Mechanism of PPAR-γ Activators in Tumour Suppression

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play essential roles in the regulation of cellular differentiation, development and metabolism. Since the introduction of the thiazolidinedione class of PPAR-γ activators in the late 1990s to treat type 2 diabetes, the use of PPAR-γ ligands to treat other conditions, including cancer, has been investigated. Researchers at the Mayo Clinic discovered that human anaplastic thyroid tumour cells treated with the PPAR-γ activator, RS5444, express a protein known as p21 that inhibits cell replication and suppresses tumour growth, but the underlying mechanism was not understood.


The group has now shown that activation of PPAR-γ with RS5444 (also known as CS-7017) turns on the RhoB tumor suppressor gene, which in turn induces p21 expression, thereby shutting down the cell cycle and blocking tumour growth. The researchers say that it is unusual for a cancer drug to be able to cause re-expression of a suppressed gene in this way, and hope that other cancers in which RhoB is deactivated, such as head and neck, brain, and lung cancers, might respond to RS5444 or to similar drugs. RS5444 is undergoing phase I/II clinical trials (in combination with paclitaxel) in patients with anaplastic thyroid cancer and phase II trials (in combination with carboplatin/paclitaxel) in patients with metastatic non-small cell lung cancer.

New Study Casts Light on Anti-Cancer Mechanism

siramesineA new study describes a high affinity interaction between siramesine and phosphatidic acid, a component of cell membranes that also acts as a signalling molecule. Siramesine is a sigma receptor agonist, selective for the σ2 subtype, which was originally under development for the treatment of anxiety but failed to show efficacy in clinical trials.

Siramesine was subsequently shown to kill cancer cells by destabilising their lysosomes. Vincristine, a microtubule destabilising antimitotic drug, which is used in various chemotherapy regimens, greatly sensitised cancer cells to the cytotoxic effects of siramesine.

The new study suggests that it may be possible to design small molecules to specifically scavenge phospholipids involved in the signalling cascades controlling cell survival.

New Antipsychotic Mechanism Discovered

PET scanIt has been estimated that as many as 50 million people worldwide suffer from schizophrenia and many of these will be treated with antipsychotic medicines. The so-called typical antipsychotics have been available since the mid-1950s and a number of newer agents, the atypical antipsychotics, have been introduced since 1990. Increased dopaminergic activity is thought to be a contributory factor in schizophrenia and all of the antipsychotic medicines interact with the dopamine D2 receptor although they have different affinities and modulate the receptor in different ways.

A new study has shown that, regardless of their effect on G-protein coupled signalling via the D2 receptor, antipsychotic drugs potently antagonize the dopamine-mediated interaction of the D2 receptor with β-arrestin-2.

Arrestins are proteins that were initially found to regulate signal transduction by silencing GPCRs, although they have recently been shown to directly activate signalling pathways. The new results suggest that selective targeting of the interaction of D2 with β-arrestin-2 may provide a new opportunity for the development of antipsychotic medicines. More generally, targeting β-arrestin signalling pathways may open opportunities in other therapeutic areas.