Transition Metal Intercalators as Anticancer Agents—Recent Advances

The huge variety of transition metal properties and ligand combinations has produced an extremely broad spectrum of intercalating anticancer complexes, each with a unique mechanism of action. The continued expansion of this spectrum has great potential to reveal metallointercalators which can outperform current metallodrugs and provide more effective chemotherapy


Review: recent advances and future development of metal complexes as anticancer agents

Since the initial discovery of applications of platinum complexes in the clinical treatment of many kinds of cancers, the efficiency of platinum complexes in inhibiting the proliferation of various types of tumors surprised researchers working on the development of anticancer drugs. Meanwhile, despite the potent clinical treatment patients get from platinum complexes, there are also disadvantages including limited solubility in aqueous media and side effects like ototoxicity, myelosuppression, nephrotoxicity, and poor selectivity toward healthy cells. For this reason, efforts have been made to search for novel solutions. Non-platinum complexes (like Fe, Pd, Ru, Cu, Bi, Zn, etc.) were found with potential anticancer activities. We here review the properties of five metal complexes as anticancer agents and make comparisons among them in biological features and cytotoxic activity. Seeking the interrelation between microstructure and mechanism of anticancer, we hope this review provides distinct insights into future study of anticancer agents.


Metal complexes in cancer therapy – an update from drug design perspective

In this review, we seek to give an overview of previous reviews on the cytotoxic effect of metal-based complexes while focusing more on newly designed metal-based complexes and their cytotoxic effect on the cancer cell lines, as well as on new approach to metal-based drug design and molecular target in cancer therapy. We are optimistic that the concept of selective targeting remains the hope of the future in developing therapeutics that would selectively target cancer cells and leave healthy cells unharmed.


Novel Metals and Metal Complexes as Platforms for Cancer Therapy

The current toolbox of active anticancer agents is broad in scope, and targets multiple cellular and biological properties across several tumor types. Over the last fifty years, the development of anticancer drugs moved away from conventional cytotoxicity and towards the rational design of selective agents that act on specific cellular targets. However,significant challenges remain, and the interface between structural biology and chemistry may provide the most productive means for discovering and improving upon novel anticancer agents. The use of nonessential metals as probes to target molecular pathways as anticancer agents is also emphasized. Finally, based on the interface between molecular biology and bioinorganic chemistry the design of coordination complexes for cancer treatment is reviewed and design strategies and mechanisms of action are discussed.


Nanostructured Materials Functionalized with Metal Complexes: In Search of Alternatives for Administering Anticancer Metallodrugs

Nanotechnology has shown great promise in unravelling several important issues of conventional anticancer chemotherapy. Expectations project that a new generation of effective cancer therapies will be developed with enormous potential to overcome the biological, biophysical and biomedical obstacles that the human body enacts against standard chemotherapeutic treatments. The uniqueness of these nanostructured materials lies in their suitability for functionalization with small molecule drugs. Recently, there has been a great deal of interest among oncologists and medicinal chemists in functionalizing nanostructured materials with anticancer metallodrugs to ensure better administration. 


New Trends for Metal Complexes with Anticancer Activity

Medicinal inorganic chemistry can exploit the unique properties of metal ions for the design of new drugs. This has, for instance, led to the clinical application of chemotherapeutic agents for cancer treatment, such as cisplatin. The use of cisplatin is, however, severely limited by its toxic side effects. This has spurred chemists to employ different strategies in the development of new metal-based anticancer agents with different mechanisms of action. Recent trends in the field are discussed in this review. These include the more selected delivery and/or activation of cisplatin-related prodrugs and the discovery of new noncovalent interactions with the classical target, DNA. The use of the metal as scaffold rather than reactive centre and the departure from the cisplatin paradigm of activity towards a more targeted, cancer cell-specific approach, a major trend, are discussed as well. All this, together with the observation that some of the new drugs are organometallic complexes, illustrates that exciting times lie ahead for those interested in ‘metals in medicine’.


Metabolic Changes in Cancer: Beyond the Warburg Effect

The shift in glucose metabolism from oxidative phosphorylation to lactate production for energy generation (the Warburg Effect) is a well-known metabolic hallmark of tumor cells, and several key signaling pathways, oncogenes, and tumor suppressors―including Akt, mTor, c-myc, and p53―are linked to the increase in glycolysis seen in tumor cells. Beyond fulfilling energy requirements, highly proliferative cells also need to produce excess lipids, nucleotides, and amino acids for the creation of new biomass. In order to do this, a number of metabolic adaptations occur in cancer cells that help generate these metabolites, fuel growth, and may also aid in the evasion of apoptosis. 


Metabolic changes in cancer: beyond the Warburg effect

Recent progress in studying isocitrate dehydrogenase 1 (IDH1) mutation, pyruvate kinase muscle form 2 (PKM2) alterations, fumarate hydratase (FH) mutations, and succinate dehydrogenase (SDH) mutations have demonstrated that mutation in metabolic enzymes alone is sufficient to initiate tumors, casting doubts to previous belief. Warburg's hypothesis that cancer cells have defect in mitochondria was not totally unfounded. Indeed, many of the metabolism genes whose mutations can cause cancers are mitochondrial genes. On one hand, mutations in oncogenes or tumor suppressor genes such as c-myc and p53 are known direct causes of cancer, on the other hand, mutations in metabolic genes such as IDH1, IDH2, SDH, and FH also cause certain types of cancers. Moreover, metabolic stresses cause tumor-associated genes, such as c-myc and p53, alterations, and changes in tumor-associated genes is now known to result in metabolic deregulations. Therefore, besides traditional concept that cell signaling disorder is the direct cause of cancer initiation, metabolic alterations could be the real causes of cancers. Two models can be proposed based on current facts about cancers. First, tumor-associated gene mutations likely cause metabolic changes first and the altered metabolism, which has a new homeostasis of metabolites, has the ability to reprogram epigenetics as well as signaling networks and to cause cancer. The second model is that altered metabolism, either caused by metabolic gene mutations or by environmental factors, can reprogram epigenetics as well as signaling networks and cause cancer; while tumor-associated gene mutations are consequences of activated gene expression. The second model, although sounds more controversial, gets some support from recent findings. In glioma, IDH1 mutations seem to happen in the early stage of disease onset, even before p53 mutation was detected in patients. Regardless of which model is more reasonable, metabolism seems to be taking center stage of cancer research. The elucidation of how metabolism changes cause cancers will shed light on future novel cancer treatment development.


Regulation of cancer cell metabolism

Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.


The Fate of Tumor Cells Survival - Autophagy - Apoptosis or Necrosis

Cancers often arise as the end stage of inflammation in adults, but not in children. As such there is a complex interplay between host immune cells during neoplastic development, with both an ability to promote cancer as well as limit or eliminate it, most often complicit with the host. In humans, defining inflammation and the presence of inflammatory cells within or surrounding the tumor is a critical aspect of modern pathology.