Metabolic effects of diethylstilbestrol and its polymer conjugate in hypoxic prostate tumour cells

The transcription factor hypoxia-inducible factor-1α (HIF-1α), whose levels are substantially elevated in several tumour types, represents a major molecular target for the development of new anti-cancer drugs. The synthetic non-steroidal estrogen diethylstilbestrol (DES) blocks HIF-dependent hypoxic responses, and its administration at low doses prior to chemotherapy represents a promising option to improve the treatment of castration-resistant prostate cancer. However, DES use is limited by poor water solubility and wide-ranging dose-related toxicities. Aiming at improving the therapeutic window of this drug, the research group of Dr. María Vicent (CIPF, Valencia, Espanha) has developed a bioresponsive polyacetal-DES conjugate (tert-DES), shown to effectively inhibit HIF-1 with little to no cell toxicity. The study now published in the Journal of Drug Targeting, which results from a scientific collaboration between the Valencia group and the group of Dr. Iola Duarte from the University of Aveiro (CICECO, Department of Chemistry), describes the effects of DES and of its polymer conjugate on the metabolism of prostate tumour cells. Based on Nuclear Magnetic Resonance (NMR) analysis, the researchers have characterised the cellular metabolic responses to hypoxia and to pharmacological HIF-1α inhibition by DES or tert-DES. Metabolites like lactate, phosphocreatine and glutathione were proposed as marker metabolites of HIF-1α inhibition. Furthermore, the impact of the free drug on the cellular metabolome was shown to be more extensive than that of tert-DES, particularly regarding the activation of de novo polyamine and pyrimidine biosynthetic pathways, indicating higher specificity and lower toxicity upon conjugation.

Authors and Affiliations:

Ana Armiñán¹, Luís Mendes², Joana Carrola², Julie Movellan¹, María J. Vicent¹, Iola F. Duarte²

¹Polymer Therapeutics Lab., Centro de Investigación Príncipe Felipe (CIPF), Av. Autopista del Saler 16, 46012 Valencia, Spain.

²CICECO – Aveiro Institute of Materials, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.

Abstract:

In this study, we have employed ¹H NMR metabolomics to assess the metabolic responses of PC3 prostate tumour cells to hypoxia and to pharmacological HIF-1α inhibition by DES or its polyacetal conjugate tert-DES. Oxygen deprivation prompted a number of changes in intracellular composition and metabolic activity, mainly reflecting upregulated glycolysis, amino acid catabolism and other compensatory mechanisms used by hypoxic cells to deal with oxidative imbalance and energy deficit. Cell treatment with a non-cytotoxic concentration of DES, under hypoxia, triggered significant changes in 17 metabolites. Among these, lactate, phosphocreatine and reduced glutathione, whose levels showed opposite variations in hypoxic and drug-treated cells, emerged as possible markers of DES-induced HIF-1α inhibition. Furthermore, the free drug had a much higher impact on the cellular metabolome than tert-DES, particularly concerning polyamine and pyrimidine biosynthetic pathways, known to be tightly involved in cell proliferation and growth. This is likely due to the different cell pharmacokinetics observed between free and conjugated DES. Overall, this study has revealed a number of unanticipated metabolic changes that inform on DES and tert-DES direct cellular effects, providing further insight into their mode of action at the biochemical level.

Journal: Journal of Drug Targeting

Link: http://www.tandfonline.com/doi/abs/10.1080/1061186X.2017.1358728?journalCode=idrt20