Linking the future of anticancer metal-complexes to the therapy of tumour metastases

Abstract

Cancer chemotherapy is almost always applied to patients with one or more diagnosed metastases and is expected to impact these lesions, thus providing significant benefits to the patient. The outcome of metastasis is determined by the interplay between the specific subpopulation of metastatic cells and host homeostatic factors in specific microenvironments. In clinical practice, metal-based drugs are represented by platinum compounds, which are constituents of a wide variety of chemotherapeutic regimens, and are only rarely active against tumour metastases unless they are combined with drugs that target specific pathways characterizing the malignancy of the tested tumour. On experimental grounds, a number of complexes based on ruthenium and other metals have been frequently studied in vitro using models and experimental conditions mimicking one or more steps of the metastatic process, such as invasion and migration. The ruthenium-based drug, NAMI-A, is the only one to have been subject to clinical testing for the treatment of metastatic tumours. The capacity of NAMI-A to modulate the relationship established between metastatic cells and their microenvironment suggests that metal-based drugs shall be viewed as an opportunity for the treatment of tumour metastases.

Comparative equilibrium and structural studies of new pentamethylcyclopentadienyl rhodium complexes bearing (O,N) donor bidentate ligands

“…In the early stages, research concentrated on Ru(III) complexes, but later a wider range of metals attracted notice in the development of new anticancer compounds. Prominent representatives of this compound class are KP1019 (indazolium [4] as well as its sodium salt IT-139 (NKP-1339) [5] and NAMI-A (imidazolium trans-[tetrachlorido(1H-imidazole)(dimethylsulfoxide)ruthenate(III)]) [6], all of which have been characterized in a variety of studies especially with regard to their growth inhibitory effects on cancer cells. IT-139 was selected as lead candidate for further clinical development due to its remarkable in vivo activity accompanied by low general toxicity as demonstrated in a phase I/IIa clinical study [5].…”

Pt(IV), Pd(II), and Rh(III) complexes induced oxidative stress and cytotoxicity in the HCT-116 colon cancer cell line

“…The development of cancer involves a series of complex mechanisms related to the individual's genetic characteristics and exposure to certain risk factors. Understanding of the targets and mechanisms of action of potential therapeutics in cancer cells is essential for drug design and clinical applications (Bergamo and Sava, 2015;Penny and Wallace, 2015).…”

“…The advantages and drawbacks of the widely used platinum-based anticancer drug cisplatin prompted a search for analogous transition metal complexes. One of the major goals of modern bioinorganic and medicinal chemistry research is the development of novel metal-based drugs with pharmaceutical activity different from that of platinumbased therapeutics (Lippert, 1999;Alessio, 2011;Bergamo and Sava, 2015).…”

Metal Anticancer Complexes – Activity, Mechanism of Action, Future Perspectives

“…[7] Among the many limits that affect this field we notice, among others: i) the general scarce interest/involvement of the pharmaceutical industry, ii) the lack of concreteness that characterizes many contributions of the chemists, often focused on compounds whose characteristics are not compatible with application; [8] iii) the general lack of simplicity: complicated constructs make nice proof-of-principle and smart publications but are highly unlikely to ever become new drugs; iv) underestimation by academics of toxicity concerns; v) the lack of effective, reliable and easily accessible screening tests; vi) the lack of convincing mechanisms, identified targets and biomarkers for activity/toxicity. [9] In conclusion, we anticipate that new advances are expected with the introduction of novel activation strategies and nanoplatforms etc. which are crucial for the development of the field in the years to come.…”