Pharmacomodulation on Gold-NHC complexes for anticancer applications - is lipophilicity the key point?

A series of four new mononuclear cationic gold(I) complexes containing nitrogen functionalized N-heterocyclic carbenes (NHCs) was synthesized and fully characterized by spectroscopic methods. The X-ray structures of three complexes are presented. These lipophilic gold(I) complexes originate from a pharmacomodulation of previously described gold(I)-NHC complexes, by replacing an aliphatic spacer with an aromatic one. The Log P values of the resulting complexes increased by 0.7-1.5, depending on the substituents in comparison to the aliphatic-linker systems. The new series of complexes has been investigated in vitro for their anti-cancer activities in PC-3 (prostate cancer) and T24 (bladder cancer) cell lines and in the non-cancerous MC3T3 (osteoblast) cell line. All tested complexes show high activities against the cancer cell lines with GI50 values lower than 500 nM. One complex (11) has been selected for further investigations. It has been tested in vitro in six cancer cell lines from different origins (prostate, bladder, lung, bone, liver and breast) and two non-cancerous cell lines (osteoblasts, fibroblasts). Moreover, cellular uptake measurements were indicative of a good bioavailability. By various biochemical assays, this complex was found to effectively inhibit the thioredoxin reductase (TrxR) and its cytotoxicity towards prostate PC-3, bladder T24 and liver HepG2 cells was found to be ROS-dependent.

Gold (III) porphyrin complexes induce apoptosis and cell cycle arrest and inhibit tumor growth in colon cancer.

BACKGROUND: Gold (III) compounds have exhibited favorable antitumor properties both in vitro and in vivo. In a previous study, the authors reported that the novel gold (III) complex 1a (gold 1a) exhibited strong cytotoxicity in some tumor cell lines. In the current study, the effect of gold 1a was investigated on colon cancer cells. METHODS: The cytotoxicity of gold 1a was determined by using the 3-(4,5-dimethyl-2-thihazyl)-2,5-diphenyl-2H-tetrazolium bromide method. Flow cytometry was used to detect apoptosis and cell cycle. The expression of protein was evaluated by Western blot assay. Tumor growth in vivo was evaluated in nude mice. RESULTS: Gold 1a exhibited marked cytotoxic effects in vitro to human colon cancer, and the concentration of drug required to inhibit cell growth by 50% compared with control (IC(50)) values ranged from 0.2 muM to 3.4 muM, which represented 8.7-fold to 20.8-fold greater potency than that of cisplatin. Gold 1a significantly induced apoptosis and cell cycle arrest and cleaved caspase 3, caspase 7, and poly(ADP-ribose) polymerase; released cytochrome C, and up-regulated p53, p21, p27, and Bax. In vivo, intraperitoneal injection of gold 1a at doses of 1.5 mg/kg and 3.0 mg/kg significantly inhibited tumor cell proliferation, induced apoptosis, and suppressed colon cancer tumor growth. An acute toxicology study indicated that gold 1a at effective antitumor concentrations did not cause any toxic side effects in mice. CONCLUSIONS: The current results suggested that gold 1a may be a new potential therapeutic drug for colon cancer.

Gold(III) compound is a novel chemocytotoxic agent for hepatocellular carcinoma.

Recently, a series of gold(III) meso-tetraarylporphyrins that are stable against demetallation in physiological conditions have been synthesized. In the present study, the antitumor effects of one of these compounds, gold(III) meso-tetraarylporphyrin 1a (gold-1a) was investigated in an orthotopic rat hepatocellular carcinoma (HCC) model as well as using a HCC cell line. The rat HCC model was induced by injection of rat hepatoma cells, McA-RH7777, into the left lobe of the liver. Seven days after tumor cell inoculation, gold-1a was injected directly into the tumor nodule at different doses, followed by the same doses via intraperitoneal injection twice a week. Gold-1a administration significantly prolonged the survival of HCC-bearing rats. Importantly, gold-1a induced necrosis as well as apoptosis in the tumor tissues, but not in the normal liver tissues. Furthermore, gold-1a treatment neither caused significant drop in body weight of the rats nor affected plasma aspartate aminotransferase level. In the in vitro studies, we observed that gold-1a treatment inhibited the proliferation of McA-RH7777 cells. Gold-1a upregulated genes that increase apoptosis, stabilize p53, decrease proliferation and downregulated genes playing roles in angiogenesis, invasion, and metabolism, as demonstrated by microarray. In particular, the compound upregulated 2 members of the growth arrest and DNA damage (Gadd) inducible gene family, Gadd34 and Gadd153. Suppression of Gadd34 and Gadd153 in McA-RH7777 cells by small hairpin RNA reduced the gold-1a-induced apoptosis and growth inhibition, indicating that gold-1a mediated its effects via upregulation of Gadd34 and Gadd153. Results from our study demonstrated that gold-1a might be a novel promising chemocytotoxic agent for treating HCC.

Physiologically stable vanadium(IV) porphyrins as a new class of anti-HIV agents.

The water soluble oxovanadium(IV) tetraarylporphyrin has demonstrated excellent solution stability against glutathione reduction and high potency (5 microM, 97% inhibition) in inhibiting HIV-1 replication in Hut/CCR5 cells.