Quest for a stable Cu-ligand complex with a high catalytic activity to produce reactive oxygen species.

Metal ion-catalyzed overproduction of reactive oxygen species (ROS) is believed to contribute significantly to oxidative stress and be involved in several biological processes, from immune defense to development of diseases. Among the essential metal ions, copper is one of the most efficient catalysts in ROS production in the presence of O2 and a physiological reducing agent such as ascorbate. To control this chemistry, Cu ions are tightly coordinated to biomolecules.

Altering relative metal-binding affinities in multifunctional Metallochaperones for mutant p53 reactivation.

The p53 protein plays a major role in cancer prevention, and over 50% of cancer diagnoses can be attributed to p53 malfunction. p53 incorporates a structural Zn site that is required for proper protein folding and function, and in many cases point mutations can result in loss of the Zn ion, destabilization of the tertiary structure, and eventual amyloid aggregation. Herein, we report a series of compounds designed to act as small molecule stabilizers of mutant p53, and feature Zn-binding fragments to chaperone Zn to the metal depleted site and restore wild-type (WT) function.

A novel ΔNp63-dependent immune mechanism improves prognosis of HPV-related head and neck cancer.

Background: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments.

Methods: Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages .

Correction: Structural tuning of organoruthenium compounds allows oxidative switch to control ER stress pathways and bypass multidrug resistance.

[This corrects the article DOI: 10.1039/C6SC00268D.].

A Novel Near-IR Absorbing Ruthenium(II) Complex as Photosensitizer for Photodynamic Therapy and its Cetuximab Bioconjugates.

A novel Ru(II) cyclometalated photosensitizer (PS), Ru-NH , for photodynamic therapy (PDT) of formula [Ru(appy)(bphen) ]PF (where appy=4-amino-2-phenylpyridine and bphen=bathophenanthroline) and its cetuximab (CTX) bioconjugates, Ru-Mal-CTX and Ru-BAA-CTX (where Mal=maleimide and BAA=benzoylacrylic acid) were synthesised and characterised. The photophysical properties of Ru-NH revealed absorption maxima around 580 nm with an absorption up to 725 nm. The generation of singlet oxygen ( O ) upon light irradiation was confirmed with a O quantum yield of 0.

Multifunctional metallochaperone modifications for targeting subsite cavities in mutant p53-Y220C.

The p53 protein, known as the 'guardian of the genome', plays an important role in cancer prevention. Unfortunately, p53 mutations result in compromised activity with over 50% of cancers resulting from point mutations to p53. There is considerable interest in mutant p53 reactivation, with the development of small-molecule reactivators showing promise.

Morpho-functional analysis of patient-derived xenografts reveals differential impact of gastric cancer and chemotherapy on the tumor ecosystem, affecting immune check point, metabolism, and sarcopenia.

Objectives: Gastric cancer (GC) is an aggressive disease due to late diagnosis resulting from the lack of easy diagnostic tools, resistances toward immunotherapy (due to low PD-L1 expression), or chemotherapies (due to p53 mutations), and comorbidity factors, notably muscle atrophy. To improve our understanding of this complex pathology, we established patient-derived xenograft (PDX) models and characterized the tumor ecosystem using a morpho-functional approach combining high-resolution imaging with molecular analyses, regarding the expression of relevant therapeutic biomarkers and the presence of muscle atrophy.

Materials And Methods: GC tissues samples were implanted in nude mice.

Inhibition of p53 protein aggregation as a cancer treatment strategy.

The p53 protein plays a critical role in the prevention of genome mutations in the body, however, this protein is frequently mutated in cancer and almost all cancers exhibit malfunction along the p53 pathway. In addition to a loss of activity, mutant p53 protein is prone to unfolding and aggregation, eventually forming amyloid aggregates. There continues to be a considerable effort to develop strategies to restore normal p53 expression and activity and this review details recent advances in small-molecule stabilization of mutant p53 protein and the design of p53 aggregation inhibitors.

Anti-tumor effects of P-LPK-CPT, a peptide-camptothecin conjugate, in colorectal cancer.

To explore highly selective targeting molecules of colorectal cancer (CRC) is a challenge. We previously identified a twelve-amino acid peptide (LPKTVSSDMSLN, namely P-LPK) by phage display technique which may specifically binds to CRC cells. Here we show that P-LPK selectively bind to a panel of human CRC cell lines and CRC tissues.

Sarcopenia remaining after intensive nutritional feeding support could be a criterion for the selection of patients for surgery for oesogastric junction adenocarcinoma.

Background: Sarcopenia is recognized as a negative prognostic factor in several cancers. The aim of this study was to investigate the impact of nutritional support with feeding jejunostomy (FJ) on the occurrence of sarcopenia and how it may affect postoperative short-term outcomes and long-term survival outcomes in patients undergoing esophagectomy for oesogastric junction adenocarcinoma (OJA).

Methods: Patients with OJA were included.

Histone Deacetylase Functions in Gastric Cancer: Therapeutic Target?

Gastric cancer (GC) is one of the most aggressive cancers. Therapeutic treatments are based on surgery combined with chemotherapy using a combination of platinum-based agents. However, at metastatic stages of the disease, survival is extremely low due to late diagnosis and resistance mechanisms to chemotherapies.

The EXTREME Regimen Associating Cetuximab and Cisplatin Favors Head and Neck Cancer Cell Death and Immunogenicity with the Induction of an Anti-Cancer Immune Response.

(1) Background: The first line of treatment for recurrent/metastatic Head and Neck Squamous Cell Carcinoma (HNSCC) has recently evolved with the approval of immunotherapies that target the anti-PD-1 immune checkpoint. However, only about 20% of the patients display a long-lasting objective tumor response. The modulation of cancer cell immunogenicity via a treatment-induced immunogenic cell death is proposed to potentially be able to improve the rate of patients who respond to immune checkpoint blocking immunotherapies.

Targeting of the intracellular redox balance by metal complexes towards anticancer therapy.

The development of cancers is often linked to the alteration of essential redox processes, and therefore, oxidoreductases involved in such mechanisms can be considered as attractive molecular targets for the development of new therapeutic strategies. On the other hand, for more than two decades, transition metals derivatives have been leading the research on drugs as alternatives to platinum-based treatments. The success of such compounds is particularly due to their attractive redox kinetics properties, favorable oxidation states, as well as routes of action different to interactions with DNA, in which redox interactions are crucial.

A role for bioinorganic chemistry in the reactivation of mutant p53 in cancer.

Metal ion dysregulation has been implicated in a number of diseases from neurodegeneration to cancer. While defective metal ion transport mechanisms are known to cause specific diseases of genetic origin, the role of metal dysregulation in many diseases has yet to be elucidated due to the complicated function (both good and bad!) of metal ions in the body. A breakdown in metal ion speciation can manifest in several ways from increased reactive oxygen species (ROS) generation to an increase in protein misfolding and aggregation.

High-Risk Mucosal Human Papillomavirus 16 (HPV16) E6 Protein and Cutaneous HPV5 and HPV8 E6 Proteins Employ Distinct Strategies To Interfere with Interferon Regulatory Factor 3-Mediated Beta Interferon Expression.

Persistent infection with some mucosal α-genus human papillomaviruses (HPVs; the most prevalent one being HPV16) can induce cervical carcinoma, anogenital cancers, and a subset of head and neck squamous cell carcinoma (HNSCC). Cutaneous β-genus HPVs (such as HPV5 and HPV8) associate with skin lesions that can progress into squamous cell carcinoma with sun exposure in Epidermodysplasia verruciformis patients and immunosuppressed patients. Here, we analyzed mechanisms used by E6 proteins from the α- and β-genus to inhibit the interferon-β (IFNB1) response.

Antitumor Immune Response Triggered by Metal-Based Photosensitizers for Photodynamic Therapy: Where Are We?

Metal complexes based on transition metals have rich photochemical and photophysical properties that are derived from a variety of excited state electronic configurations triggered by visible and near-infrared light. These properties can be exploited to produce powerful energy and electron transfer processes that can lead to oxygen-(in)dependent photobiological activity. These principles are the basis of photodynamic therapy (PDT), which is a clinically approved treatment that offers a promising, effective, and noninvasive complementary treatment or even an alternative to treat several types of cancers.

Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer.

The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.

Current Clinical and Pre-Clinical Imaging Approaches to Study the Cancer-Associated Immune System.

In the light of the success and the expected growth of its arsenal, immuno-therapy may become the standard neoadjuvant procedure for many cancers in the near future. However, aspects such as the identity, organization and the activation status of the peri- and intra-tumoral immune cells would represent important elements to weigh in the decision for the appropriate treatment. While important progress in non-invasive imaging of immune cells has been made over the last decades, it falls yet short of entering the clinics, let alone becoming a standard procedure.

Bypassing the Resistance Mechanisms of the Tumor Ecosystem by Targeting the Endoplasmic Reticulum Stress Pathway Using Ruthenium- and Osmium-Based Organometallic Compounds: An Exciting Long-Term Collaboration with Dr. Michel Pfeffer.

Metal complexes have been used to treat cancer since the discovery of cisplatin and its interaction with DNA in the 1960's. Facing the resistance mechanisms against platinum salts and their side effects, safer therapeutic approaches have been sought through other metals, including ruthenium. In the early 2000s, Michel Pfeffer and his collaborators started to investigate the biological activity of organo-ruthenium/osmium complexes, demonstrating their ability to interfere with the activity of purified redox enzymes.

Gold(III) to Ruthenium(III) Metal Exchange in Dithiocarbamato Complexes Tunes Their Biological Mode of Action for Cytotoxicity in Cancer Cells.

Malignant tumors have affected the human being since the pharaoh period, but in the last century the incidence of this disease has increased due to a large number of risk factors, including deleterious lifestyle habits (i.e., smoking) and the higher longevity.

Isoforms of the p53 Family and Gastric Cancer: A Ménage à Trois for an Unfinished Affair.

Gastric cancer is one of the most aggressive cancers, with a median survival of 12 months. This illustrates its complexity and the lack of therapeutic options, such as personalized therapy, because predictive markers do not exist. Thus, gastric cancer remains mostly treated with cytotoxic chemotherapies.

The atypical cadherin MUCDHL antagonizes colon cancer formation and inhibits oncogenic signaling through multiple mechanisms.

Cadherins form a large and pleiotropic superfamily of membranous proteins sharing Ca-binding repeats. While the importance of classic cadherins such as E- or N-cadherin for tumorigenesis is acknowledged, there is much less information about other cadherins that are merely considered as tissue-specific adhesion molecules. Here, we focused on the atypical cadherin MUCDHL that stood out for its unusual features and unique function in the gut.

A balancing act: using small molecules for therapeutic intervention of the p53 pathway in cancer.

Referred to as the "guardian of the genome", p53 is the most frequently mutated protein in cancer and almost all cancers exhibit malfunction along the p53 pathway. As an overexpressed and tumour-specific target, the past two decades have seen considerable dedication to the development of small molecules that aim to restore wild-type function in mutant p53. In this review we collect and communicate the chemical principles involved in small molecule drug design for misfolded proteins in anticancer therapy.

How to Prevent Sarcopenia Occurrence during Neoadjuvant Chemotherapy for Oesogastric Adenocarcinoma?

The aim of this study was to evaluate the impact of a preoperative feeding jejunostomy (FJ) on the occurrence of sarcopenia before and after preoperative chemotherapy for patients with an oesogastric adenocarcinoma (OGA). Forty-six patients with potentially resectable OGA were enrolled in a perioperative chemotherapy protocol. Sarcopenia was evaluated by measuring muscle surfaces (psoas, paraspinal and abdominal wall muscles) on abdominal CT images at the level of the 3rd lumbar vertebra.