Peroxisome Proliferator-Activated Receptors (PPAR)γ Agonists as Master Modulators of Tumor Tissue

Abstract

In most clinical trials, thiazolidinediones do not show any relevant anti-cancer activity when used as mono-therapy. Clinical inefficacy contrasts ambiguous pre-clinical data either favoring anti-tumor activity or tumor promotion. However, if thiazolidinediones are combined with additional regulatory active drugs, so-called ‘master modulators’ of tumors, i.e., transcriptional modulators, metronomic low-dose chemotherapy, epigenetically modifying agents, protein binding pro-anakoinotic drugs, such as COX-2 inhibitors, IMiDs, etc., the results indicate clinically relevant communicative reprogramming of tumor tissues, i.e., anakoinosis, meaning ‘communication’ in ancient Greek. The concerted activity of master modulators may multifaceted diversify palliative care or even induce continuous complete remission in refractory metastatic tumor disease and hematologic neoplasia by establishing novel communicative behavior of tumor tissue, the hosting organ, and organism. Re-modulation of gene expression, for example, the up-regulation of tumor suppressor genes, may recover differentiation, apoptosis competence, and leads to cancer control—in contrast to an immediate, ‘poisoning’ with maximal tolerable doses of targeted/cytotoxic therapies. The key for uncovering the therapeutic potential of Peroxisome proliferator-activated receptor γ (PPARγ) agonists is selecting the appropriate combination of master modulators for inducing anakoinosis: Now, anakoinosis is trend setting by establishing a novel therapeutic pillar while overcoming classic obstacles of targeted therapies, such as therapy resistance and (molecular-)genetic tumor heterogeneity.

Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1α/PPAR-γ/PKM2-mediated glycolysis

“…PPAR-γ plays an important role in maintaining energy homeostasis through the modulation of glucose and lipid metabolism, and PPAR-γ is usually overexpressed in cancer cells causing accelerated tumor growth [58,59]. However, the role of PPAR-γ agonists and antagonists in tumor treatment is complex, as both have been found to inhibit the growth of tumor cells [58,[60][61][62]. PPAR-γ has been found to promote glucose uptake during lipid metabolism, and can induce the expression of glycolytic proteins, including GLUT-4 [63].…”

Clinical Efficacy of a Novel Therapeutic Principle, Anakoinosis

“…Glitazones are the most frequently used transcriptionally active master modulators for anakoinosis induction besides glucocorticoids (Heudobler et al, 2018b ). For example, pioglitazone, a peroxisome-proliferator-activated receptor (PPAR) γ/α agonist, seems to be an important many-sided applicable master modulator for communicative processes in neoplasia.…”

PPARs as Nuclear Receptors for Nutrient and Energy Metabolism

“…However, it was first reported that GW501516, a PPARβ/δ agonist, protected mice on a HFD from obesity by activating the lipin1-PGC1α-PPARα pathway, thus increasing fatty acid intake and oxidation [74]. In addition, given the high expression of PPARβ/δ in the intestine, HFD- and agonist-activating PPARβ/δ promoted organoid to product progenitors and even facilitated tumor formation in vivo to inhibit the tumor suppressor adenomatous polyposis coli (APC) protein [75,76]. For mice fed a HFD, the expression of PPARs depended on many factors, including species and tissue type and period of development.…”