Regression of Lung Cancer by Hypoxia-Sensitizing Ruthenium Polypyridyl Complexes

Abstract

The ruthenium (II) polypyridyl complexes (RPCs) Δ-[(phen)2Ru(tatpp)]Cl2 (Δ-[3]Cl2) and ΔΔ-[(phen)2Ru(tatpp)Ru(phen)2]Cl4 (ΔΔ-[4]Cl4) are a new generation of metal-based anti-tumor agents. These RPCs bind DNA via intercalation of the tatpp ligand which itself is redox-active and easily reduced at biologically relevant potentials. We have previously shown that RPC 44+ cleaves DNA when reduced by glutathione to a radical species, and that this DNA cleavage is potentiated under hypoxic conditions in vitro. Here we show that 32+ also exhibits free-radical mediated DNA cleavage in vitro, and that 32+ and 44+ both exhibit selective cytotoxicity towards cultured malignant cell lines, and marked inhibition of tumor growth in vivo. The murine acute toxicity of RPCs 32+ and 44+ (maximum tolerable doses (MTD’s) ~ 65 µmol/kg) is comparable with that for cisplatin (LD50 ~57 µmol/kg) but unlike cisplatin, RPC’s are generally cleared from the body unchanged via renal excretion without appreciable metabolism or nephrotoxic side effects. RPCs 32+ and 44+ are demonstrated to suppress growth of human non-small cell lung carcinoma (~83%), show potentiated cytotoxicity in vitro under hypoxic conditions, and induce apoptosis through both intrinsic and extrinsic pathways. The novel hypoxia-enhanced DNA cleavage activity and biological activity suggest a promising new anti-cancer pharmacophore based on metal complexes with aromatic ligands that are easily reduced at biologically accessible potentials.

Monomeric and dimeric coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes as anticancer drug candidates

“…MacDonnell and co-workers hypothesised the likely mechanism of DNA damage: the tatpp carbon radical in the reduced species abstracts a H-atom from the deoxyribose unit. 160 The concentration of the key intermediate is [162,163] while it seems reasonable to assume that complexes 106 and 107 enter cells via active transport as already demonstrated for Ru(II) polypyridyl complexes containing the tpphz…”

“…in Figure 25). 160 The authors showed a significant tumour growth repression and a doubling of the survival time of mice with H358…”

A ruthenium(II) complex inhibits tumor growth in vivo with fewer side-effects compared with cisplatin

“…The anticancer mechanisms of these complexes are including interaction with DNA [27], mitochondria targeting [28], and hypoxia-sensitizing [29]. Moreover, we have recently reported that the Ru(II) complex Δ-Ru1 (Δ-[Ru(bpy) 2 (HPIP)](ClO 4 ) 2 , bpy = 2,2′-bipyridine, HPIP = 2-(2-hydroxyphenyl)imidazo [4,5-f] [1,10]phenanthroline, Fig.…”

Temperature and oxygen-concentration dependence of singlet oxygen production by RuPhen as induced by quasi-continuous excitation

“…21,22 From a clinical point of view, low dark toxicity and a relatively high clearance rate make RuPhen attractive for in vivo timeresolved pO 2 detection. [23][24][25][26] There are a few publications reporting on a weak photo-cytotoxicity of RuPhen. 27,28 These observations are in agreement with our preliminary results obtained in vivo with RuPhen applied to the chorioallantoic membrane (CAM) system.…”