Endocrine disrupting and genotoxic potential of protein kinase inhibitors: relevance for environmental hazard

Principal investigator at the Institute of Oncology Ljubljana: Maja Čemažar PhD

Scientific and public concern regarding the occurrence of residues of pharmaceuticals in the environment has been increasing, as their presence has been demonstrated across a wide variety of hydrological, climatic and land-use settings, where they have been consistently detected. Pharmaceuticals excreted through feces and urine predominantly enter the aquatic environment via the effluent from hospital and municipal wastewater treatment plants. Based on their therapeutic functions and mechanisms of action, certain groups of pharmaceuticals are believed to represent a risk for non-target organisms, even at concentrations of a few nanograms per liter, and particularly under conditions of chronic exposure [Fent et al., 2006]. One such group of pharmaceuticals is the anti-cancer drugs. Of particular concern are their potential genotoxic and endocrine disrupting activities.

Inhibitors of protein tyrosin kinases (TKIs) are small molecules directed against specific kinases to specifically interfere with signaling pathways that are deregulated in certain types of cancers. Side effects associated with TKIs that were observed in treated patients include alterations in thyroid function, bone metabolism, gonadal function, fetal development, adrenal function, and glucose metabolism (Lodish, 2013) as well as occurrence of chromosomal aberrations in disease unrelated cells (Gniot et al., 2014) secondary cancers (Kyo et al., 2012). 

Over the past 15 years TKIs have become the pharmaceutical industry's most important class of target drug in the field of cancer treatment.  Some 20 drugs that target TKs have been approved for clinical use and hundreds more are undergoing clinical trials (Cohen and Alessi, 2013). Therefore, with the increasing clinical use of TKIs it is expected that also the occurrence of the residues of these drugs in the aquatic environment will increase. 

The main objectives of the proposed project will be: 

  1. To explore the consumption of TKIs in Slovenia and assess their environmental occurrence. 
  2. To explore genotoxic and endocrine activity of TKIs in current clinical use, in relation to their specific protein kinase targets. 
  3. To explore the underlying molecular mechanisms of TKIs induced genotoxic and/or endocrine disrupting activities. 

The result of the project will be new knowledge that will contribute to the missing information necessary to evaluate the risk for environment and human health upon exposure to the residues of these drugs.

Details about the project are available on the website SICRIS: Endocrine disrupting and genotoxic potential of protein kinase inhibitors: relevance for environmental hazard.