SKI may function as a tumor suppressor in some cell types. The TGFβ superfamily has been implicated in cancer progression and germ cell migration. Testicular cancer afflicts men during their peak reproductive years and is the most common cancer among men of this age group. Cisplatin-based chemotherapy is the standard treatment for testicular cancer. This treatment can lead to undesirable side effects, including infertility. We have shown that SKI expression is decreased in testicular germ cell …

The Function And Mechanism Of Chmp1a In Tumor Development, Jing Li

Theses, Dissertations and Capstones

Chmp1A (Chromatin modifying protein 1A/Charged multivesicular protein 1A) is a member of the ESCRT-III (Endosomal Sorting Complex Required for Transport) family, which mediates trafficking via MVB (multivesicular body) formation and sorting. Our studies suggest that Chmp1A is a novel tumor suppressor, especially in the pancreas. Knockdown of Chmp1A resulted in an increase of anchorage-independent growth of HEK 293T cells. Moreover, we showed that Chmp1A depleted HEK 293T cells forms tumor in xenograft mice. Knockdown of Chmp1A in PanC-1 cells promoted cell growth. In contrast, Doxycycline induced over-expression of Chmp1A in pancreatic cancer cells (PanC-1) resulted in cell growth inhibition, tumor …

Effects Of Tamoxifen On Mitochondrial Nos Activity: Alteration In The Intramitochondrial Ca2+ Homeostasis, Sandeep S. Joshi

Theses, Dissertations and Capstones

Tamoxifen (Tam) is an anticancer drug that induces oxidative stress and apoptosis via mitochondria- and nitric oxide (NO)-dependent pathways. Here, we report that therapeutic concentrations of Tam stimulate the mitochondrial NO synthase (mtNOS) activity of isolated rat liver mitochondria by increasing the intramitochondrial ionized Ca²⁺ concentration ([Ca²⁺]_m). Tam decreases transmembrane potential (∆ψ) due to increased [Ca²⁺]_m that neutralizes the negative charges of the inner mitochondrial membrane. Thus, the present study reports a novel mechanism for the widely used anti- caner drug, Tam.

The Role Of Ap-1 Transcription Complex In Retinoic Acid-Dependent B16 Melanoma Cell Growth Arrest And Differentiation, Ying Huang

Theses, Dissertations and Capstones

Our laboratory has been studying the effects of all-trans retinoic acid (atRA) on the growth and differentiation of the B16 mouse melanoma cells. RA inhibits both anchorage-dependent and –independent growth and stimulates melanin production in B16 cells, which are accompanied by an increase in AP-1 activity. To further investigate the RA-induced AP-1 activity, I established clones of B16 stably expressing an AP-1-luciferase reporter gene. Treatment of these clones with phorbol dibutyrate (PDB), a known activator of AP-1, rapidly increased AP-1 activity which reached its maximum level at 2-4 h and returned to baseline level by 24 h. In contrast, RA …