Mixed copper(ii)–phenanthroline complexes induce cell death of ovarian cancer cells by evoking the unfolded protein response

Abstract

There is an ongoing need for development of new therapeutics that override acquired resistance to cancer therapy. Targeting endoplasmic reticulum by Cu(ii)–phenanthroline complexes may represent such alternative strategy to current cytotoxic drugs.

The first copper(ii) complex with 1,10-phenanthroline and salubrinal with interesting biochemical properties

“…In contrast, treatment by C0 induced massive alterations of endoplasmic reticulum (ER) and partially also mitochondria. 9 Then, to assess cytotoxic properties of newly synthetized C0SAL compound, we performed viability assay based on activity of cellular NAD(P)H-dependent oxidoreductases (MTT assay). While the treatment by SAL had no significant effect in wide concentration range (Fig.…”

“…[3][4][5][6][7][8] The involved molecular mechanism has been partially unveiled in a recent study where it has been evidenced how these compounds induce the pro-apoptotic branch of Unfolded Protein Response (UPR). 9 UPR is a coordinating adaptive program that responds to accumulation of incorrectly processed proteins in the endoplasmic reticulum (ER), a condition known as ER stress. The final cell response is dependent on a specific activity of individual pathways and can lead to adaptation or apoptosis, especially when ER stress is prolonged or severe.…”

Copper(II) Phenanthroline-Based Complexes as Potential AntiCancer Drugs: A Walkthrough on the Mechanisms of Action

“…All the studied compounds can interact with DNA, but the inversely correlated relation between DNA binding constants and anticancer potencies, brings to exclude that the biological properties observed would arise from a direct interaction with this target [ 25 ]. Recent results have partially unveiled the biological mechanism in ovarian (A-2780) cells of 2a , which induces Endoplasmic Reticulum (ER) Stress by activating the pro-apoptotic branch of the Unfolded Protein Response (UPR), as observed by overexpression of typical biomarkers, such as PERK, IRE1 and DDIT3, and alleviation of cytotoxicity in co-administration with ER-stress modulator Taursodeoxycholic Acid (TUDCA) [ 27 ].…”

“…As shown for 2a , complexes 4a – c exert their anticancer properties in A-2780 cells by inducing ER-stress and activating the pro-apoptotic branch of UPR. The cytotoxicity of these compounds, which differs according to the alkyl groups in the ITHn backbone, can be reduced by co-administration with TUDCA [ 27 ].…”

Cell-Tak coating may cause mis-normalization of Seahorse metabolic flux data

“…The extracellular flux (XF) measurement technology developed by Seahorse (Agilent) is an elegant method of measuring oxygen consumption and extracellular acidification rates in relatively small amounts of live biological material. We have previously used the Seahorse analyzer to study the effect of lipophilic cations on mitochondrial metabolism [1] inhibitory effect of the lipophilic positively charged moiety of methyltriphenylphosphonium (TPMP) on 2-oxoglutarate dehydrogenase [2] and the effect of Cu(II)–phenanthroline complexes on cellular metabolism [3] and in other studies.…”