Auranofin and its analogs as prospective agents for the treatment of colorectal cancer

Today colorectal cancer(CRC)is one of the leading causes of cancer death worldwide.This disease is poorly chemo-sensitive toward the existing medical treatments so that new and more effective therapeutic agents are urgently needed and intensely sought.Platinum drugs,oxaliplatin in particular,were reported to produce some significant benefit in CRC treatment,triggering the general interest of medicinal chemists and oncologists for metal-based compounds as candidate anti-CRC drugs.Within this frame,gold compounds and,specifically,the established antiarthritic drug auranofin with its analogs,form a novel group of promising anticancer agents.Owing to its innovative mechanism of action and its favorable pharmacological profile,auranofin together with its derivatives are proposed here as novel experimental agents for CRC treatment,capable of overcoming resistance to platinum drugs.Some encouraging results in this direction have already been obtained.A few recent studies demonstrate that the action of auranofin may be further potentiated through the preparation of suitable pharmaceutical formulations capable of protecting the gold pharmacophore from unselective reactivity or through the design of highly synergic drug combinations.The perspectives of the research in this field are outlined.

Metallomics:An integrated biometal science

Metallomics is an emerging scientific area integrating the research fields related to the understanding of the molecular mechanisms of metal-associated life processes and the entirety of metal and metalloid species within a cell or tissue type. In metallomics,metalloproteins,metalloenzymes and other metal-containing biomolecules in a biological system are referred to as metallomes,similar to genomes and proteomes in genomics and proteomics,respectively. This review discusses the concept of metallomics with a focus on analytical techniques and methods,particularly the so-called hyphenated techniques which combine a high-resolution separation technique (gel electrophoresis/laser ablation,chromatography or capillary electrophoresis) with a highly sensitive detection method such as elemental (inductively coupled plasma,ICP) or molecular (electron spray ionization (ESI) or matrix-assisted laser desorption/ionization (MALDI)) mass spectrometry,or nuclear X-ray fluorescence/absorption spectrometry. The applications of these advanced analytical methods in the identification of metallo-/phospho-/seleno-proteins,probing of relationships between structure and function of metal-loproteins,and study of clinically used metallodrugs will be selectively outlined,along with their advantages and limitations.

The induction of PANoptosis in KRAS-mutant pancreatic ductal adenocarcinoma cells by a multispecific platinum complex

Oncogenic KRAS reprograms pancreatic ductal adenocarcinoma(PDAC) cells to a state that is awfully resistant to apoptosis.An alternative coping strategy is to trigger a nonapoptotic cell death.Herein,a multi specific platinum complex SEP was constructed by conjugating a quinone derivative seratrodast to a prodrug of cisplatin.Interestingly,SEP-treated KRAS-mutant PDAC cells showed the characteristics of pyroptosis,apoptosis and necroptosis,similar to PANoptosis(a newfound inflammatory cell death).Mechanistically,SEP could enter cancer cells effectively,then damage nuclear DNA,boost mitochondrial superoxide anion radicals and affect various signaling pathways related to redox homeostasis and tumor metabolism.To our best knowledge,SEP is the first metal complex,even small molecule,to elicit PANoptosis(pyroptosis,apoptosis and necroptosis) in cancer cells,providing a new strategy to overcome apoptotic resistance of KRAS-mutant PDAC.

Copper-thioguanine metallodrug with self-reinforcing circular catalysis for activatable MRI imaging and amplifying specificity of cancer therapy

For chemotherapy, drug delivery systems often suffer from the inefficient drug loading capability, which usually cause systems toxicity and extra burden to excrete carrier itself. Moreover, the cancer therapeutic efficacy is also greatly limited by the specificity of tumor microenvironment for reactive oxygen species(ROS) based cancer therapeutic strategy(e.g., chemodynamic therapy). Herein, we have developed metal-drug coordination nanoplatform that can not only be responsive to tumor microenvironment but also modulate it, so as to achieve efficient treatment of cancer. Excitingly, by employing small molecule drug(6-thioguanine) as ligand copper ions, we achieve a high drug loading rate(60.1%) and 100% of utilization of metal-drug coordination nanoplatform(Cu-TG). Interestingly, Cu-TG possessed high-efficiently horseradish peroxidase-like, glutathione peroxidase-like and catalase-like activity. Under the tumor microenvironment, Cu-TG exhibited the self-reinforcing circular catalysis that is able to amplify the cellular oxidative stress, inducing notable cancer cellular apoptosis. Moreover, Cu-TG could be activated with glutathione(GSH) and facilitated for GSH triggered 6-TG release, higher selective therapeutic effect toward cancer cells, and GSH activated T1 weight-magnetic resonance imaging. Based on the above properties, Cu-TG exhibited magnetic resonance imaging(MRI) guiding, efficient and synergistic combination of chemodynamic and chemotherapy with self-reinforcing therapeutic outcomes in vivo.

Manganese-Fluorouracil Metallodrug Nanotheranostic for MRI-Correlated Drug Release and Enhanced Chemoradiotherapy

For cancer therapy,drug delivery systems are often limited by insufficient drug loading capacity,which usually results in systemic toxicity and heavy metabolic burden to excrete the carriers.Herein,we reported a“one-pot”method for constructing metal(Mn^(2+))–fluorouracil(FU)-coordinated nanotheranostics(Mn-FU)by self-assembly of FU(as bridging ligands)and Mn^(2+)(as metal nodes)through Mn–N/O coordination interactions.Importantly,owing to the effective coordination between Mn and FU,Mn-FU exhibits high drug loading efficacy(47.7 wt%),encapsulation efficacy(82.6%),and relatively large yield(1 g/pot).In acidic tumor microenvironments,efficient release of FU and Mn^(2+)is realized because of nitrogen protonation.The released FU and Mn^(2+)from Mn-FU are used for chemotherapy and turn on magnetic resonance imaging(MRI),respectively,achieving MRI-correlated drug release.After PEG modification,Mn-FU displays high tumor homing ability via enhanced permeability and retention effects and quick renal clearance owing to the disassembly in acidic biological conditions.As a result,Mn-FU substantially enhances the synergistic effects of chemoradiotherapy.Meanwhile,the systemic toxic side effects of free FU-based chemoradiotherapy were greatly reduced through this nanotheranostic.Our strategy offers a facile way to construct metallodrug nanotheranostics for efficient cancer theranostics.