While medicinal inorganic chemistry has been practised for over 5000 years, it was not until the late 1800s when Alfred Werner published his ground-breaking research on coordination chemistry that we began to truly understand the nature of the coordination bond and the structures and stereochemistries of metal complexes. We can now readily manipulate and fine-tune their properties. This had led to a multitude of complexes with wide-ranging biomedical applications. This review will focus on the use and potential of metal complexes as important therapeutic agents for the treatment of cancer. With major advances in technologies and a deeper understanding of the human genome, we are now in a strong position to more fully understand carcinogenesis at a molecular level. We can now also rationally design and develop drug molecules that can either selectively enhance or disrupt key biological processes and, in doing so, optimize their therapeutic potential. This has heralded a new era in drug design in which we a...

Toward Multi-Targeted Platinum and Ruthenium Drugs-A New Paradigm in Cancer Drug Treatment Regimens?

Cancer with heavily economic and social burden is the hot point in the field of medical research. Some remarkable achievements have been made; however, the exact mechanisms of tumor initiation and development remain unclear. Cancer is a complex, whole-body disease that involves multiple abnormalities in the levels of DNA, RNA, protein, metabolite and medical imaging. Biological omics including genomics, transcriptomics, proteomics, metabolomics and radiomics aims to systematically understand carcinogenesis in different biological levels, which is driving the shift of cancer research paradigm from single parameter model to multi-parameter systematical model. The rapid development of various omics technologies is driving one to conveniently get multi-omics data, which accelerates predictive, preventive and personalized medicine (PPPM) practice allowing prediction of response with substantially increased accuracy, stratification of particular patients and eventual personalization of medicine. This review article describes the methodology, advances, and clinically relevant outcomes of different “omics” technologies in cancer research, and especially emphasizes the importance and scientific merit of integrating multi-omics in cancer research and clinically relevant outcomes.

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The crucial role of multiomic approach in cancer research and clinically relevant outcomes

A strong relationship exists between tumor and inflammation, which is the hot point in cancer research. Inflammation can promote the occurrence and development of cancer by promoting blood vessel growth, cancer cell proliferation, and tumor invasiveness, negatively regulating immune response, and changing the efficacy of certain anti-tumor drugs. It has been demonstrated that there are a large number of inflammatory factors and inflammatory cells in the tumor microenvironment, and tumor-promoting immunity and anti-tumor immunity exist simultaneously in the tumor microenvironment. The typical relationship between chronic inflammation and tumor has been presented by the relationships between Helicobacter pylori, chronic gastritis, and gastric cancer; between smoking, development of chronic pneumonia, and lung cancer; and between hepatitis virus (mainly hepatitis virus B and C), development of chronic hepatitis, and liver cancer. The prevention of chronic inflammation is a factor that can prevent cancer, so it effectively inhibits or blocks the occurrence, development, and progression of the chronic inflammation process playing important roles in the prevention of cancer. Monitoring of the causes and inflammatory factors in chronic inflammation processes is a useful way to predict cancer and assess the efficiency of cancer prevention. Chronic inflammation-based biomarkers are useful tools to predict and prevent cancer.

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Chronic inflammation: key player and biomarker-set to predict and prevent cancer development and progression based on individualized patient profiles

Recent studies show that biomaterials are capable of regulating immune responses to induce a favorable osteogenic microenvironment and promote osteogenesis and angiogenesis. In this study, we investigated the effects of zinc silicate/nanohydroxyapatite/collagen (ZS/HA/Col) scaffolds on bone regeneration and angiogenesis and explored the related mechanism. We demonstrate that 10ZS/HA/Col scaffolds significantly enhanced bone regeneration and angiogenesis in vivo compared with HA/Col scaffolds. ZS/HA/Col scaffolds increased tartrate-resistant acid phosphatase (TRAP)-positive cells, nestin-positive bone marrow stromal cells (BMSCs) and CD31-positive neovessels, and expression of osteogenesis (Bmp-2 and Osterix) and angiogenesis-related (Vegf-α and Cd31) genes increased in nascent bone. ZS/HA/Col scaffolds with 10 wt % ZS activated the p38 signaling pathway in monocytes. The monocytes subsequently differentiated into TRAP+ cells and expressed higher levels of the cytokines SDF-1, TGF-β1, VEGF-α, and PDGF-BB, which recruited BMSCs and endothelial cells (ECs) to the defect areas. Blocking the p38 pathway in monocytes reduced TRAP+ differentiation and cytokine secretion and resulted in a decrease in BMSC and EC homing and angiogenesis. Overall, these findings demonstrate that 10ZS/HA/Col scaffolds modulate monocytes and, thereby, create a favorable osteogenic microenvironment that promotes BMSC migration and differentiation and vessel formation by activating the p38 signaling pathway.

Zinc Silicate/Nano-Hydroxyapatite/Collagen Scaffolds Promote Angiogenesis and Bone Regeneration via the p38 MAPK Pathway in Activated Monocytes

The drug discovery process starts with identification of a disease-modifying target. This critical step traditionally begins with manual investigation of scientific literature and biomedical databases to gather evidence linking molecular target to disease, and to evaluate the efficacy, safety and commercial potential of the target. The high-throughput and affordability of current omics technologies, allowing quantitative measurements of many putative targets (e.g. DNA, RNA, protein, metabolite), has exponentially increased the volume of scientific data available for this arduous task. Therefore, computational platforms identifying and ranking disease-relevant targets from existing biomedical data sources, including omics databases, are needed. To date, more than 30 drug target discovery (DTD) platforms exist. They provide information-rich databases and graphical user interfaces to help scientists identify putative targets and pre-evaluate their therapeutic efficacy and potential side effects. Here we survey and compare a set of popular DTD platforms that utilize multiple data sources and omics-driven knowledge bases (either directly or indirectly) for identifying drug targets. We also provide a description of omics technologies and related data repositories which are important for DTD tasks.

An omics perspective on drug target discovery platforms.

Exploration of variations in proteome and metabolome for predictive diagnostics and personalized treatment algorithms: Innovative approach and examples for potential clinical application.

Two-dimensional gel electrophoresis (2DE) in proteomics is traditionally assumed to contain only one or two proteins in each 2DE spot. However, 2DE resolution is being complemented by the rapid development of high sensitivity mass spectrometers. Here we compared MALDI-MS, LC-Q-TOF MS and LC-Orbitrap Velos MS for the identification of proteins within one spot. With LC-Orbitrap Velos MS each Coomassie Blue-stained 2DE spot contained an average of at least 42 and 63 proteins/spot in an analysis of a human glioblastoma proteome and a human pituitary adenoma proteome, respectively, if a single gel spot was analyzed. If a pool of three matched gel spots was analyzed this number further increased up to an average of 230 and 118 proteins/spot for glioblastoma and pituitary adenoma proteome, respectively. Multiple proteins per spot confirm the necessity of isotopic labeling in large-scale quantification of different protein species in a proteome. Furthermore, a protein abundance analysis revealed that most of the identified proteins in each analyzed 2DE spot were low-abundance proteins. Many proteins were present in several of the analyzed spots showing the ability of 2DE-MS to separate at the protein species level. Therefore, 2DE coupled with high-sensitivity LC-MS has a clearly higher sensitivity as expected until now to detect, identify and quantify low abundance proteins in a complex human proteome with an estimated resolution of about 500 000 protein species. This clearly exceeds the resolution power of bottom-up LC-MS investigations.

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How many proteins can be identified in a 2DE gel spot within an analysis of a complex human cancer tissue proteome

Mitogen-activated protein kinases (MAPKs) include ERK, p38, and JNK MAPK subfamilies, which are crucial regulators of cellular physiology, cell pathology, and many diseases including cancers. For the MAPK signaling system in pituitary adenomas (PAs), the activation of ERK signaling is generally thought to promote cell proliferation and growth; whereas the activations of p38 and JNK signaling are generally thought to promote cell apoptosis. The role of MAPK in treatment of PAs is demonstrated through the effects of currently used medications such as somatostatin analogs such as SOM230 and OCT, dopamine agonists such as cabergoline and bromocriptine, and retinoic acid which inhibit the MAPK pathway. Further, there are potential novel therapies based on putative molecular targets of the MAPK pathway, including 18beta-glycyrrhetinic acid (GA), dopamine-somatostatin chimeric compound (BIM-23A760), ursolic acid (UA), fulvestrant, Raf kinase inhibitory protein (RKIP), epidermal growth factor pathway substrate number 8 (Eps8), transmembrane protein with EGF-like and two follistatin-like domains (TMEFF2), cold inducible RNA-binding protein (CIRP), miR-16, and mammaliansterile-20-like kinase (MST4). The combined use of ERK inhibitor (e.g., SOM230, OCT, or dopamine) plus p38 activator (e.g., cabergoline, bromocriptine, and fulvestrant) and/or JNK activator (e.g., UA), or the development of single drug (e.g., BIM-23A760) to target both ERK and p38 or JNK pathways, might produce better anti-tumor effects on PAs. This article reviews the advances in understanding the role of MAPK signaling in pituitary tumorigenesis, and the MAPK pathway-based potential therapeutic drugs for PAs.

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The MAPK Pathway-Based Drug Therapeutic Targets in Pituitary Adenomas.

Non-functional pituitary adenoma (NFPA) seriously affects hypothanamus-pituitary-target organ axis system, with a series of molecule alterations in the multiple levels of genome, transcriptome, proteome, and post-translational modifications, and those molecules mutually interact in a molecular-network system. Meta analysis coupled with IPA pathway-network program was used to comprehensively analyze nine sets of documented NFPA omics data, including NFPA quantitative transcriptomics data [280 differentially expressed genes (DEGs)], NFPA quantitative proteomics data [50 differentially expressed proteins (DEPs)], NFPA mapping protein data (218 proteins), NFPA mapping protein nitration data (9 nitroproteins and 3 non-nitrated proteins), invasive NFPA quantitative transriptomics data (346 DEGs), invasive NFPA quantitative proteomics data (57 DEPs), control mapping protein data (1469 proteins), control mapping protein nitration data (8 nitroproteins), and control mapping phosphorylation data (28 phosphoproteins). A total of 62 molecular-networks with 861 hub-molecules and 519 canonical-pathways including 54 cancer-related canonical pathways were revealed. A total of 42 hub-molecule panels and 9 canonical-pathway panels were identified to significantly associate with tumorigenesis. Four important molecular-network systems, including PI3K/AKT, mTOR, Wnt, and ERK/MAPK pathway-systems, were confirmed in NFPAs by PTMScan experiments with altered expression-patterns and phosphorylations. Nineteen high-frequency hub-molecules were also validated in NFPAs with PTMScan experiment with at least 2.5-fold changes in expression or phosphorylation, including ERK, ERK1/2, Jnk, MAPK, Mek, p38 MAPK, AKT, PI3K complex, p85, PKC, FAK, Rac, Shc, HSP90, NFκB Complex, histone H3, AP1, calmodulin, and PLC. Furthermore, mTOR and Wnt pathway-systems were confirmed in NFPAs by immunoaffinity Western blot analysis, with significantly decreased expression of PRAS40 and increased phosphorylation levels of p-PRAS40 (Thr246) in mTOR pathway in NFPAs compared to controls, and with the decreased protein expressions of GSK-3β and GSK-3β, significantly increased phosphorylation levels of p-GSK3α (Ser21) and p-GSK3β (Ser9), and increased expression level of β-catenin in Wnt pathway in NFPAs compared to controls. Those findings provided a comphrensive and large-scale pathway network data for NFPAs, and offer the scientific evidence for insights into the accurate molecular mechanisms of NFPA and discovery of the effective biomarkers for diagnosis, prognosis, and determination of therapeutic targets.

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Miaolong Lu

Papers

The crucial role of multiomic approach in cancer research and clinically relevant outcomes

Exploration of variations in proteome and metabolome for predictive diagnostics and personalized treatment algorithms: Innovative approach and examples for potential clinical application.

How many proteins can be identified in a 2DE gel spot within an analysis of a complex human cancer tissue proteome

The MAPK Pathway-Based Drug Therapeutic Targets in Pituitary Adenomas.

Multiomics-Based Signaling Pathway Network Alterations in Human Non-functional Pituitary Adenomas.