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Tumor Discovery PPAR agonist and cancer

in overcoming the challenges associated with finding as therapeutic targets with a wide range of potential
new agents. The process of using an already-approved applications in cell differentiation, apoptosis, angiogenesis,
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medication or drug candidate for a new medical condition epithelial–mesenchymal transition, and other biological
or treatment for which it was not previously recommended processes that are deregulated in cancer. 41,42
is known as “drug repurposing.” 29,30 To expedite the drug
discovery process and address the pressing needs in 4. PPAR modulators
healthcare, drug repurposing has become essential. In PPAR modulators are molecules that modulate the activity
drug repurposing, a drug is identified, preclinical models of PPAR receptors. PPAR agonists are compounds that
are used to assess its efficacy, and Phase II clinical trials activate the PPAR pathway. These ligands are developed
are then conducted. Among the various drugs that can to treat various diseases and disorders related to lipid
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be repurposed for synergistic cancer treatment, PPAR metabolism, diabetes, and metabolic syndromes. PPAR-α
agonists show promising results. agonists are primarily used to treat dyslipidemia, whereas
PPAR-γ agonists are prescribed for the treatment of
3. PPARs
Type 2 diabetes. PPAR-α agonists include a class of
PPARs are a group of nuclear receptor superfamily members chemicals called fibrates, which encompasses fenofibrate,
that play a major role in gene expression and metabolism gemfibrozil, bezafibrate, ciprofibrate, and clofibrate.
regulation. PPARs bind to ligands and translocate to the Several other compounds, such as pemafibrate, Wy-14643
cell nucleus. Together with their ligands, PPARs act as (pirinixic acid), and GW7674, are also known to act as
transcription factors that bind to specific DNA sequences PPAR-α agonists. In addition to these, omega-3 fatty
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known as peroxisome proliferator-responsive elements acids, curcumin, and sesquiterpenes are recognized for
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and heterodimerize with retinoid X receptors. The PPAR their PPAR-α agonist activity. PPAR-γ agonists are the
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superfamily comprises three subtypes: PPAR-α, PPAR-γ, most widely used. Several other compounds, including
and PPAR-β/δ. These PPAR subtypes share a relatively natural compounds and synthetic derivatives, have been
high similarity in molecular structure; however, there are identified as PPAR-γ agonists. This group includes a
significant differences in their biological functions, tissue class of drugs called thiazolidinediones (TZDs), whose
distribution, and ligand affinities. Figure 1 illustrates antidiabetic properties were discovered in the early 1980s.
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the differences between the PPAR subtypes and their Various natural products derived from traditionally
interactions with DNA. PPAR-α expression is primarily used medicinal plants and foods activate the PPAR-γ
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found in the liver, brown adipose tissue, heart, kidney, and receptor. Different fatty acids and fatty acid derivatives,
muscle tissue, where it regulates fatty acid β-oxidation and such as eicosanoids (e.g., 8‐S‐hydroxyeicosatetraenoic acid
energy homeostasis. PPAR-β/δ is ubiquitously expressed, [HETE] and leukotriene B4), can also activate PPAR-γ. In
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often at high levels in skeletal muscle, adipose tissue, heart, addition, several prostanoids, such as 15-deoxy-Δ12,14-
and the gastrointestinal tract, and it regulates fatty acid prostaglandin J2 (15d-PGJ2) and 15-HETE, can activate
metabolism and blood glucose levels. 35,36 PPAR-γ is highly PPAR-γ as well. Many in vivo studies have shown
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expressed in the heart, muscle, gastrointestinal tract, that some natural activators of PPAR-γ (e.g., honokiol,
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kidney, adipose tissue, immune cells, and endothelial cells. amorphofurtin 1, amorphofurtin B, and amorphastilbol)
PPARs are also important lipid sensors and regulators of improve metabolic parameters in diabetic animal
various metabolic pathways. They can promote endothelial models. 48-50 TZDs include pioglitazone, rosiglitazone,
nitric oxide synthase activation and modulate immune troglitazone (TGZ), rivoglitazone, and netoglitazone. Dual
and inflammatory responses. In addition to their well- or pan-PPAR agonists have also been developed, including
established roles, discoveries are being made regarding muraglitazar, tesaglitazar, and saroglitazar. 51-54 We have
the functions of PPARs in cancer. 38,39 Previous studies compiled a comprehensive review that summarizes the
have shown that the expression of PPAR-β/δ correlates available literature supporting the beneficial effects of
with tumor proliferation, whereas the activation of treatment with PPAR ligands in combination with existing
PPAR-α and PPAR-γ is associated with tumor suppression. therapies in cancer. Numerous examples exist where
Such generalizations may be overly simplistic due to the combination therapy has produced synergistic or additive
complex regulatory signals of PPARs, and their intricate effects on apoptosis, differentiation, and the ability to
mechanisms require further investigation. Consequently, reduce cell proliferation and tumor burden. Some studies
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the role of PPARs in cancer has gradually become a focal indicate that pretreatment with PPAR ligands can overcome
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40
point of research. More specifically, initially recognized resistance and reduce toxicity. Several mechanisms have
as key players in adipocyte differentiation and glucose been investigated to explain these protective effects. This
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regulation, PPAR-γ and PPAR-α have now been identified article focuses on studies that provide strong arguments
Volume 3 Issue 4 (2024) 3 doi: 10.36922/td.4003