Evaluation of the therapeutic efficacy of DPP-4 and SGLT-2 inhibitors in papillary thyroid cancer: In vitro studies

<p>

<span lang="EN-US" style="font-family:&#39;times new roman&#39; , serif">Papillary
thyroid carcinoma (PTC) is the most common type of thyroid cancer. Some of its
variants exhibit more aggressive features, including angioinvasion, which
refers to the ability of cancer cells to infiltrate blood vessels.
Angioinvasive cells typically function under conditions of oxidative stress,
characterized by excessive production of reactive oxygen species (ROS). These
molecules may damage DNA, proteins, and lipids and can also promote tumor
growth and aggressive behavior. Understanding how cancer cells respond to the
modulation of oxidative stress and cellular metabolism is therefore important
for the development of new therapeutic strategies.</span></p>

<p class="MsoNormal" style="text-align:justify;line-height:115%"><span lang="EN-US" style="font-family:&#39;times new roman&#39; , serif">Within
the scope of this scientific activity, the effects of two drugs commonly used
in the treatment of type 2 diabetes—SGLT2 and DPP-4 inhibitors—on oxidative
stress and cellular metabolism were evaluated in three thyroid cell lines,
including two cancer cell lines with angioinvasive characteristics. The cells
were treated with the inhibitors for 48 hours, after which the levels of ROS,
lipid peroxidation (MDA), total antioxidant capacity (TAC), and the
concentration of XIAP protein, which plays a key role in protecting cells from
programmed cell death, were determined. In addition, changes in cellular
metabolism were analyzed based on glucose consumption and lactate production,
as well as the concentration of the Ki67 protein, a commonly used marker of
cellular proliferative activity.</span></p>

<p class="MsoNormal" style="text-align:justify;line-height:115%"><span lang="EN-US" style="font-family:&#39;times new roman&#39; , serif">Analysis
of metabolic parameters demonstrated that the investigated drugs influenced the
way cells utilized glucose. In some cancer cell lines, changes were observed in
glycolytic indices based on the lactate-to-glucose ratio, suggesting modulation
of the so-called Warburg effect, a metabolic pattern characteristic of many
cancers. At the same time, Ki67 levels did not always change in parallel with
metabolic parameters, indicating that alterations in cellular metabolism do not
necessarily translate directly into changes in the rate of cell proliferation. The
results of the metabolic indices confirmed that SGLT2 and DPP-4 inhibitors may
affect the metabolic burden of cancer cells, particularly in cell lines with a
more aggressive phenotype. Under control conditions, these cells exhibited
higher glucose consumption and greater oxidative stress, whereas treatment with
the inhibitors led to partial stabilization of these parameters. The results
related to oxidative stress were consistent across all analyzed cell lines,
with the most pronounced changes observed in angioinvasive cancer cells.
Following treatment with SGLT2 and DPP-4 inhibitors, ROS levels decreased
markedly, and MDA concentrations were reduced, indicating diminished oxidative
damage to cellular membranes. At the same time, TAC increased, suggesting that
the cells were better equipped to neutralize excess free radicals.</span></p>

<p class="MsoNormal" style="text-align:justify;line-height:115%"><span lang="EN-US" style="font-family:&#39;times new roman&#39; , serif">Particularly
noteworthy were the results concerning XIAP protein. In cells treated with the
inhibitors, intracellular XIAP levels remained higher, while its concentration
in the culture medium was lower. Because XIAP is not physiologically secreted,
its presence outside the cell may indicate membrane damage or cell death.
Reduced release of XIAP therefore suggests improved cellular stability and
lower susceptibility to damage.</span></p>

<p class="MsoNormal" style="text-align:justify;line-height:115%"><span lang="EN-US" style="font-family:&#39;times new roman&#39; , serif">These
findings expand current knowledge on the relationship between oxidative stress,
metabolism, and the behavior of aggressive variants of papillary thyroid
carcinoma. They also demonstrate that drugs commonly used in diabetes therapy
may influence oxidative stress–related parameters in cancer cells by modulating
their metabolism and response to increased ROS production. Although SGLT2 and
DPP-4 inhibitors are not anticancer drugs, the obtained results provide a basis
for further research into the role of metabolism and redox balance in potential
therapeutic strategies for more invasive forms of PTC.</span></p>