Rational Design of Heterometallic Water-Soluble Yttrium Complexes with Selective In Vitro and In Vivo Anticancer Activity

Abstract

Heterometallic complexes, [M(L)₃][Y(NO₃)₅] (L = 2,2'-bipyridine, Вpy (I–III), and 1,10-phenanthroline, Рhen (IV–VI), M = Co (I, IV), Ni (II, V), Zn (III, VI)), were prepared and studied as anticancer agents. Pronounced in vitro toxicity vs. several cancer cell lines is demonstrated. Compared to homometallic [M(Рhen)₃](NO₃)₂ (MPhen) and Y(NO₃)₃·6H₂O (Y) references, complexes IV–VI exhibit the synergism in cytotoxicity vs. breast cancer cells and its doxorubicin-resistant subline (HBL-100 and HBL-100/Dox) while IV and VI are efficient vs., respectively, cutaneous melanoma (Mel IS) and glioblastoma (T98G) cells. On the other hand, the entire MPhen series show higher toxicity vs. renal cancer (Rpoch-1-KK) cells. Noteworthy, all studied complexes, except for II and V ones are of acceptable toxicity vs. normal cutaneous fibroblasts (PBK) cells. Such a selective toxicity arises from the interactions with key molecular targets such as chaperone proteins nucleolin and nucleophosmin which are over-expressed in cancer cells and play key role in their metabolism. As a result, cell death is induced via the apoptosis processing through several paths as well as the autophagy. The in vivo studies revealed the antitumor potential of complexes I, III, IV and VI vs. Mel IS xenografts. Noteworthy, these complexes are the first yttrium-containing ones with unambiguously demonstrated anticancer activity arising from the induction of various cell death paths. In the latter regard, homometallic [M(Рhen)₃](NO₃)₂ complexes, although on the in vitro level for now, are also of interest.