PPAR-γ Agonists As Antineoplastic Agents in Cancers with Dysregulated IGF Axis

Abstract

It is now widely accepted that insulin resistance and compensatory hyperinsulinemia are associated to increased cancer incidence and mortality. Moreover, cancer development and progression as well as cancer resistance to traditional anticancer therapies are often linked to a deregulation/overactivation of the insulin-like growth factor (IGF) axis, which involves the autocrine/paracrine production of IGFs (IGF-I and IGF-II) and overexpression of their cognate receptors [IGF-I receptor, IGF-insulin receptor (IR), and IR]. Recently, new drugs targeting various IGF axis components have been developed. However, these drugs have several limitations including the occurrence of insulin resistance and compensatory hyperinsulinemia, which, in turn, may affect cancer cell growth and survival. Therefore, new therapeutic approaches are needed. In this regard, the pleiotropic effects of peroxisome proliferator activated receptor (PPAR)-γ agonists may have promising applications in cancer prevention and therapy. Indeed, activation of PPAR-γ by thiazolidinediones (TZDs) or other agonists may inhibit cell growth and proliferation by lowering circulating insulin and affecting key pathways of the Insulin/IGF axis, such as PI3K/mTOR, MAPK, and GSK3-β/Wnt/β-catenin cascades, which regulate cancer cell survival, cell reprogramming, and differentiation. In light of these evidences, TZDs and other PPAR-γ agonists may be exploited as potential preventive and therapeutic agents in tumors addicted to the activation of IGF axis or occurring in hyperinsulinemic patients. Unfortunately, clinical trials using PPAR-γ agonists as antineoplastic agents have reached conflicting results, possibly because they have not selected tumors with overactivated insulin/IGF-I axis or occurring in hyperinsulinemic patients. In conclusion, the use of PPAR-γ agonists in combined therapies of IGF-driven malignancies looks promising but requires future developments.

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“…Conversely, PPARɣ has been shown in in vitro studies to promote growth inhibition, apoptosis, cell cycle arrest, and re-differentiation of a malignant cell line. [80][81][82] As a result, both substrates provide an opportunity for cancer cell targeting and inhibition of growth and development by way of inhibition of COX-2 and activation of PPARɣ. Uram and colleagues (2018) achieved this by utilizing the COX-2 inhibitor, celecoxib, and PPARɣ agonist, Fmoc-L -Leucine, to conjugate with biotinylated G3 PAMAM dendrimers (G3-BCL).…”

Gastric Damage and Cancer-Associated Biomarkers in Helicobacter pylori-Infected Children

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“…As will be discussed in the next section, a wide variety of phytochemicals have PPARγ ligand activity, so it is possible that the betel nut may contain a compound with PPARγ ligand activity as well. Nonetheless, this lack of a consistent correlation between TZD use on oral and head and neck cancer risk is seen in other cancers, as recent meta‐analyses indicate that TZD use has modest to no association with reduced cancer risk . This lack of conclusive epidemiological evidence demonstrating an antineoplastic activity of PPARγ agonists in SCC of the skin or upper gastrointestinal tract may be due to the fact that the studies are retrospective in nature and are limited to TZD‐class PPARγ ligands and to diabetics.…”

“…Nonetheless, this lack of a consistent correlation between TZD use on oral and head and neck cancer risk is seen in other cancers, as recent meta-analyses indicate that TZD use has modest to no association with reduced cancer risk. 30,31 This lack of conclusive epidemiological evidence demonstrating an antineoplastic activity of PPARγ agonists in SCC of the skin or upper gastrointestinal tract may be due to the fact that the studies are retrospective in nature and are limited to TZD-class PPARγ ligands and to diabetics. Since TZDs generally represent second or third line treatments in diabetics, significant ascertainment bias is possible since TZD use is associated with patients who are typically older, have had diabetes for a longer period of time, and have a higher likelihood of poor glycemic control, all of which may be associated with a higher cancer risk.…”