Anticancer and Antiangiogenic Iron(II) Complexes That Target Thioredoxin Reductase to Trigger Cancer Cell Apoptosis

Abstract

Thioredoxin reductase (TrxR) is a selenoenzyme that could regulate intracellular oxidative balance and found to be overexpressed in many human tumor cells. Due to its important role in cancer progression, TrxR is becoming an attractive target in chemotherapeutic drug design. In this study, a new class of Fe(II) complexes with phenanthroline derivatives as ligands were synthesized and characterized. The mechanism of cell death induced by complex 3 revealed that the growth of cancer cells was suppressed by apoptosis and specifically inhibited the activities of TrxR. Furthermore, complex 3 exhibited brilliant antiangiogenic activity against HUVEC cells and inhibited cell migration and invasion. In addition, results of hematological analysis and H&E staining demonstrated that complex 3 has negligible toxicity on function of the major organs of mice. Taken together, this study provides a strategy for drug design to exploit Fe-based phenanthroline derivative as a chemotherapeutic agent in cancer treatment.

Cancer‐Targeting Functionalization of Selenium‐Containing Ruthenium Conjugate with Tumor Microenvironment‐Responsive Property to Enhance Theranostic Effects

“…[20] Cytosolic iron(II) complexes exhibiteda nticancer and antiangiogenic potencies by targeting mitochondriat ot rigger cancerc ell apoptosis. [21] Therefore, in this study,w en ext set out to elucidate the relationship between the anticancer action mechanisms and cellular localization of Ru-BSe.R u-BSe accumulatedi nt he cytoplasm after incubation for 6h.T he notable merge of mitochondria( green) and the conjugate (red) was observed ( Figure 5a), with Pearson's co-localization coefficient at 0.90. Meanwhile,q uantification of the luminescence intensity further confirmed the overlap of mitochondriaa nd Ru-BSe (Figure 5b).…”

“…Previously, we found that the cellular localization of iron(II) polypyridyl complexes determines their anticancer action mechanisms . Cytosolic iron(II) complexes exhibited anticancer and antiangiogenic potencies by targeting mitochondria to trigger cancer cell apoptosis . Therefore, in this study, we next set out to elucidate the relationship between the anticancer action mechanisms and cellular localization of Ru‐BSe.…”

Selenoproteins and Metastasis

“…One exception to this is the demonstrated importance of TXNRD1 in angiogenesis during the metastatic process. Reduced expression of TXNRD1 or treatment with reagents that target the TXNRD members exhibit antiangiogenic properties (Xie et al, 2016a). A pro-invasive role for TXNRD1 was shown in breast cancer studies using MDA-MB-231 cells and meta-analysis of 25 gene array studies with 5910 patients showed that thioredoxin-1 and TXNRD1 were both associated with a poor patient prognosis in terms of overall survival, distant metastasis free survival and disease free survival (Bhatia et al, 2016).…”

Iron(III) bis‐complexes of Schiff bases of S‐methyldithiocarbazates: Synthesis, structure, spectral and redox properties and cytotoxicity

“…Therefore to overcome the side effects new non‐platinum‐based drugs are being designed, synthesized and studied . Among the transition metal complexes of Cu(II), iron(III), Co(III), Ni(II), Zn(II) and Ru(II), those of Cu(II) and Fe(III) have now attracted much attention because they are essential trace metals that exist in more than one oxidation state within the human body and take part in many biological processes . The redox activity of the metals enables them to be incorporated with different organic and inorganic ligands to form complexes, and this property has been harnessed for the development of unique therapeutic compounds.…”