| dc.description.abstract | Muscle Invasive Bladder Cancers (MIBCs) contributes to approximately 30% of bladder
cancer at initial diagnosis in patients, accompanied by an only 50% five-year survival
rate. The standard procedure for treating this type of cancer has not changed for
years, still relying on cystectomy accompanied with chemotherapy, thus encouraging
new endeavours in this field of cancer research.
One such approach is looking at interactions between the essential scaffold protein
PCNA and proteins containing the Akt2 homologoue PCNA Interacting Motif (APIM).
Due to the fact that these proteins handles stress responses in the cell, an inhibition of
the Motif could therefore greatly affect traditional chemotherapy.
The UM-UC-3 cell line chosen for this study had already presented good initial
results, seeing increased apoptosis upon a combinatorial treatment consisting of the
chemotherapy drug cisplatin together with a APIM peptide developed at IKM called
ATX-101. This project was designed to further elucidate the influence of this treatment,
performing a metabolic study looking at the changes in amino acids, low molecular
weight organic acids and phosphorylated metabolites of the endometabolome. There
was also performed an exometabolic study measuring the consumption of d-Glucose, l-
Lactate and l-Glutamine. The experimental set up consisted of four different treatments
a control, two single and a combinatorial treatment using ATX-101 and cisplatin
with a time frame of exposure of 24h before harvesting.
Two of three replicates saw a significant doubling in Glucose uptake under Cisplatin
stress, while no significant changes took place for the other treatments in regards to
control. There were found no significant changes in Lactate production, and unfortu-
nately the Glutamine data obtained was inconclusive. There was a large separation
between cisplatin treated groups against non-treated groups for all endometabolites,
where cisplatin provided a significant doubling in concentration for nearly all metabol-
ites. While a distinction by ATX-101 was not so easily discerned, for organic and amino
acids the increase of the combinatorial group was halted, leading to fewer doubled meta-
bolite concentrations. It was however found that ATX-101 did significantly influence
the glycolysis and pentose phosphate pathway both alone and in a combinatorial set-
ting. Cisplatin exposed treatments also saw at least a doubling for nearly all nucleoside
phosphates, while having a lowered over all energy charge in regards to control.
These findings demonstrates that while ATX-101 does not exhibit significant change
upon the distribution of amino and organic acids, it does act significantly upon the
energy pathways of the cell both alone and in combination with a chemotherapeutic
drug such as cisplatin. This further inspires more research to be performed on this
topic, paving the way for new cancer treatments of the future. | en |
