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Journal of Medicinal Chemistry Sep 2023Herein, four planar cyclometalated platinum(II) complexes with a main ligand of enlarged aromatic rings have been assessed as effective anticancer theranostic agents for...
Herein, four planar cyclometalated platinum(II) complexes with a main ligand of enlarged aromatic rings have been assessed as effective anticancer theranostic agents for the first time. With an increased number of aromatic rings in the N∧N ligand, - exhibit increased lipophilicity and cytotoxicity selectivity. The intensity of the Pt-Pt interaction of each complex can be indicated by an enhanced near-infrared (NIR) emission in phosphate-buffered saline (PBS), their binding activity with biomolecules of bovine serum albumin (BSA) is accompanied by a vivid turn-on green emission, and the intensity gradually decreased from to , which is consistent with the docking of two complexes with BSA. Both "turn-on" NIR and green emission of can be mainly observed in nuclei of living cell within 24 h, while two phosphorescence traces of were recorded in lysosomes by confocal imaging. Moreover, shows the highest efficiency in inducing oncosis of Hela cells, and the relative process was investigated.
Topics: Humans; HeLa Cells; Ligands; Platinum; Precision Medicine; Antineoplastic Agents; Serum Albumin, Bovine
PubMed: 37724909
DOI: 10.1021/acs.jmedchem.3c01126 -
Biomaterials Oct 2023Chemotherapy-conjugated immunotherapy in clinical oncology conceptually resembles the combined effects of cytoreduction and immunostimulation in membrane targeted cell...
Chemotherapy-conjugated immunotherapy in clinical oncology conceptually resembles the combined effects of cytoreduction and immunostimulation in membrane targeted cell killings mediated by pore-forming proteins or host defense peptides. Of the similar concept, targeting cancer cell membrane using membrane active peptides is a hopeful therapeutic modality but had long been hindered from in vivo application. Here we report an enabling strategy of pre-opsonizing a membrane penetrating Ir-complexed octa-arginine peptide (iPep) with serum albumin via intrinsic amphipathicity-driven bimodal interactions into nanoparticles (NP). We found that NP triggered stress-mediated 4T1 cell oncosis which induced potent immunological activation, surpassing several well-known immunogenic medicines. Vested with albumin-enhanced in vivo tumor targeting specificity and pharmacokinetic properties, NP showed combined chemo to immunotherapies of s. c. tumors in mice, with decreased percentages of MDSC, Treg, M2-like macrophage and improved infiltration of CTLs in tumor site, caused complete regression of 4T1 and CT26 tumors, outperforming clinical medicines. In a challenging orthotopic breast cancer model, boost i. v. injections of NP acted as in situ tumor vaccine that drastically enhanced 4T1-specific cellular and humoral immunities to reverse disease progression. Thus, with combined effects of direct cytoreduction, immune activation and tumor vaccine, iPep-NP presents the promise and potential of a new modality of cancer medicine.
Topics: Mice; Animals; Cancer Vaccines; Nanomedicine; Neoplasms; Immunotherapy; Albumins; Cell Line, Tumor; Nanoparticles
PubMed: 37573840
DOI: 10.1016/j.biomaterials.2023.122269 -
International Journal of Molecular... Jul 2023Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT)...
Lung cancer is one of the leading causes of cancer death. Non-small-cell lung cancer (NSCLC) accounts for the majority of lung cancer diagnoses. Dihydrotanshinone (DHT) is a compound extract from , which has favorable anti-inflammatory and anti-cancer activities. However, the role of DHT in NSCLC has not been fully studied. The anti-cancer drugs used for treating lung cancer often lead to apoptosis; however, the drug resistance of apoptosis restricts the effect of these drugs. Oncosis is a passive form of cell death that is different from apoptosis. It is characterized by cell swelling, and Porimin is a specific marker for oncosis. In this study, the role of DHT in mediating oncosis in A549 cells was investigated. In vitro, the MTS assay was used to detect cell activity after DHT treatment. Microscopy and electron microscopy were used to observe cell morphology changes. Western blotting was used to detect protein expression. Flow cytometry was used to detect intracellular reactive oxygen species (ROS) level, calcium ion (Ca) level, and cell mortality. The intracellular Lactic dehydrogenase (LDH) level was detected by an LDH detection kit after DHT treatment. The ATP level was detected using an ATP detection kit. In vivo, Lewis lung cancer (LLC) xenograft mice were used to evaluate the anti-tumor effect of DHT. Hematoxylin and eosin (HE) staining was used to detect the pathology of lung cancer tumors. The detection of Porimin in the tumor tissues of the mice after DHT administration was assessed by immunohistochemistry (IHC). The results of this study showed that DHT treatment changed the cell morphology; destroyed the mitochondrial structure; increased the expression of Porimin; increased the levels of LDH, ROS, and Ca; decreased the mitochondrial membrane potential and ATP level; and played an anti-tumor role in vitro by mediating oncosis in A549 cells. The in vivo studies showed that DHT could effectively inhibit tumor growth. The results of protein detection and IHC detection in the tumor tissues showed that the expression of Porimin was increased and that oncosis occurred in the tumor tissues of mice. DHT triggered Porimin-dependent oncosis by ROS-mediated mitochondrial dysfunction in NSCLC. The in vivo studies showed that DHT could inhibit tumor growth in LLC xenograft mice by triggering oncosis. This study indicates the potential for DHT to treat NSCLC.
Topics: Animals; Humans; Mice; Adenosine Triphosphate; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Lung Neoplasms; Mitochondria; Reactive Oxygen Species
PubMed: 37569328
DOI: 10.3390/ijms241511953 -
Journal of the American Chemical Society Jun 2023Photosensitizers to precise target and change fluorescence upon light illumination could accurately self-report where and when the photosensitizers work, enabling us to...
Photosensitizers to precise target and change fluorescence upon light illumination could accurately self-report where and when the photosensitizers work, enabling us to visualize the therapeutic process and precisely regulate treatment outcomes, which is the unremitting pursuit of precision and personalized medicine. Here, we report self-immolative photosensitizers by adopting a strategy of light-manipulated oxidative cleavage of C═C bonds that can generate a burst of reactive oxygen species, to cleave to release self-reported red-emitting products and trigger nonapoptotic cell oncosis. Strong electron-withdrawing groups are found to effectively suppress the C═C bond cleavage and phototoxicity via studying the structure-activity relationship, allowing us to elaborate - that could temporarily inactivate the photosensitizer and quench the fluorescence by different glutathione (GSH)-responsive groups. Thereinto, with 2-cyano-4-nitrobenzene-1-sulfonyl group displays excellent GSH responsiveness than the other four. Surprisingly, shows better reactivity with GSH in weakly acidic condition, which inspires the application in weakly acidic tumor microenvironment where GSH elevates. To this end, we further synthesize by anchoring integrin αβ binding cyclic pentapeptide (cRGD) for tumor targeting. In A549 xenografted tumor mice, successfully deprotects to restore near-infrared fluorescence because of elevated GSH in tumor site, which is subsequently cleaved upon light irradiation releasing red-emitting products to report photosensitizer working, while effectively ablating tumors via triggered oncosis. The advanced self-immolative organic photosensitizer may accelerate the development of self-reported phototheranostics in future precision oncology.
Topics: Mice; Animals; Photosensitizing Agents; Neoplasms; Self Report; Precision Medicine; Glutathione; Photochemotherapy; Cell Line, Tumor; Nanoparticles; Tumor Microenvironment
PubMed: 37216494
DOI: 10.1021/jacs.3c01666 -
Animal Models and Experimental Medicine Apr 2023Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron-sulfur cluster synthesis proteins. This...
BACKGROUND
Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron-sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death.
METHODS
We generated neuron-specific Isca1 knockout rat (Isca1 -NeuN-Cre) using CRISPR-Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons.
RESULTS
This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis.
CONCLUSIONS
This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.
Topics: Rats; Humans; Animals; Syndrome; Mitochondrial Diseases; Iron-Sulfur Proteins; Mitochondria; Neurons; Adenosine Triphosphate; Mitochondrial Proteins
PubMed: 37140997
DOI: 10.1002/ame2.12318 -
Journal of Wound Care May 2023The identification of novel treatments for severe burn wounds relies on accurate clinical assessments of the extent of injury. However, evaluation of burn wound depth... (Review)
Review
The identification of novel treatments for severe burn wounds relies on accurate clinical assessments of the extent of injury. However, evaluation of burn wound depth can be challenging due to the tendency for burn wounds to progress over time in a little-understood process known as 'burn wound conversion'. Local factors affecting the burn wound, such as inflammation, oxidative stress-induced tissue damage, vasostasis and bacterial infections, lead to increased cell death by apoptosis or oncosis, while systemic events may promote burn wound conversion. Acute shock, metabolic derangements, age or immunomodulation can modify cytokine secretion, lower immune responses, decrease blood flow or cause bacterial infection at the burn wound site. Therefore, therapeutic approaches targeting specific mechanisms that reduce cell death, improve wound reperfusion and promote tissue regrowth should favourably enhance burn wound healing, and long-term functional and aesthetic outcomes. Our current understanding of these mechanisms mostly comes from animal studies, underscoring the need for extensive research in humans. A streamlined approach would be to investigate the parallels in other disease states that exhibit ischaemia and potential reperfusion, such as ischaemic stroke and myocardial infarction. Moreover, in view of the limited knowledge available on the subject, the need exists for further clinical research into burn wound conversion and novel target pathways to ameliorate its effects. This review describes events that affect the viability of cells at the burn wound site resulting in burn wound conversion, and identifies potential targets for clinical interventions that may diminish burn wound conversion.
Topics: Animals; Humans; Brain Ischemia; Stroke; Wound Healing; Burns; Bacterial Infections
PubMed: 37121662
DOI: 10.12968/jowc.2023.32.Sup5.S11 -
Theranostics 2023Chemodynamic therapy (CDT) is well-known for using the tumor microenvironment to activate the Fenton reaction or Fenton-like reaction to generate strong oxidative... (Review)
Review
Chemodynamic therapy (CDT) is well-known for using the tumor microenvironment to activate the Fenton reaction or Fenton-like reaction to generate strong oxidative hydroxyl radicals for tumor-specific treatment. It is highly selective and safe, without depth limitation of tissue penetration, and shows its potential as a new green therapeutic method with great clinical application. However, the catalytic efficiency of reagents involved in the Fenton reaction is severely affected by the inherent microenvironmental limitations of tumors and the strict Fenton reaction-dependent conditions. With the increasing application of nanotechnology in the medical field, combined therapies based on different types of functional nanomaterials have opened up new avenues for the development of next-generation CDT-enhanced system. This review will comprehensively exemplify representative results of combined therapies of CDT with other antitumor therapies such as chemotherapy, phototherapy, sonodynamic therapy, radiation therapy, magnetic hyperthermia therapy, immunotherapy, starvation therapy, gas therapy, gene therapy, oncosis therapy, or a combination thereof for improving antitumor efficiency from hundreds of the latest literature, introduce strategies such as the ingenious design of nanomedicines and tumor microenvironment regulations to enhance the combination therapy, and further summarize the challenges and future perspective of CDT-based multimodal anticancer therapy.
Topics: Humans; Nanomedicine; Hyperthermia, Induced; Neoplasms; Phototherapy; Combined Modality Therapy; Tumor Microenvironment; Cell Line, Tumor; Nanoparticles
PubMed: 37064867
DOI: 10.7150/thno.80887 -
Chemical Society Reviews Apr 2023The great clinical success of cisplatin and its derivatives has convinced people that metal complexes could play a more significant role in human cancer therapy.... (Review)
Review
The great clinical success of cisplatin and its derivatives has convinced people that metal complexes could play a more significant role in human cancer therapy. However, targeting and drug resistance are still two dominant problems that need to be urgently solved for metallodrugs' efficacy and clinical translation. As an important component of metal complexes, organometallics have been experiencing rapid development in recent years. Compared with platinum drugs, emerging anti-tumor organometallics targeting dynamic bioprocesses provide an effective strategy to overcome conventional problems. This review focuses on burgeoning anti-tumor strategies and provides up-to-date advances in anti-tumor organometallics development based on their action mechanisms. Specifically, important tumor-overexpressed proteins and nucleic acids as organometallics' anti-tumor targets are systematically presented, followed by organometallics that exert their anti-tumor activity by perturbing tumor intracellular energy/redox/metal/immune homeostasis. Finally, nine cell death pathways including apoptosis, paraptosis, autophagy, oncosis, necrosis, necroptosis, ferroptosis, pyroptosis, and immunogenic cell death (ICD) that can be induced by organometallics are reviewed, and their morphological and biochemical features are summarised. This review at the interface of chemistry, biology, and medicine aims to enlighten the rational development of organometallic anti-tumor agents.
Topics: Antineoplastic Agents; Organometallic Compounds; Humans; Membrane Transport Proteins; Receptors, Cell Surface; Neoplasms; Homeostasis; Animals; Oxidation-Reduction; Cell Death
PubMed: 37014670
DOI: 10.1039/d2cs00757f -
Molecules (Basel, Switzerland) Jan 2023Cancer is currently considered one of the most threatening diseases worldwide. Diet could be one of the factors that can be enhanced to comprehensively address a cancer... (Review)
Review
Cancer is currently considered one of the most threatening diseases worldwide. Diet could be one of the factors that can be enhanced to comprehensively address a cancer patient's condition. Unfortunately, most molecules capable of targeting cancer cells are found in uncommon food sources. Among them, depsipeptides have emerged as one of the most reliable choices for cancer treatment. These cyclic amino acid oligomers, with one or more subunits replaced by a hydroxylated carboxylic acid resulting in one lactone bond in a core ring, have broadly proven their cancer-targeting efficacy, some even reaching clinical trials and being commercialized as "anticancer" drugs. This review aimed to describe these depsipeptides, their reported amino acid sequences, determined structure, and the specific mechanism by which they target tumor cells including apoptosis, oncosis, and elastase inhibition, among others. Furthermore, we have delved into state-of-the-art in vivo and clinical trials, current methods for purification and synthesis, and the recognized disadvantages of these molecules. The information collated in this review can help researchers decide whether these molecules should be incorporated into functional foods in the near future.
Topics: Humans; Depsipeptides; Antineoplastic Agents; Carboxylic Acids; Peptides, Cyclic
PubMed: 36677728
DOI: 10.3390/molecules28020670 -
Oncology Letters Feb 2023Colorectal cancer (CRC) has high morbidity and mortality, particularly if diagnosed at an advanced stage. Although there have been several studies on CRC, few have...
Colorectal cancer (CRC) has high morbidity and mortality, particularly if diagnosed at an advanced stage. Although there have been several studies on CRC, few have investigated the relationship between oncosis and CRC. Thus, the purpose of the present study was to identify oncosis-related long noncoding RNAs (lncRNAs) and to establish a clinical prognostic model. Original data were acquired from The Cancer Genome Atlas database and PubMed. Differentially expressed oncosis-related lncRNAs (DEorlncRNAs) were identified and were subsequently formed into pairs. Next, a series of tests and analyses, including both univariate and multivariate analyses, as well as Lasso and Cox regression analyses, were performed to establish a receiver operating characteristic curve. A cut-off point was subsequently used to divide the samples into groups labelled as high- or low-risk. Thus, a model was established and evaluated in several dimensions. Six pairs of DEorlncRNAs associated with prognosis according to the algorithm were screened out and the CRC cases were divided into high- and low-risk groups. Significant differences between patients in the different risk groups were observed for several traits, including survival outcomes, clinical pathology characteristics, immune cell infiltration status and drug sensitivity. In addition, PCR and flow cytometry were performed to further verify the model. In summary, a new risk model algorithm based on six pairs of DEorlncRNAs in CRC, which does not require specific data regarding the level of gene expression, was established and validated. This algorithm may be used to predict patient prognosis, immune cell infiltration and drug sensitivity.
PubMed: 36644148
DOI: 10.3892/ol.2022.13650