Latest ArticlesCisplatin is one of the most commonly used chemotherapeutic drugs in clinic and has good therapeutic effect on various cancers, but the development of drug resistance limits its clinical treatment. The development of cisplatin resistance is caused by many factors, including the decrease of intracellular cisplatin accumulation, the inactivation of cisplatin by mercaptan proteins, the increase of DNA damage repair, apoptosis inhibition, tumor microenvironment and cancer stem cells. In recent years, traditional Chinese medicine (TCM) has been favored for its remarkable effect of reversing cisplatin resistance. This review will explore the mechanisms of cisplatin resistance and the combined modality treatment strategy of TCM to reverse cisplatin resistance, hoping to provide reference for clinical and scientific research.
Breast cancer is the most common malignant tumor in women worldwide. In breast cancer tumor tissues, a variety of targets related to the occurrence and development of breast cancer have been observed, and many drugs have been used in clinical applications for these targets. However, most of these drugs are small molecule inhibitors. With the long-term use of these drugs, acquired drug resistance often occurs in breast cancer patients. To overcome the drug resistance, the development of more efficient drugs is highly desirable in the treatment of breast cancer. Proteolysis targeting chimera (PROTAC) technology is a new kind of targeted protein degradation technology, which has shown broad prospect of applications in the field of drug development. The use of PROTAC technology to target the degradation of relevant targets in breast cancer has become a feasible strategy for breast cancer treatment.
In recent years the role of sphingosine kinase 2 (SphK2), a key enzyme in the sphingolipid pathway, in the process of tumorigenesis has gradually been elucidated. Recent research has shown that SphK2 inhibitors can be used as anticancer drugs alone or in combination with existing drugs to increase the therapeutic sensitivity of drug-resistant tumors. Among them, one selective SphK2 inhibitor, ABC294640, shows excellent oral bioavailability and biodistribution in vivo and has now entered Phase Ⅱ clinical research. Therefore, developing innovative drugs based on SphK2 is of great interest. Herein, we discuss progress in understanding the role of SphK2 in tumorigenesis and review the recent development of inhibitors of SphK2.
Ursodeoxycholic acid (UDCA) is an essential drug for the treatment of cholestatic liver diseases. As the most important representative of endogenous drugs, the metabolism and disposition of UDCA in human is characterized by both host-gut microbial co-metabolism and hepato-billilary-intestinal circulation. These distinct metabolic and pharmacokinetic features have brought great challenges into the bioequivalence (BE) evaluation of UDCA generic formulations. These challenges include not only biopharmaceutical problems derived from the unique physiochemical properties of amphiphilic molecules and the large single dose, but also the drug metabolism and pharmacokinetic problems associated with endogenous metabolism, long terminal half-life, high inter-and intra-individual variations, as well as accurate determination of UDCA and its metabolites. This review summarized academic and industrial literatures about the clinical pharmacokinetics and endogenous metabolism of UDCA. Current guidelines and technical challenges of UDCA BE studies were extensively discussed. Knowledge summarized in this review is expected to provide valuable reference for the development of UDCA generic formulations.
In order to achieve rapid proliferation and adapt to the complex microenvironment, tumor cells have dominant characteristics such as unique metabolic patterns and the ability to escape from immunoregulation. Tumor cells reprogram multiple metabolic pathways to promote immune escape, which impacts tumor diagnosis, treatment and prognosis. Based on the effect of metabolic changes on tumor immune escape and its molecular mechanism, metabolic regulation provides new approaches to enhance immunotherapy. We review recent advances in tumor immuno-escape and immunotherapy based on metabolic regulation. Cutting-edge analytical techniques and methods for tumor metabolism research such as metabolomics, mass spectrometry imaging-based spatially-resolved metabolomics and metabolic flow analysis are also discussed.
In recent years therapeutic proteins products including therapeutic antibodies have become a major driving force for the modern biopharmaceutical industry. However, they have complex product quality attributes (PQAs) which limit product development and quality control (QC). Recent advances in high resolution mass spectrometry (MS) have led to the use of an MS-based multi-attribute method (MAM) for quality control testing of therapeutic proteins, which allows for direct measurement of multiple PQAs and identification of impurities. MAM helps to promote the improvement of product quality and QC and a reduction in manufacturing cost. To explore the application of MAM in QC, we discuss generic MAM workflow, the current state of MAM application in product development and QC, identify points to consider for use of MAM as a QC test, and summarize MAM's advantages and challenges in this article. The future application of MAM for therapeutic antibodies and the opportunities for its further development, use, and substitution for conventional methods is presented.
Ferroptosis is a cell death path for the abnormal accumulation of iron dependent reactive oxygen species, which leads to the dysregulation of redox homeostasis. As a new type of cancer treatments, ferroptosis has attracted extensive attention of researchers. With the development of nanoscience, various functional nanomaterials can produce H2O2, exhaust glutathione, and gather Fenton reaction catalysts in tumor site. Therefore, these nanomaterials can play a stronger role in tumor inhibition in coordination with the ferroptosis-inducing agents. Firstly, this paper introduced the mechanism of ferroptosis and the feasibility of ferroptosis-inducing strategy in cancer therapy. Secondly, we summarized the construction strategies of the ferroptosis-inducing nanomedicines for cancer therapy, including accelerating intracellular Fenton reaction, inhibiting the activity of glutathione peroxidase 4, and increasing the exogenous delivery of lipid peroxides. In addition, we also discussed the combination therapy based on ferroptosis, including the combination of ferroptosis with traditional therapy strategies (combined with apoptosis-inducing drugs, immunotherapy and gene therapy) and external energy (including ultrasound therapy and photodynamic therapy). Finally, the expectations and challenges of ferroptosis-inducing nanomedicines for cancer therapy in the future were discussed.
Tanshinones and salvianolic acids are important materials in the treatment of coronary heart disease, myocardial infarction, hypertension, hyperlipidemia, stroke and others illnesses. In recent years, with the development of genomics, transcriptome, metabolomics and bioinformatics, many advances have been made in the biosynthesis and transcriptional regulation of tanshinones and salvianolic acids. This paper summarizes these advances and suggests further study on the downstream synthesis pathways and transcriptional regulatory mechanisms to reveal new molecular mechanism of synthesis, transport, regulation and modification. Additionally, we discuss the design and construction of new biological pathways to increase the expression of biosynthesis genes and the production of secondary components, is a newly developing research field.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the pathogen that caused the global COVID-19 outbreak. The 3C-like protease (3CLpro) of SARS-CoV-2 plays a key role in virus replication and has become an ideal target for antiviral drug design. In this paper, we report the validation and use of bioluminescence resonance energy transfer (BRET) technology to establish a cell-based assay for screening for SARS-CoV-2 virus 3CL protease inhibitors. The results show that the method is able to monitor the cleavage efficiency of 3CL protease with good reproducibility (Z' factor is 0.59), and is consistent with antiviral activity analysis in cell culture. This work demonstrates that this method can be applied to the screening and evaluation of 3CL protease inhibitors, providing a powerful tool for the development of new drugs.
This study was designed to investigate the effect of dihydromyricetin (DHM) on inducing apoptosis of ovarian cancer cells A2780 through endoplasmic reticulum stress (ERS) pathway and the mechanisms involved in vitro and in vivo. A2780 cells were treated with different concentrations of DHM, and the protein expression levels of glucose-regulated protein 78 (GRP78) which is related to ERS increased, apoptotic proteins C/EBP-homologous protein (CHOP), and cysteinyl aspartate specific proteinase-12 (caspase-12) elevated. After pretreatment with ERS inhibitor, 4-phenyl butyric acid (4-PBA), following the intervention with DHM, the A2780 cell viability decreased and apoptotic rate increased. All animal welfare and experimental procedures were approved by the Animal Ethics Committee of Chongqing Medical University. Intraperitoneal injection of DHM suspension into nude mice with ovarian cancer could significantly inhibit the growth of transplanted tumor in vivo, increase the protein expression levels of GRP78, CHOP, and caspase-3. Moreover, swollen and broken endoplasmic reticulum could be observed in tumor tissues, suggesting that DHM intervention induces apoptosis mediated by ERS. The results indicated that DHM could induce apoptosis of ovarian cancer cells and inhibit the growth of transplanted tumors in nude mice, which might be related to the activation of ERS pathway.
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