Cancer Biology Commons^™

Melittin: A Natural Component Of Honeybee Venom As A Potential Anti-Cancer Therapy, Niamh Donnellan, Anne M. Friel

SURE Journal: Science Undergraduate Research Experience Journal

Cancer is a major cause of death worldwide and while chemotherapy is the main approach there are many negative associations in current treatment procedures. These include lack of selectivity, side effects and drug resistance. The hallmarks of cancer are a fundamental concept which aids the development of new means to treat human cancers through the understanding of the acquisition of these hallmarks from cells.

Melittin is a major peptide component of bee venom which has shown to be efficacious as an anticancer agent in preclinical and animal models. Melittin has many biological functions including pore formation in the phospholipid bilayer …

Kinome Profiling Identifies Mark3 And Stk10 As Potential Therapeutic Targets In Uveal Melanoma, Usman Baqai, Alison M. Kurimchak, Isabella Trachtenberg, Timothy J. Purwin, Jelan I. Haj, Anna Han, Kristine Luo, Nikole Fandino Pachon, Angela Jeon, Vivian Chua, Michael A. Davies, J Silvio Gutkind, Jeffrey L. Benovic, James S. Duncan, Andrew E. Aplin

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Most uveal melanoma cases harbor activating mutations in either GNAQ or GNA11. Despite activation of the mitogen-activated protein kinase (MAPK) signaling pathway downstream of Gαq/11, there are no effective targeted kinase therapies for metastatic uveal melanoma. The human genome encodes numerous understudied kinases, also called the "dark kinome". Identifying additional kinases regulated by Gαq/11 may uncover novel therapeutic targets for uveal melanoma. In this study, we treated GNAQ-mutant uveal melanoma cell lines with a Gαq/11 inhibitor, YM-254890, and conducted a kinase signaling proteomic screen using multiplexed-kinase inhibitors followed by mass spectrometry. We observed downregulated expression and/or activity of 22 kinases. …

Enteroendocrine Cell Regulation Of The Gut-Brain Axis, Joshua Barton, Annie Londregan, Tyler Alexander, Ariana Entezari, Manuel Covarrubias, Scott Waldman

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Enteroendocrine cells (EECs) are an essential interface between the gut and brain that communicate signals about nutrients, pain, and even information from our microbiome. EECs are hormone-producing cells expressed throughout the gastrointestinal epithelium and have been leveraged by pharmaceuticals like semaglutide (Ozempic, Wegovy), terzepatide (Mounjaro), and retatrutide (Phase 2) for diabetes and weight control, and linaclotide (Linzess) to treat irritable bowel syndrome (IBS) and visceral pain. This review focuses on role of intestinal EECs to communicate signals from the gut lumen to the brain. Canonically, EECs communicate information about the intestinal environment through a variety of hormones, dividing EECs into …

International Conference On Cancer Health Disparities, Juhi Rais, Asif Jafri, Neelam Shivnath, Habiba Khan, Md Arshad

Research Symposium

Background: Biochanin A, an isoflavone that is mainly present in red clover, has potent chemopreventive properties against many cancers. Ovarian carcinoma is fifth most common and deadliest gynaecological malignancy that causes the highest mortality in females worldwide. Hence a substantial need for new therapies for combating this gynaecological malignancy arises.

Methods: The present study aimed to investigate anti-cancerous potentials of biochanin A on cultured human ovarian carcinoma PA-1 cells through the cell viability assay, cellular apoptosis, disruption of mitochondrial membrane potential (MMP), involvement of ROS, cell cycle kinetics, and expression of apoptosis-related genes namely, p53, Bax, Bcl-2, Noxa and Puma. …

Effects Of B4galnt1 Expression On Metastatic Phenotype And Response To Treatment In Osteosarcoma Cell Lines, Fatemeh Zareihajiabadi

Annual Research Symposium

No abstract provided.

Modulatory Effects Of Deacetylated Sialic Acids On Breast Cancer Resistance Protein-Mediated Multidrug Resistance And Receptor Tyrosine Kinase-Targeted Therapy, Isaac Tuffour

Electronic Theses and Dissertations

Multidrug resistance (MDR) remains a major challenge in cancer treatment, accounting for over 90% of chemotherapeutic failures. Cancers utilize sugar residues to engage in multidrug resistance. The underlying mechanism of action involving glycans, specifically the glycan sialic acid (Sia) and its various functional group alterations, has not been explored. ATP-binding cassette (ABC) transporter proteins, key proteins utilized by cancers to engage in MDR pathways, contain Sias in their extracellular domains. Modulating the expression of acetylated-Sias on Breast Cancer Resistance Protein (BCRP), a significant ABC transporter implicated in MDR, in lung and colon cancer cells directly impacted the ability of cancer …

Beyond Mitosis, Plk1-Mediated Phosphorylation Re-Wires Cancer Metabolism And Promotes Cancer Progression, Qiongsi Zhang

Theses and Dissertations--Toxicology and Cancer Biology

Polo-like kinase 1 (PLK1) is a well- characterized regulator of cell division and is known to be highly expressed in certain types of tumors. It has been demonstrated the multifaceted roles of PLK1 in regulation of transcription, translation, epigenetics, DNA damage and cellular metabolism et al. Despite these findings, the precise mechanisms by which PLK1 regulates these processes beyond mitosis remain unclear. PLK1-mediated phosphorylation and misregulation of its substrates has been linked to tumorigenesis, cancer progression, drug resistance and worse prognosis. In this study, we investigated the non-canonical functions of PLK1 in cancer metabolism and drug resistance. We found that …

Inhibition Of Rad18 By Arsenic, Lindsay B. Volk

Biomedical Sciences ETDs

Arsenite exposure leads to the retention of UV-induced DNA damage, thus burdening translesion synthesis (TLS). Rad18 is an essential factor in initiating TLS through PCNA monoubiquitination and is implicated in homologous recombination. It contains two functionally and structurally distinct zinc fingers that are potential targets for arsenite binding. Results from this study reveal arsenite binding to both zinc fingers of Rad18 and a corresponding loss of domain function. Importantly, arsenite inhibited Rad18 RING-dependent PCNA monoubiquitination and polymerase eta recruitment to DNA damage. Further analysis demonstrated multiple effects of arsenite, including the reduction in the nuclear localization and UV-induced chromatin recruitment …

Exposure To Endocrine Disrupting Chemicals And The Effects On Inflammation And Mammary Tumor Progression, Stephanie Morin

Doctoral Dissertations

The vast majority of breast cancers, ~70%, are not directly related to an inherited genetic mutation. Environmental factors play a dominant role in the etiology of most breast cancers. There is a subset of chemicals that are able to affect the homeostasis of hormones called endocrine disrupting chemicals (EDCs). Many of these chemicals are pervasive and persistent making the chances for lifetime exposure more prevalent. While many of these chemicals have been deemed safe, a subset of them have come under review to reassess their safety. As estrogen is critical for breast development and can act as a mitogen in …

Roles Of Oxidative Stress And Dna Methylation In Cigarette Smoking-Induced Accelerated Acute Myeloid Leukemia Progression, Mary Figueroa

Dissertations & Theses (Open Access)

Acute myeloid leukemia (AML) is a commonly diagnosed cancer in smokers. When current or former smokers have AML, they have worse survival compared to never smoking patients. This has been observed clinically for decades, but then it is unknown how smoking leads to worsened AML survival. Smoking causes oxidative stress and altered DNA methylation that persists for decades in peripheral blood mononuclear cells, but these changes from smoking have not been evaluated in the context of AML. We hypothesize that smoking-induced molecular changes, including altered DNA methylation associated with poor AML prognosis, promote AML. We developed a novel model to …

The Roles Of Pon2 In Mitochondrial Physiology, Lung Tumor Cell Proliferation, And Lung Tumorigenesis., Aaron Whitt

Electronic Theses and Dissertations

Paraoxonase 2 (PON2) is an intracellular, multifunctional enzyme with near-ubiquitous tissue distribution. Within cells, PON2 is localized to mitochondria and endoplasmic reticulum (ER), where it mitigates the formation of reactive oxygen species (ROS). PON2’s chief enzymatic function is its lactonase activity, through which it catalyzes the hydrolysis of a bacterial quorum-sensing molecule, N-(3-oxododecanoyl)-l-homoserine lactone (C12), effectively disrupting bacterial intercellular communication and protecting against infection. C12 is produced by the opportunistic pathogen Pseudomonas aeruginosa and has been shown to disrupt various aspects of eukaryotic host cell physiology and evoke apoptotic cell death through the activity of PON2. Additionally, PON2 has garnered …

The Effects Of Paclitaxel On Cellular Migration And The Cytoskeleton, Ashley Salguero-Gonzalez

Thinking Matters Symposium

In a clinical setting, some patients are exposed to an anti-cancer chemotherapy agent, paclitaxel. Cancerous cells undergo rapid, continuous cell division without control. Chemotherapy treatments try to slow and stop the uncontrollable cell division cycles and eliminate cancerous cells in the process. Paclitaxel serves as a treatment for some types of cancers, including lung, melanoma, bladder, and esophageal. Because it targets the cytoskeleton, paclitaxel can also influence cell migration. This project utilizes a cellular migration assay and an immunohistochemistry assay to analyze the effects of paclitaxel on the movement of cells and on the cytoskeleton of neuroglia rat cells with …

Investigating The Efficacy Of Tazemetosttat For In Vitro Treatment Of Human Triple Negative Breast Cancer Cells, Harshita Indukuri

Honors Scholars Collaborative Projects

Cancer is a formidable, genetic disease that affects many people, either directly or indirectly. Breast cancer is the most commonly diagnosed cancer worldwide (31). Triple-negative breast cancer (TNBC) is a type of breast cancer that has a higher lethality compared to other breast cancers and has a poor prognosis due to its highly invasive nature and limited treatment options. Finding safe, effective, and accessible treatment for TNBC is integral to treating TNBC patients. Tazemetostat is an EZH2-inhibitor that has recently been approved for use in epithelioid sarcoma (23). EZH2 is an overexpressed protein in many cancers, including TNBC (11). However, …

Repurposing Metformin And Antifolates For The Treatment Of Hepatocellular Carcinoma, Sherouk Mohamed Tawfik

Theses and Dissertations

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Due to its safety, wide availability and previously reported anti-cancer effects, metformin (MET) serves to be a possible therapeutic agent when combined with other well-known anti-cancer agents. The aim of this study was to investigate the potential anti-cancer effects of MET, an anti-diabetic agent, when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate …

Differentiating The Mechanistic Role And Chemotherapeutic Potential Of Src And Podoplanin In Oncogenic Transformation, Edward P. Retzbach

Graduate School of Biomedical Sciences Theses and Dissertations

There were an estimated 20 million new cancer cases worldwide in 2020, resulting in nearly 1000 deaths per hour [1]. Oral cancer exemplifies the difficulties of treating cancer patients. The first line for oral cancer treatment is surgery and radiation that can lead to patient disfigurement and decreased quality of life in cancer survivors [2-4]. Though there have been many developments in chemotherapy in the last 30 years, the 50% mortality rate associated with oral cancer has not changed [4, 5]. Longitudinal studies that track survival rates in oral cancer patients demonstrate a 3-fold reduction in patient deaths when patients …

Innate Immune Activation By Checkpoint Inhibition In Human Patient-Derived Lung Cancer Tissues, Teresa W. M. Fan, Richard M. Higashi, Huan Song, Saeed Daneshmandi, Angela L. Mahan, Matthew S. Purdom, Therese J. Bocklage, Thomas A. Pittman, Daheng He, Chi Wang, Andrew N. Lane

Center for Environmental and Systems Biochemistry Faculty Publications

Although Pembrolizumab-based immunotherapy has significantly improved lung cancer patient survival, many patients show variable efficacy and resistance development. A better understanding of the drug’s action is needed to improve patient outcomes. Functional heterogeneity of the tumor microenvironment (TME) is crucial to modulating drug resistance; understanding of individual patients’ TME that impacts drug response is hampered by lack of appropriate models. Lung organotypic tissue slice cultures (OTC) with patients’ native TME procured from primary and brain-metastasized (BM) non-small cell lung cancer (NSCLC) patients were treated with Pembrolizumab and/or beta-glucan (WGP, an innate immune activator). Metabolic tracing with ¹³C₆-Glc/ …

Utilizing Proteolysis-Targeting Chimeras To Target The Transcriptional Cyclin-Dependent Kinases 9 And 12, Hannah King

Theses & Dissertations

Cyclin-dependent kinases (CDKs) are a family of serine-threonine kinases involved in various cellular functions, such as regulating the cell cycle and gene transcription. CDK9, a transcriptional CDK, regulates highly expressed enhancer-associated oncogenic transcription factors, including the oncogene Myc. CDK9 is responsible for the transcription and stabilization of Myc; consequently, it was a validated target for pancreatic cancer treatment.

As such, we developed a panel of aminopyrazole based proteolysis targeting chimera where we identified PROTAC 2 as a selective degrader of CDK9 (DC₅₀ = 158 ± 6 nM). PROTAC 2 was capable of cereblon mediated proteasomal degradation of CDK9 while …

Investigations Into The Cellular Target Of 4-Trifluoromethoxy Chalcone Via Darts Method, Jordan Stacy

Undergraduate Theses

Cellular drug target discovery is an important step in any drugs journey from bench to bedside. This is true for our lab's molecule of interest, the Chalcone. The Chalcone molecule and its derivatives have been identified as small, plant-derived secondary metabolites that, when interacting with human cancer cell lines, trigger apoptotic pathways leading to varying levels of cell death. One derivative, 4-Trifluoromethoxy Chalcone (4TFM), was identified through screenings as inducing the highest death rate in A549 cancer cells, in conjunction with having the lowest IC50, making it a good candidate to use in searching for the currently unknown cellular target …

Propranolol Sensitizes Vascular Sarcoma Cells To Doxorubicin By Altering Lysosomal Drug Sequestration And Drug Efflux, Jhuma Saha, Jong Hyuk Kim, Clarissa N. Amaya, Caleb M. Witcher, Ali Khammanivong, Derek M. Korpela, David R. Brown, Josephine Taylor, Brad A. Bryan, Erin B. Dickerson

Faculty Publications

Angiosarcoma is a rare cancer of blood vessel–forming cells with a high patient mortality and few treatment options. Although chemotherapy often produces initial clinical responses, outcomes remain poor, largely due to the development of drug resistance. We previously identified a subset of doxorubicin-resistant cells in human angiosarcoma and canine hemangiosarcoma cell lines that exhibit high lysosomal accumulation of doxorubicin. Hydrophobic, weak base chemotherapeutics, like doxorubicin, are known to sequester within lysosomes, promoting resistance by limiting drug accessibility to cellular targets. Drug synergy between the beta adrenergic receptor (β-AR) antagonist, propranolol, and multiple chemotherapeutics has been documented in vitro, and …

Amphiphilic Cell-Penetrating Peptides Containing Natural And Unnatural Amino Acids As Drug Delivery Tools And Antimicrobial Agents, David Salehi

Pharmaceutical Sciences (MS) Theses

Cell-penetrating peptides containing arginine as positively charged residues and tryptophan or diphenylalanine as hydrophobic residues were synthesized. The synthesis was accomplished through the Fmoc solid-phase peptide synthesis in the presence of HBTU and DIPEA. The side-chain protected linear peptides were cleaved from the resin and cyclized in the presence of DIC and HOAt in the solution phase overnight. MALDI-TOF mass spectrometry was used to characterize the peptides.

The cytotoxicity of the synthesized peptides was determined in CCRF-CEM (human, lymphoblast peripheral blood), and HEK-293 (human, embryonic epithelial kidney healthy) cells using the MTS assay. A concentration of 10 µM was found …

Elucidating The Role Of The Tyrosine Phosphatase, Shp-2, In Regulation Of Pd-L1 Expression In Non-Small Lung Cancer Using Both Biochemical Analyses And Real-World Genomic Information, Keller Toral

Theses and Dissertations--Pharmacy

Immune checkpoint inhibitors (ICIs), especially those that target programmed cell death protein 1 (PD-1) and programmed cell death ligand-1 (PD-L1), have been shown to provide substantial clinical benefit in many patients with non-small cell lung cancer (NSCLC). While these therapeutic agents can be highly effective in the correct context, the biological systems that malignant cells draft from normal activities of the cell are poorly characterized. Tumor cell-specific expression of PD-L1 is likely important for clinical benefit from PD-1 and PD-L1 inhibitors. It is known that PD-L1 is inappropriately expressed in many cancers harboring mutations in the RAS family of genes. …

Bypassing The Blood-Brain Barrier: A Physical And Pharmacological Approach For The Treatment Of Metastatic Brain Tumors, Samuel A. Sprowls

Graduate Theses, Dissertations, and Problem Reports

This dissertation (a) provided an in depth literature review of methods to disrupt the BBB/BTB and improve therapeutic distribution to brain tumors, (b) evaluated the use of azacitidine as a single agent therapy for the treatment of brain metastasis of breast cancer and a potential molecular mechanism by which brain tropic cells are sensitized to hypomethylating agents, (c) determined the impact cannabidiol has on P-glycoprotein mediated efflux at the blood-brain barrier and its potential for use as a single agent treatment for metastatic brain tumors, (d) developed a preclinical radiation therapy protocol for use in small animals and in vitro …

Develop A High-Throughput Screening Method To Identify C-P4h1 (Collagen Prolyl 4-Hydroxylase 1) Inhibitors From Fda-Approved Chemicals, Shike Wang, Kuo-Hao Lee, Nathália Victoria Araujo, Chang-Guo Zhan, Vivek M. Rangnekar, Ren Xu

Pharmaceutical Sciences Faculty Publications

Collagen prolyl 4-hydroxylase 1 (C-P4H1) is an α-ketoglutarate (α-KG)-dependent dioxygenase that catalyzes 4-hydroxylation of proline on collagen. C-P4H1-induced prolyl hydroxylation is required for proper collagen deposition and cancer metastasis. Therefore, targeting C-P4H1 is considered a potential therapeutic strategy for collagen-related cancer progression and metastasis. However, no C-P4H1 inhibitors are available for clinical testing, and the high content assay is currently not available for C-P4H1 inhibitor screening. In the present study, we developed a high-throughput screening assay by quantifying succinate, a byproduct of C-P4H-catalyzed hydroxylation. C-P4H1 is the major isoform of collagen prolyl 4-hydroxylases (CP4Hs) that contributes the majority prolyl 4-hydroxylase …

Microrna Expression Profiling Of Normal And Malignant Human Colonic Stem Cells Identifies, Vignesh Viswanathan, Lynn Opdenaker, Shirin Modarai, Jeremy Z Fields, Gregory Gonye, Bruce M Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

MicroRNAs (miRNAs) have a critical role in regulating stem cells (SCs) during development, and because aberrant expression of miRNAs occurs in various cancers, our goal was to determine if dysregulation of miRNAs is involved in the SC origin of colorectal cancer (CRC). We previously reported that aldehyde dehydrogenase (ALDH) is a marker for normal and malignant human colonic SCs and tracks SC overpopulation during colon tumorigenesis. MicroRNA expression was studied in ALDH-positive SCs from normal and malignant human colon tissues by Nanostring miRNA profiling. Our findings show that: (1) A unique miRNA signature distinguishes ALDH-positive CRC cells from ALDH-positive normal …

Computational Chemistry - Ulk 101, Michaela Montpas

Scholar Week 2016 - present

Autophagy is a process that generates the necessary building components for cells by cytoplasmic breakdown of unnecessary materials (Martin, Celano, Solitro, Gunaydin, Scott, et. al., 2018). This is a survival technique for cells in times of stress, especially during periods of nutrient starvation. Cancer cells, unfortunately, benefit from this process due to their ability to flourish in nutrient-starved environments, becoming resistant to therapy. The primary protein in mammals responsible for this process is a serine/threonine kinase called ULK 1 (unc-51 like autophagy initiating kinase 1). As such, inhibitors of ULK 1 can be used in cancer therapies in order to …

Tip60 Regulation Of Δnp63Α Is Associated With Cisplatin Resistance, Akshay Hira, Andrew Stacy, Jin Zhang, Michael P. Craig, Madhavi Kadakia

Symposium of Student Research, Scholarship, and Creative Activities Materials

About 5.4 million basal and squamous cell skin cancers are diagnosed every year in the US. ΔNp63a, a member of the p53 transcription factor family, is overexpressed in non-melanoma skin cancer and regulates cell survival, migration and invasion. TIP60 is histone acetyltransferase (HAT) which mediates cellular processes such as transcription and the DNA damage response (DDR). Previous studies in our lab have shown that overexpression of TIP60 induces ΔNp63a protein stabilization in a catalytic-dependent manner. Since ΔNp63a is known to transcriptionally regulate several DDR genes and promote cisplatin resistance, its stabilization by TIP60 may contribute to the failure of platinum-based …

Toxicity Of Novel Platinum Compounds In Mammalian Cancer Cells, Vanesa Veletanlic

Masters Theses & Specialist Projects

There are currently three FDA platinum compounds approved for use as chemotherapeutics, where each drug has variable efficacies for different cancer types depending on cancer’s tissue of origin. The approved compounds are platinum(II) complexes with four coordination sites on the platinum atom allowing two types of ligands to attach: leaving ligands, which are removed from the platinum atom in solution, and non-leaving ligands, which remain complexed to the platinum. Carboplatin, the preferred compound used to treat ovarian and small-cell lung cancers, has a characteristic cyclobutanedicarboxylic acid leaving ligand and two ammonia non-leaving ligands. A novel compound, 1,1-cyclobutanedicarboxylato(ethylenediamine)platinum (II), or Pt(en)CBDCA, …

Environmental Risk Factors For Inflammatory Bowel Disease: Triclosan And Other Consumer Antimicrobials, Katherine Z. Sanidad

Doctoral Dissertations

Inflammatory bowel disease (IBD) has become a serious health problem since the incidence and prevalence of IBD has dramatically increased throughout the world. There is evidence that environmental factors are primarily responsible for the increase of IBD, therefore, it is important to identify novel environmental risk factors to reduce the risk of IBD and its associated diseases. Antimicrobials used in consumer products might serve as environmental risk factors for IBD and its associated diseases. Triclosan (TCS), triclocarban (TCC), benzalkonium chloride (BAC), benzethonium chloride (BET), and chloroxylenol (PCMX) are widely used antimicrobial ingredients in consumer products and are ubiquitous contaminants in …

Cold Atmospheric Plasma Induces Accumulation Of Lysosomes And Caspase-Independent Cell Death In U373mg Glioblastoma Multiforme Cells, Gillian Conway, Zhonglei He, Ana L. Hutanu, George P. Cribaro, Eline Manaloto, Alan Casey, Damien Traynor, Vladimir Milosavljevic, Orla Howe, Carlos Barcia, James T. Murray, Patrick Cullen, James Curtin

Articles

Room temperature Cold Atmospheric Plasma (CAP) has shown promising efficacy for the treatment of cancer but the exact mechanisms of action remain unclear. Both apoptosis and necrosis have been implicated as the mode of cell death in various cancer cells. We have previously demonstrated a caspase-independent mechanism of cell death in p53-mutated glioblastoma multiforme (GBM) cells exposed to plasma. The purpose of this study was to elucidate the molecular mechanisms involved in caspase-independent cell death induced by plasma treatment. We demonstrate that plasma induces rapid cell death in GBM cells, independent of caspases. Accumulation of vesicles was observed in plasma …

Reversal Of P-Glycoprotein And Breast Cancer Resistance Protein Mediated Multidrug Resistance In Vitro Using In Silico Identified Novel Compounds, Amila Nanayakkara

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) is a major cause of chemotherapy failure. Overexpression of ATP-binding cassette (ABC) transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two well-studied drug transporters which are associated with MDR. These two transporters also act as a major functional unit of the blood brain barrier to protect the brain from xenobiotics and toxins. Lack of clinically approved P-gp and BCRP inhibitors renders chemotherapy treatments of many MDR cancers ineffective and obstructs drug uptake into the brain.

Using computational methods, we have identified new compounds that inhibit P-gp (Brewer et al., Mol. Pharmacol. 2014). Several of …