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Tumor Discovery PPAR agonist and cancer

of the high-affinity PPAR-γ agonist RS5444 and paclitaxel As shown in Figure 3, the PPAR agonist pioglitazone
exhibited a reduction in the proliferation rate of cells and and the histone deacetylase inhibitor valproic acid
minimized tumor growth of undifferentiated thyroid synergistically regulate E-cadherin expression and inhibit
neoplasm carcinoma in vivo. Although RS5444 alone did not the growth and invasion of prostate cancer compared to
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induce apoptosis, its combination with paclitaxel increased individual therapies. The PPAR-γ agonist rosiglitazone, in
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the apoptotic index twofold compared to paclitaxel alone. combination with radiotherapy, enhances the effectiveness
Moreover, activation of PPAR-γ by its ligand pioglitazone of radiotherapy to improve local tumor control, decrease
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intensifies the effects of cisplatin, inhibiting MDA-MB-231 the risk of distant metastasis, and delay tumor recurrence.
cell survival compared to chemotherapy alone. This effect Survivin is the smallest member of the apoptosis inhibitor
may be attributed to enhanced apoptosis resulting from protein family, and its aberrant expression is correlated
the downregulation of the antiapoptotic protein Bcl-2 with tumor cell proliferation, progression, angiogenesis,
and increased levels of caspase-9 and cleaved PARP, as resistance to therapy, and poor prognosis. Survivin is
explained in Figure 2. Pouya et al. illustrated that the predominantly expressed in most human malignancies,
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co-delivery of capecitabine–pioglitazone-loaded triblock including lung, pancreatic, and breast cancers, compared
nanoparticles effectively destroyed colorectal cancer cells to normal tissues. A natural PPAR-γ agonist, 15d-
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in vitro. This approach could achieve the co-delivery of PGJ2 (15-Deoxy-Δ12,14-PGJ2), has been investigated for
capecitabine and pioglitazone, utilizing the potential of over a decade. Studies have shown that it possesses pro-
both drugs and increasing the longevity of patients with apoptotic, anti-inflammatory, antiangiogenic, and anti-
colorectal cancer. 75 metastatic properties, along with significant anticancer
effects. Co-treatment with 15d-PGJ2 and survivin RNAi
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4.3. PPAR agonists for prevention of cell migration synergistically inhibits the stem cell phenotype and cell
and invasion proliferation of bladder cancer in vitro by upregulating ROS
The first stage of the metastatic cascade is invasion, which production and generating oxidative stress mediated by
occurs when tumor cells migrate, infiltrate the surrounding NADPH oxidase 2. This study suggests that the combined
tissue, and enter lymphatic and blood vessels to spread. treatment of survivin inhibitors and PPAR-γ agonists may
A growing body of research suggests that mutations may have therapeutic significance in the clinical treatment of
drive and accelerate the invasion and migration of various various cancers. 83
cancer cell types. The antimigration and anti-invasion
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effects of radiation were enhanced by rosiglitazone, a 4.4. PPAR agonists for induction of oxidative stress
PPAR-γ agonist that decreased cell viability. Rosiglitazone ROS plays a major role in regulating normal cellular
increased the radiosensitivity of PANC1 xenografts and functions, but when they are uncontrolled, they can
pancreatic cancer cells. According to microarray studies, contribute to diseases such as cancer. Increased ROS
the combination of rosiglitazone and radiation altered generation has been observed in several studies, activating
the expression of several genes and impacted various protumorigenic signaling, enhancing cell survival and
pathways. In addition, a novel PPAR-γ ligand, CB13, proliferation, and promoting DNA damage and genetic
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inhibits cell growth by increasing lactate dehydrogenase instability. However, it has also been discovered that higher
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release, decreasing cell viability, and enhancing caspase-3 concentrations of ROS can encourage antitumorigenic
and caspase-9 activities in non-small cell lung cancer signaling by triggering oxidative stress-induced tumor
(NSCLC) and radioresistant NSCLC cell lines (A549R and cell death. Tumor cells adapt by producing higher levels
H460R). Furthermore, CB13 generates reactive oxygen of antioxidant proteins to detoxify excess ROS while
species (ROS) and induces endoplasmic reticulum (ER) maintaining protumorigenic signaling and resistance
stress, leading to cell death. When CB13 is combined to apoptosis. The effects of various PPAR agonists on
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with radiation, ER stress, and cell death are significantly elevating ROS levels in cancer cells are summarized in
increased compared to using CB13 alone. 56 Figure 4.
Lyon et al. were the first to demonstrate that long-term The combination therapy of PPAR-γ ligands and COX-2
in vivo treatment with a chemopreventive mixture, which inhibitors has shown anti-inflammatory and antineoplastic
includes selenium (an antioxidant), rosiglitazone, sodium effects in vitro and has been evaluated for its therapeutic
phenylbutyrate or valproic acid (histone deacetylase potential in several preclinical and clinical studies. As
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inhibitors), and hydralazine (a cytosine-demethylating agent), illustrated in Figure 4, PPAR-γ ligands can enhance γ-H2AX
could effectively block the development of premalignant expression, thereby magnifying the DNA damage response
lung cancer in the A/J mouse model treated with NNK induced by γ-radiation. Furthermore, the combined
(4-methylnitrosamino)-1-(3-pyridyl)-1-butanone. 78 treatment significantly increased ROS generation, whereas

Volume 3 Issue 4 (2024) 6 doi: 10.36922/td.4003