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Investigation of G1 Arrest Mechanisms Induced by Sanguisorba officinalis Extracts in B16F10 Cells / Sanguisorba officinalis の抽出物がB16F10細胞に誘導するG1 arrest の誘導機構の解析Tan, Yi-Hsun 25 November 2019 (has links)
京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第22136号 / 生博第423号 / 新制||生||55(附属図書館) / 京都大学大学院生命科学研究科高次生命科学専攻 / (主査)教授 垣塚 彰, 教授 原田 浩, 教授 豊島 文子 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM
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Cellular Inactivation Using Nanosecond Pulsed Electric FieldsAginiprakash Dhanabal (8734527) 12 October 2021 (has links)
<div>Pulsed electric fields (PEFs) can induce numerous biophysical phenomena, especially perturbation of the outer and inner membranes, that may be used for applications that include nonthermal pasteurization, enhanced permeabilization of tumors to improve the transport of chemotherapeutics for cancer therapy, and enhanced membrane permeabilization of individual cells to enhance RNA and DNA delivery for gene therapy. The applied electric field and pulse duration determine the density, size, and reversibility of the created membrane pores. PEFs with durations longer than the outer membrane’s charging time will induce pore formation with the potential for application in irreversible electroporation for cancer therapy and microorganism inactivation. Shorter duration PEFs, particularly on the nanosecond timescale (nsPEFs), induce a larger density of smaller membrane pores with the potential to permeabilize intracellular membranes, such as the mitochondria, to induce programmed cell death. Thus, the PEFs can effectively kill multiple types of cells, dependent upon the cells. This thesis assesses the ability of nsPEFs to kill different cell types, specifically microorganisms with and without antibiotics as well as varying the parameters to affect populations of immortalized leukemia cells (Jurkats).</div><div>Antibiotic resistance has been an acknowledged challenge since the initial development of penicillin; however, recent discoveries by the CDC and the WHO of microorganisms resistant to last line of defense drugs combined with predictions of potential infection cases reaching 50 million a year globally and the absence new drugs in the discovery pipeline highlight the need to develop novel ways to combat and overcome these resistance mechanisms. Repurposing drugs, exploring nature for new drugs, and developing enzymes to counter the resistance mechanisms may provide potential alternatives for addressing the scarcity of antibiotics effective against gram-negative infections. One may also leverage the abundance of drugs effective against gram-positive infections by using nsPEFs to make them effective against gram-negative infections, including bacterial species with multiple natural and acquired resistance mechanisms. Numerous drug and microbial combinations for different doses and pulse treatments were tested and presented here.</div><div>Low intensity PEFs may selectively target cell populations at different stages of the cell cycle (quiescence and mitosis) to modify cancer cell population dynamics. Experimental studies of cancer cell growth when exposed to a low number of nsPEFs, while varying pulse duration, field intensity and number of pulses reveals a threshold beyond which cell recovery is not possible, but also a point of diminishing returns if cell death is the intention. A theory comprised of coupled differential equations representing the proliferating and quiescent cells showed how changing PEF parameters altered the behavior of these cell populations after treatment. These results may provide important information on the impact of PEFs with sub-threshold intensities and durations on cell population growth and potential recurrence.</div>
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Integrative Click Chemistry for Tuning Physicochemical Properties of Cancer Cell-Laden HydrogelsHunter Caleb Johnson (8764017) 30 April 2020 (has links)
<p>The pancreas is a
vital organ that secretes key metabolic hormones and digestive enzymes. In
pancreatic ductal adenocarcinoma (PDAC), one of the leading causes of cancer-related
death in the world, limited advances in diagnosis or therapies have been made
over decades. Key features of PDAC progression include an elevated matrix
stiffness and an increased deposition of extracellular matrices (ECM), such as hyaluronic
acid (HA). Understanding how cells interact with components in the tumor microenvironment (TME) as PDAC progresses can assist
in developing diagnostic tools and therapeutic treatment options. In recent
years, hydrogels have proven to be an excellent platform for studying cell-cell
and cell-matrix interactions. Utilizing chemically modified and naturally
derived materials, hydrogel networks can be formed to encompass not only the
components, but also the physicochemical properties of the dynamic TME. In this
work, a dynamic hydrogel system that integrates multiple click chemistries was
developed for tuning matrix physicochemical properties in a manner similar to the
temporally increased matrix stiffness and depositions of HA. Subsequently,
these dynamic hydrogels were used to investigate how matrix stiffening and
increased HA presentation might affect survival of PDAC cells and their
response to chemotherapeutics. </p>
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PKM2-EZH2 INTERACTION ELICITS METABOLIC VULNERABILITY FOR TREATMENT OF TRIPLE- NEGATIVE BREAST CANCERYingsheng Zhang (8801084) 07 May 2020 (has links)
<p>Triple Negative Breast
Cancer (TNBC) is the most aggressive type of breast cancer. TNBC patients are
resistant to virtually all target therapies and suffer a higher post-chemotherapy
relapse with a worse overall survival compared with other types of breast
cancers. Therefore, the development of an effective therapy is urgently needed.
PKM2 plays a prominent role in mediating<b>
</b>tumor glycolysis and PKM2 is often overexpressed in human cancers. However,
whether PKM2 mediated glycolysis is necessary for cancer cell growth is
questionable. Here, I have found that inhibition of PKM2 does not affect TNBC cell
growth due to a metabolic switch from glycolysis to fatty acid oxidation (FAO).
We show that PKM2 directly interacts with EZH2 to coordinately mediate
epigenetic silencing of SLC16A9, transporter of a key player in FAO, Carnitine.
Inhibition of either PKM2 or EZH2 increases levels of SLC16A9 and intracellular
Carnitine to promote FAO and thereby sustains cancer cell growth. Direct
inhibition of EZH2 using a clinically tested EZH2 inhibitor, GSK126, is able to
elicit a previously unidentified vulnerability to a clinically tested FAO
inhibitor, Etomoxir. As a result, combined GSK126-Etomoxir treatment
synergistically abolishes TNBC xenograft tumor growth in vivo. Together, this
study uncovers PKM2-EZH2 mediated metabolic reprogramming that leads to a new
drug combination therapy by dual targeting of EZH2 and FAO for effective
treatment of TNBC.<b>
</b></p>
<p> </p>
<p>Furthermore, Dendritic Cell
(DC) vaccination has shown promise in treating cancer patients. However, the <i>in
vitro</i> generation of a fully functional DC remains a big challenge in this
field. EZH2 inhibition has shown to be able to create an immunologically ‘hot’ tumors.
Nonetheless, the role of EZH2 in regulation of DC function is still unclear. I
found that the expression levels of EZH2 and its functional maker, H3K27Me3,
are enhanced following maturation from immature DC (iDC) into two functional
DCs, α-type 1-polarized-DC
(αDC) and gold
standard DC (sDC). Moreover, inhibition of EZH2 by GSK126 treatment elicits a
dependency of sDC on FAO.
These results suggest that EZH2 plays a role in maturation of DC through metabolic
reprogramming, which may also provide new DC based immunotherapy of
TNBC. </p>
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Vliv akalabrutinibu a ibrutinibu na účinek daunorubicinu v nádorových buňkách. / The effect of acalabrutinib and ibrutinib on the efficacy of daunorubicin in cancer cells.Čermáková, Lucie January 2020 (has links)
Charles University Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Lucie Čermáková Supervisor: RNDr. Eva Novotná, Ph.D. Title of diploma thesis: The effect of acalabrutinib and ibrutinib on the efficacy of daunorubicin in cancer cells Leukemia presents malignant diseases of hematopoiesis, which essence is the malignant transformation of a hematopoietic stem cell at various levels of maturation and increased proliferative activity. Chemotherapy is the gold standard in the treatment of leukemia. One of the many treatments is the use of anthracycline chemotherapeutics, especially daunorubicin (DAU). Anthracyclines are widely used in clinical practice but have high cardiotoxic effects that limit their dosage. One of the main causes of side effects is the reduction of an anthracycline chemotherapeutic to the appropriate toxic metabolite, which accumulates in the heart. Carbonyl, reducing enzymes from the superfamily aldo-ketoreductase (AKR), and short-chain dehydrogenase/reductase (SDR) are involved in this reduction. At the same time, carbonyl reducing enzymes, has been shown to be involved in the mechanisms that cause tumor cells to be resistant to anthracyclines, thereby reducing the inhibition of the growth of these cells. In the diploma thesis we found that...
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ROLE OF TET2 IN LUMINAL DIFFERENTIATION AND HORMONE THERAPY RESPONSE IN BREAST CANCERMi Ran Kim (8066174) 03 December 2019 (has links)
<p>Epigenetic mechanisms, including
DNA methylation, play an important role in regulation of stem cell fate and
tumorigenesis. The Ten-Eleven-Translocation 2 (TET2) is a core enzyme for DNA
demethylation by catalyzing the conversion of 5-methylcytosine (5mC) to
5-hydromethylcytosine (5hmC). It has been shown that TET2 is the main regulator
of hematopoietic stem cell homeostasis and loss of TET2 is highly associated
with hematopoietic malignancies. Our previous work has also shown that loss of
TET2 expression is linked to promotion of an epithelial-mesenchymal-transition phenotype
and expansion of a breast cancer stem cell-like population with skewed
asymmetric cell division in vitro;
however, the in vivo role that
TET2 plays in regulation of mammary stem cell (MaSC) fate and development of
mammary pathology has yet to be determined. Here, using our newly established
mammary-specific Tet2-knockout mouse model, the data reveals for the first time
that TET2 plays a pivotal role in mammary gland development via directing MaSC
to luminal lineage commitment in vivo. Furthermore, we find that TET2
coordinates with FOXP1 to target and demethylate FOXA1, GATA3, and ESR1, key
transcription factors that orchestrate mammary luminal lineage specification
and endocrine response and are often silenced by DNA methylation in aggressive
human breast cancers. Finally, loss of TET2 expression leads to promotion of
mammary tumor development with defective luminal cell differentiation and tamoxifen
resistance in a PyMT;Tet2 deletion breast cancer mouse model. As a result, this study provides a previously
unidentified role for TET2 in governing luminal lineage specification and
endocrine response that underlies resistance to anti-estrogen treatments.</p>
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The Role of Signal Transducer and Activator of Transcription 1 (STAT1) and 3 (STAT3) in Primary and Metastatic Breast CancerRemah Ali (8086364) 05 December 2019 (has links)
<p>Breast cancer is the most frequently diagnosed malignancy and the second
most lethal cancer in women. Metastasis in breast cancer is invariably responsible for patient death
and is comprised of
many steps, of which proliferation in vital organs is responsible for morbidity
and mortality due to vital organ failure. Patients with the metastatic disease
are limited to chemotherapy, which non-specifically targets proliferating
cells. Despite it being initially effective, chemotherapy is associated with high
toxicity and many patients develop resistance. Thus, there is an urgent need to
characterize the biology of metastatic breast cancer to develop targeted
therapies for the late-stage disease.</p>
<p>EGFR is a member of the ErbB family of receptor tyrosine kinases, which
have particular relevance in breast tumorigenesis. Clinical studies show that
high expression levels of EGFR in the primary mammary tumors correlate with
poor prognosis and decreased survival of breast cancer patients due to
metastasis. Patient data is supported by experimental and pre-clinical studies,
which describe various signaling pathways that mediate the oncogenic effects of
EGFR, such as the MAPK, STAT3, and PI3K pathways. Despite these well-documented
roles of EGFR, clinical trials evaluating EGFR inhibitors (EGFRi) in metastatic
breast cancer have been unanimously unsuccessful in improving patient
prognosis, and the mechanisms that contribute to this intrinsic resistance are
unknown.</p>
<p>To characterize the signaling events that govern EGFR behavior in
metastatic breast cancer resistant to EGFRi, we utilized multiple pre-clinical
breast cancer progression series and patient-derived cells that display the intrinsic resistance phenomenon.
In these models, EGFR functions as a pro-apoptotic molecule whose
ligand-mediated activation results in growth inhibition and/or apoptosis of
metastatic breast cancer cells. Here we show that in the later stages of metastasis, increased nuclear translocation
of EGFR leads to increased physical access to STAT1 and STAT3 molecules
residing in the nucleus. Indeed, an EGFR mutant that is defective in
endocytosis is unable to elicit STAT1/3 phosphorylation. Additionally, specific
inhibition of nuclear EGFR function using the EGFR kinase inhibitor gefitinib
linked to a nuclear localization signal (NLS-gefitinib) prevents EGF-induced
STAT1/3 phosphorylation. Altogether, these findings implicate nuclear
localization of EGFR in downstream STAT1/3 signaling in metastatic breast
cancer.</p>
<p>Subsequently, we examined the involvement of nuclearly-activated STAT1/3
signaling in the apoptotic function of EGFR. NLS-gefitinib treatment or
genetic/pharmacologic inhibition of STAT1/3 efficiently blocks EGF-induced
apoptosis in metastatic breast cancer cells resistant to EGFRi. These findings were utilized
therapeutically by activating EGFR with EGF treatment while simultaneously
blocking the downstream proliferative MAPK:ERK1/2 pathway using the MEK1/2
inhibitor trametinib. EGF + trametinib combination preserved STAT1 signaling
while effectively blocking the MAPK pathway, thus potentiating EGF-mediated
apoptosis in metastatic breast cancer cells. Importantly, combined
administration of trametinib and EGF resulted in STAT1-mediated apoptosis of
primary mammary tumor cells, which respond to EGF in a proliferative fashion.
These data provide a novel approach of targeting metastatic breast cancer by
biasing EGFR signaling towards nuclear activation of STAT1/3 signaling
resulting in apoptosis.</p>
Our studies herein also
examined the role of STAT3 in primary mammary tumor cells overexpressing EGFR.
Depletion of STAT3 expression normalized the transformed phenotype of these
cells <i>in vitro</i> and resulted in
smaller mammary tumors <i>in vivo</i>. These
results implicate STAT3 in EGFR-driven breast tumorigenesis localized to the
mammary tissues. Further, systemic dissemination of breast cancer is associated
with activation of the JAK1/2:STAT3 signaling axis. Despite the involvement of
STAT3 in EGFR-mediated oncogenesis in the primary tumor setting, targeting
JAK1/2:STAT signaling with the JAK1/2 inhibitor ruxolitinib proved ineffective
in inhibiting the growth and invasion of metastatic cells derived from these
primary tumors. These results are in agreement with the role of STAT1/3 in
driving the pro-apoptotic function of EGFR in metastatic breast cancer cells.
Altogether, these investigations provide a plausible explanation for the
inability of JAK1/2 inhibitors to effectively target metastatic breast cancer
in clinical and experimental investigations. Further, these findings indicate
that the development of therapeutics or molecular tools that efficiently
activate STAT1/3 signaling in metastatic breast cancer may represent an
important concept for eradicating tumors resistant to targeted therapies.
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EFFECTS OF THROMBIN ON THE GROWTH OF PANCREATIC CANCER CELLS AND CANCER ASSOCIATED FIBROBLASTS USING A MICROFLUIDIC MODELJonathan J Gilvey (10708920) 01 June 2021 (has links)
Thrombotic events are known to be associated with various cancers and recent research has implicated parts of the coagulation systemin promoting cancer progression. In particular, thrombin has been studied for its mitogenic effects in 2D cultures as well as in cancer progression in vivo in animal models however, conflicting results exist. Studies of proliferation in response to thrombin stimulation, of pancreatic cancer cells or pancreatic cancer-associated fibroblasts (CAFs) in vitro, that utilize a3D culture platform are significantly limited. In this study, PDAC cancer cells and cancer-associated fibroblast (CAF) cells were exposed to thrombin using a microfluidic device that mimics in vivo conditions. The cells used herein were cultured in a microfluid device, suspended inside of a 3D collagen matrix, and exposed to daily stimulation of 1 U/mL of thrombin in serum-free media for one hour. The findings of this study are that there is no statistically significant effect, promotive or inhibitory, on the proliferation of the cells used in this study, these results were unexpected. At the end of this paper, a review of potential reasons as to why no significant effect was seen on the cells is presented.
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Regulation of Energy Metabolism in Extracellular Matrix Detached Breast Cancer CellsMadeline Sheeley (10676388) 07 May 2021 (has links)
<p>Breast cancer is the
predominant cancer diagnosed among women, and the second most deadly cancer.
The vast majority of cancer-related deaths is caused by the metastatic spread
of cancer from the primary tumor to a distant site in the body. Therefore, new
strategies which minimize breast cancer metastasis are imperative to improve
patient survival. Cancer cells which acquire anchorage independence, or the
ability to survive without extracellular matrix attachment, and metabolic flexibility
have increased potential to metastasize. In the present studies, the ability to
survive detachment and subsequent metabolic changes were determined in human
Harvey-<i>ras</i> transformed MCF10A-<i>ras</i> breast cancer cells. Detachment
resulted in reduced viability in a time-dependent manner with the lowest cell
viability observed at forty hours. In addition, decreased cell viability was
observed in both glutamine and glucose depleted detached conditions, suggesting
a dependence on both nutrients for detached survival. Compared to attached
cells, detached cells had reduced total pool sizes of pyruvate, lactate, α-ketoglutarate, fumarate, malate, alanine,
serine, and glutamate, suggesting the metabolic stress which occurs under
detached conditions. However, intracellular citrate and aspartate pools were
unchanged, demonstrating a preference to maintain these pools in detached
conditions. Compared to attached cells, detached cells had suppressed glutamine
metabolism, as determined by decreased glutamine flux into the TCA cycle and
reduced mRNA abundance of glutamine metabolizing enzymes. Further, detached
glucose anaplerosis through pyruvate dehydrogenase activity was decreased,
while pyruvate carboxylase (PC) expression and activity were increased. A
switch in metabolism was observed away from glutamine anaplerosis to a
preferential utilization of PC activity to replenish the TCA cycle, determined
by reduced PC mRNA abundance in detached cells treated with a cell-permeable
analog of α-ketoglutarate,
the downstream metabolite of glutamine which enters the TCA cycle. These
results suggest that detached cells elevate PC to increase flux of carbons into
the TCA cycle when glutamine metabolism is reduced. </p>
<p>Vitamin D is recognized for its role in preventing breast cancer
progression, and recent studies suggest that regulation of energy metabolism
may contribute to its anticancer effects. Vitamin D primarily acts on target
tissue through its most active metabolite, 1α,25-dihydroxyvitamin D (1,25(OH)<sub>2</sub>D). The present work
investigated 1,25(OH)<sub>2</sub>D’s effects on viability of detached cells
through regulation of energy metabolism. Treatment of MCF10A-<i>ras</i> cells
with 1,25(OH)<sub>2</sub>D resulted in decreased viability of detached cells.
While 1,25(OH)<sub>2</sub>D treatment did not affect many of the glucose
metabolism outcomes measured, including intracellular pyruvate and lactate pool
sizes, glucose flux to pyruvate and lactate, and mRNA abundance of enzymes
involved in glucose metabolism, 1,25(OH)<sub>2</sub>D treatment reduced detached
PC expression and glucose flux through PC. A reduction in glutamine metabolism
was observed with 1,25(OH)<sub>2</sub>D treatment, although no 1,25(OH)<sub>2</sub>D
target genes were identified. Further, PC depletion by shRNA decreased cell
viability in detached conditions with no additional effect with 1,25(OH)<sub>2</sub>D
treatment. Moreover, PC overexpression resulted in increased detached cell
viability and inhibited 1,25(OH)<sub>2</sub>D’s negative effects on viability.
These results suggest that 1,25(OH)<sub>2</sub>D reduces detached cell
viability through regulation of PC. Collectively this work identifies a key
metabolic adaptation where detached cells increase PC expression and activity
to compensate for reduced glutamine metabolism and that 1,25(OH)<sub>2</sub>D
may be utilized to reverse this effect and decrease detached cell viability.
These results contribute to an increased understanding of metastatic processes
and the regulation of these processes by vitamin D, which may be effective in
preventing metastasis and improve breast cancer patient survival.</p>
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Facile Synthesis of Anticancer Drug NCX 4040 in Mild ConditionsXiao, Mei, Yang, Hongsong, Klein, Suzane M., Muenyi, Christian M., Stone, William L., Jiang, Yu L. 01 October 2008 (has links)
A simple method is reported to synthesize an anticancer drug, NCX 4040, conveniently in mild conditions using silicon chemistry. A starting material, 4-hydroxybenzyl alcohol, was silylated selectively first to give t-butyldimethylsilyl 4-hydroxybenzyl ether, which was then converted to NCX 4040 by esterification, desilylation, hydrochlorination and nitration.
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