The application of inorganic chemistry to medicine is a rapidly developing field, and novel therapeutic and diagnostic metal complexes are now having an impact on medical practice. Advances in biocoordination chemistry are crucial for improving the design of compounds to reduce toxic side effects and understand their mechanisms of action. Cisplatin, as one of the leading metal-based drugs, is widely used in the treatment of cancer. Significant side effects and drug resistance, however, have limited its clinical applications. Biological carriers conjugated to cisplatin analogs have improved specificity for tumor tissue, thereby reducing side effects and drug resistance. Platinum complexes with distinctively different DNA binding modes from that of cisplatin also exhibit promising pharmacological properties. This review focuses on recent advances in developing platinum anticancer agents with an emphasis on platinum coordination complexes.
The purine nucleoside analog (PNA) - cladribine (2-CdA, 2-chlorodeoxyadenosine) is a cytotoxic agent of high efficacy in lymphoid and myeloid malignancies. This drug was approved by the FDA for treatment of hairy cell leukemia and in some European countries for treatment of refractory/relapsed chronic lymphocytic leukemia. 2-CdA is usually administered as continuous or intermittent intravenous infusion. Recently however, new formulations of this agent has been developed for subcutaneous and oral administration. In contrast to other PNA, 2-CdA is equally cytotoxic to both proliferating and quiescent cells and several pathways may be responsible for the mechanism of its action. In addition, recent data indicate that 2-CdA combined with other cytotoxic agents and monoclonal antibodies show synergistic proapoptotic and cytotoxic activity on lymphoid and myeloid neoplastic cells. This review article summarizes recent achievements in the understanding of 2-CdA mechanism of action, pharmacokinetics of different pharmaceutical formulations and its approved and possible future applications in the treatment of hematological malignancies. The most important recent patents concerning oral formulations of 2-CdA have been presented.
Poly(ADP-ribose) polymerases (PARPs) are defined as a family of cell signaling enzymes present in eukaryotes, which are involved in poly(ADP-ribosylation) of DNA-binding proteins. The best studied of these enzymes (PARP-1) is involved in the cellular response to DNA damage so that in the event of irreparable DNA damage overactivation of PARP-1 leads to necrotic cell death. Inhibitors of PARP-1 activity in combination with DNA-binding antitumor drugs may constitute a suitable strategy in cancer chemotherapy. When DNA is moderately damaged, PARP-1 participates in the DNA repair process and the cell survives. However, in the case of extensive DNA damage PARP-1 overactivation induces a decrease of NAD+ and ATP levels leading to cell dysfunction or even to necrotic cell death. So, due to PARP-1 involvement in cell death, pharmacological inhibition of PARP-1 activity by PARP-1 inhibitors may constitute a suitable target to enhance the activity of antitumor drugs through inhibition of necrosis and activation of apoptosis. PARP-1 inhibitors such as 3-aminobenzamide, 1,5-dihydroxyisoquinolinone and the recently patented tryciclic benzimidazoles have shown potent inhibitory effects of PARP-1 activity in tumor cells. The present review gives an update of the state-of-the-art of inhibition of PARP-1 activity as adjuvant therapy in cancer treatment.
Cell cycle ckeckpoints are activated in response to DNA damage. Their role consists in blocking the cell cycle to allow time for DNA repair. The activity of the G1 checkpoint is dependent on the p53 protein. In more than 50% of human tumor cells, the p53 gene is mutated. In the p53 mutated cells, the G1 checkpoint is lacking. In these cells, only the G2 checkpoint, although weaker than in healthy cells, provides cancer cells with the opportunity to repair the DNA after damage. Therefore, combining a G2 checkpoint inhibitor with a DNA damaging agent should force, selectively cancer cells, into a premature and lethal mitosis, due to an accumulation of DNA lesions. Among the regulators of the G2 checkpoint, Checkpoint 1 kinase (Chk1) plays a major role. A widespread interest has been recently devoted to the discovery of Chk1 inhibitors as potential useful compounds to enhance the antitumor efficiency of DNA damaging agents. This review article will summarize: (i) the chemical structures of the novel Chk1 inhibitors reported in the recent patents; (ii) their inhibitory activity towards Chk1; (iii) their effects on tumor cells in combination with DNA damaging agents; and (iv) the in vivo results on animal models.
A leading cause of death, cancer remains the bane of modern society and one of the most challenging research fields. Cancer is initially a localized disease that can be often treated well at a very early stage. However the vast majority of cancer deaths result from a pernicious progression of the disease, the development of distant metastases. It must therefore be a pressing research goal to focus on the pharmacological prevention of metastasis development. This review summarizes the current understanding of the cellular and molecular mechanisms of metastasis development, and suggests possible approaches for its inhibition.
Since cell death by apoptosis plays a key role in the regulation of tissue homeostasis, any defect in this intrinsic death program may result in tumor formation. "Inhibitor of apoptosis proteins" (IAPs) block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases. Aberrant expression and/or function of IAPs have been implied to be involved in the pathogenesis and progression of various human diseases including cancer, autoimmune disorders or neurodegeneration. Recent insights into the regulation of IAPs have provided the basis for various exciting discoveries aimed at modulating expression or dysfunction of IAPs. Thus, targeting IAPs, e.g. by antisense approaches, RNA interference or small molecules, may proof to be a novel strategy for the diagnosis and treatment of human diseases.
The matrix metalloproteinases (MMPs), belonging to the family of proteolytic enzymes, are well-known for their ability to degrade the extracellular matrix, and are involved in many aspects of both physiological cellular processes and pathological situations, such as tumor growth, invasion and metastasis. MMPs have been considered prognostic factors in various types of cancer as well as promising targets for cancer therapy. Although preclinical studies of a number of different synthetic MMP inhibitors have been identified as cytostatic and anti-angiogenic agents and have begun clinical testing, the past years have produced a consistent number of disappointments and limited successes. In view of their specific implication in malignant tissues, several natural compounds were utilized, and the results were so satisfactory as to encourage several clinical trials in order to improve efficacy and to reduce the side effect profile. The natural protection against cancer has been receiving a great deal of attention, and the critical examination of previous studies shed light on new information about the source and function of MMPs, focusing the attention on the identification of MMP targets in tumors. This review discusses the current knowledge and research in the field of natural MMP inhibitor as innovative therapeutic intervention in cancer.
The proliferation and motility of vascular endothelial cells (ECs) are critical steps in angiogenesis and are strictly controlled by different extracellular signals. Among mitogens, peptides binding to tyrosine kinase receptors (i.e. VEGFs and FGFs) are well known and are released by several cell types, including ECs and tumor cells. The binding of mitogens to their specific receptors triggers intracellular signaling cascades, involving a number of messengers working in a sort of network. In particular, in this review we describe the increases of calcium levels in the cytosol, a universal, evolutionary conserved and highly versatile signal involved in the regulation of ECs proliferation and motility. Most mitogens, including angiogenic factors, generate cytosolic calcium rises through two mechanisms: entry from extracellular medium, through the opening of calcium permeable channels in the plasma membrane, or release from intracellular organelles (mainly endoplasmic reticulum, ER). Calcium entry, the main topic of this review, can be dependent on previously IP3-activated emptying of calcium stores (store-dependent or capacitative calcium entry - CCE), or independent on it (non capacitative calcium entry, NCCE). The intracellular pathways underlying calcium entry are under investigation and recently arachidonic acid (AA) and nitric oxide (NO) metabolism have been suggested to play a key role, at least in some cell types. Even if some calcium entry blockers are under clinical trial with encouraging results, a better knowledge about the molecular nature of calcium channels and their intracellular regulation, together with a more detailed description of spatiotemporal dynamics of intracellular calcium events, could lead to new and more specific strategies in therapeutical approach to cancer progression and angiogenesis.
Newer treatments of advanced human cancer increasingly rely on combinations of drugs that have quite different actions yet unexpectedly potentiate each others effects. Recent research in stem cell biology suggests a model for tumors in which tumor growth is governed by the generation of cells from tumor cell niches rather than from the population as a whole. Each niche contains a population of tumor stem cells supported by a closely associated vascular bed comprising mesenchyme-derived cells and an extracellular matrix. Division of tumor stem cells is asymmetric in the sense that some daughter cells are always retained within the niche while others leave the niche to proliferate further and eventually die. One important potential difference between normal and tumor stem cell niches is that while most normal stem cells are in a non-proliferating or Go-state, tumor stem cells are continuously in cycle. Combinations of cytotoxic drugs and antagonists of survival factors to reduce the stem cell population may require the addition of vascular disrupting agents to compromise the function of the tumor cell niche. As well as providing opportunities for new drug discovery, this model of tumor growth also presents challenges as to how the contributions of individual drugs in a combination might be assessed in individual patients.
The use of anticancer agents forms an important part for treatment of cancer of various types. Complexes with cis-platinum compounds have been used for the prevention and treatment of cancers. Quite a number of these metalcontaining complexes have been isolated, chemically prepared and characterized for the treatment of cancer. Many of these compounds display potent cytotoxic effects, although there is a considerable progress made in the design of novel anticancer agents. Some of these compounds showed strong inhibitory effects on cancer growth with a potential to become anti-cancer drugs. However, the unwanted deleterious effects hamper the common use of these agents as anticancer drugs. Nevertheless, the use of protective agents during, before or after treatment with anti-cancer agents in combination therapy has proven effective in the treatment. The results prompt the study of the biologic activities and the design of better modality for treatment and prevention of cancer. Here, we review the potential and reduction of cytotoxic properties of the prominent member of this class of metal compounds for the treatment of cancer.