Volume 10, Nº 4 (2010)

In this review paper we aim at giving a detailed overview on our research work devoted to the design of gold-based anticancer agents. In particular, during the last decade, we have been developing some gold(III)-dithiocarbamato derivates showing outstanding in vitro and in vivo antitumor properties and reduced, or even no, systemic and renal toxicity, compared to the reference clinically-established anticancer drug cisplatin. Starting from the rationale behind our investigations, we here summarize the results achieved so far, focusing on the latest in-depth mechanistic studies that have recently provided insights into their mechanism of action, thus opening up new prospects for further pharmacological testing and, hopefully, to enter clinical trials.

The organometallic compound titanocene (bis(cyclopentadienyl)titanium(IV) dichloride) showed promising preclinical anticancer activity in generally resistant tumors in vitro and in vivo but failed in clinical trials. A broad range of analogs with modified cyclopentadienyl ligands conferring increased stability and higher cytotoxicity were developed. Titanium was found to accumulate in the nucleus and inhibit DNA replication and transcription. The active species causing irreversible damage and exact mechanisms of action resulting in cell cycle arrest and apoptosis have not been identified to date. Our group investigated changes in global gene expression of NCI-H526 small cell lung cancer cells in response to the novel analog titanocene C (bis-N,N-dimethylamino-2-(N-methylpyrrolyl) methyl cyclopentadienyl titanium (IV)). Differences observed in transcript levels indicated downregulation of DNA unwinding by topoisomerases I and IIα and activation of responses to DNA damage and cellular stress, as well as shutdown of energy metabolism and, finally, apoptosis. Besides direct interaction of Ti2+ with DNA, induction of the MT1 family of metallothionein genes and downregulation of cellular Zn2+ uptake in response to titanocene C pointed to disturbed Zn2+ homeostasis, which triggers cell cycle arrest and apoptosis due to defective transcription factors and metalloenzymes. In particular, histone H4 genes dependent on Zn2+-containing transcription factors H4TF-1/2 were specifically downregulated, and accumulation of defective metalloproteins in the endoplasmatic reticulum seemed to activate unfolded protein response. In conclusion, according to these results, we propose a model of titanocene-induced cytotoxicity, comprising direct DNA damage and perturbation of Zn2+ homeostasis with impairment of the functions of cellular metalloproteome.

Since the discovery of cisplatin and its introduction in the clinics, metal compounds have been intensely investigated in view of their possible application in cancer therapy. In this frame, a deeper understanding of their mode of action, still rather obscure, might turn crucial for the design and the obtainment of new and better anticancer agents. Due to the extreme complexity of the biological systems, it is now widely accepted that innovative and information-rich methods are absolutely needed to afford such a goal. Recently, both proteomic and metallomic strategies were successfully implemented for the elucidation of specific mechanistic features of anticancer metallodrugs within an innovative “Systems Biology” perspective. Particular attention was paid to the following issues: i) proteomic studies of the molecular basis of platinum resistance; ii) proteomic analysis of cellular responses to cytotoxic metallodrugs; iii) metallomic studies of the transformation and fate of metallodrugs in cellular systems. Notably, those pioneering studies, that are reviewed here, allowed a significant progress in the understanding of the molecular mechanisms of metal based drugs at the cellular level. A further extension of those studies and a closer integration of proteomic and metallomic strategies and technologies might realistically lead to rapid and significant advancements in the mechanistic knowledge of anticancer metallodrugs.

In the last few years boron (B) compounds became increasingly frequent in the chemotherapy of some forms of cancer with high malignancy and of inoperable cancers. As more B-based therapy chemicals are developed it is necessary to review the correlation between B and the incidence of different forms of cancer, the biochemical and molecular mechanisms influenced by B and to explore the relevance of B in the chemoprevention of cancer. This minireview analyzes dietary and therapeuptic principles based on the chemistry of B compounds. We summarize studies correlating B-rich diets or B-rich environments with regional risks of specific forms of cancers, and studies about the utilization of natural and synthetic B-containing compounds as anticancer agents. We review mechanisms where B-containing compounds interfere with the physiology and reproduction of cancer cells. Types of cancers most frequently impacted by B-containing compounds include prostate, breast, cervical and lung cancer. Mechanisms involving B activity on cancer cells are based on the inhibition of a variety of enzymatic activities, including serine proteases, NAD-dehydrogenases, mRNA splicing and cell division, but also receptor binding mimicry, and the induction of apoptosis. Boron-enriched diets resulted in significant decrease in the risk for prostate and cervical cancer, and decrease in lung cancer in smoking women. Boron-based compounds show promising effects for the chemotheraphy of specific forms of cancer, but due to specific benefits should also be included in cancer chemopreventive strategies.