Latest ArticlesThe preparation of polymorphic forms of rivaroxaban was carried out using a recrystallization method based on that for crystal form-Ⅰ. Preparation methods were developed for two crystal forms-Ⅱ (medicinal crystal form) and five crystal forms-Ⅳ and the crystals were then characterized. The crystalline form was identified by applying modern analytical means including X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), element analysis (EA), mass spectrometry (MS), and infrared spectrum (IR), and the morphology of different crystal forms was observed by scanning electron microscopy (SEM). The results show that the PXRD and DSC characteristics of prepared crystal forms-Ⅱ and Ⅳ are consistent with those described in patents at home and abroad, and the test results with EA, MS and IR are in accordance with the chemical structure of rivaroxaban. The crystal form-Ⅰ is lamellar, the crystal form-Ⅱ is linear and crystalline form-Ⅳ is striped as determined by SEM. In summary, the methods for preparing crystal form-Ⅱ and form-Ⅳ are reliable, the required reagents are easily available, the experimental conditions are easy to implement and the preparation process is simple. Our study provides a new reference for the production and application of rivaroxaban.
Polymyxin B and polymyxin E (colistin) are increasingly used as last-resort drugs for treatment of infections caused by multidrug-resistant gram-negative pathogens. Unfortunately, the application was limited due to the serious side effects, especially nephrotoxicity. Very recently, the need for developing more tolerated and more effective polymyxin analogues has grown. This study details the design, synthesis, and evaluation of two classes of polymyxin B analogues with varying hydrophobicity and bulkiness at the N-terminal fatty acyl chain or position 6 amino acid. 20 polymyxin B analogues were synthesized and the chemical structures of the analogues were confirmed by HR-MS and 1H NMR spectra. Compounds 7e (MIC:0.5-4 μg·mL-1) and 7l (MIC:0.25-2 μg·mL-1) showed similar or better antimicrobial activity against both susceptible and resistant strains of Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa compared to polymyxin B (MIC:0.5-2 μg·mL-1). Besides, compound 7l (CC50:217.1±13.2 μg·mL-1) displayed noticeably decreased renal cytotoxicity compared to polymyxin B (CC50:120.3±6.0 μg·mL-1). This work establishes the base of further study on the structure-activity relationship of polymyxin B.
Post-translational modifications (PTMs) of proteins is an important mode of protein function regulation, which is essential for the structure and function of proteins under physiological and pathological conditions, and the types of modifications is wide. Cancer immunotherapy refers to an effective method for cancer treatment by activating or normalizing disabled immune cells. In recent years, researchers have found that many types of PTM are involved in the process of proliferation, activation and metabolic reprogramming of immune cells in cancer microenvironment, and may affect the efficacy of cancer immunotherapy. Therefore, this article reviews the effects of several different PTMs on immune cells in cancer microenvironment, and aims to provide new ideas for cancer immunotherapy.
In recent years, the role of ketone body metabolism in tumor growth, invasion and metastasis has attracted much attention. Succinyl-CoA transferase (SCOT) is a key enzyme in the metabolism of ketone bodies. Its function is to transfer the coenzyme A group of succinyl-CoA to acetoacetate and catalyze the formation of acetoacetyl-CoA, which is the first rate-limiting step in ketone metabolism. Then acetoacetyl-CoA further breaks into two molecules of acetyl-CoA and enters the tricarboxylic acid cycle. Studies have shown that SCOT is highly expressed in a variety of tumors, and is closely related to tumor progression and prognosis of patients, which makes SCOT a potential marker for clinical diagnosis and prognosis evaluation; in addition, inhibition of SCOT activity can hinder the metabolism of ketone bodies in tumor cells, that is, reduce the production of ATP, thereby inhibiting tumor growth, proliferation, invasion and metastasis. This review aims to explore the important role of SCOT in metabolic pathways and its relationship with tumorigenesis and development, and to provide new ideas for exploring tumor metabolism and targeting molecular drugs.
Signal transducer and activator of transcription 3 (STAT3) was found in an abnormal constitutively active status in certain cancer tissues, and under these circumstances the interruption of STAT3 signaling pathway was proposed with the potential anti-cancer efficacy. In this study, our previous reported STAT3 inhibitor Bt354 can inhibit tumor growth in DU145 xenograft mice without affecting body weight. In groups treated with Bt354, the inhibition rate of tumor weight was 58.8%, 62.7% and 73.5% in 10, 20, 40 mg·kg-1 group, respectively. Particularly, the number of Ki 67 positive cells in the tumor sections was significantly decreased in Bt354 groups. Furthermore, Bt354 inhibited the nuclear translocation of STAT3 and consequently induced cell growth inhibition, apoptosis in DU145 cells. These findings suggest that Bt354 may be a potent anticancer agent for STAT3 activated prostate cancer cells. Procedures for animal study were performed with approval of the Animal Care and Use Committee of the Chinese Academy of Medical Sciences and Peking Union Medical College.
Immunotherapy has emerged as one of the major modalities for clinical cancer therapy, along with surgery, chemotherapy, radiotherapy and targeted therapy. However, tumor-targeted delivery of immune therapeutics is challenged by a series of barriers including non-specific release, poor tumor penetration capacity, and insufficient cellular uptake of the therapeutic regimens, which seriously restricted the efficiency and efficacy of immunotherapy. To address above challenges, nanosized drug delivery systems (NDDS) have been extensively exploited to achieve tumor-targeted delivery of immunotherapy drugs. It has been well investigated that solid tumors are of unique characteristics including acidic, hypoxic and enzymatic extracellular microenvironment. Meanwhile, the tumor cells are of acidic, reductant and reactive oxygen species intracellular microenvironment. In recent years, a large variety of tumor microenvironment-activatable NDDS have been exploited to respond specifically to the stimulus of extracellular or intracellular tumor microenvironment for enhancing the accumulation, retention and penetration in the tumor tissue. These NDDS were also employed to promote intracellular uptake and tunable drug release inside the tumor cells. In this review article, we summarized the recent progress of our laboratory using the tumor microenvironment-activatable NDDS for immune efficient therapeutics delivery, and improved cancer immunotherapy. We also briefly discussed the challenges and provided perspective of NDDS-based cancer immunotherapy.
Programmed cell death protein 1 (PD-1) is an important immunosuppressive molecule, which combines with programmed cell death 1 ligand 1 (PD-L1) to initiate programmed T-cell death, leading to immune escape of tumor cells. Immune checkpoint inhibitors kill tumor cells by blocking the binding of PD-1 to PD-L1 and reactivating the patient's own immune system. With the approval of anti-PD-1 monoclonal antibodies nivolumab, pembrolizumab and anti-PD-L1 monoclonal antibody atezolizumab by FDA for the treatment of melanoma, advanced non-small cell lung cancer and other cancers, cancer treatment has ushered in a new dawn. However, only 20% of patients achieved long-term efficacy after treatment, and most patients relapsed later. Therefore, it is significant to identify effective biomarkers and develop new targets to improve the response of patients to immuno-therapy. This article reviews on the mechanism of action of anti-PD-1/PD-L1 drugs in tumors, potential biomarkers and the mechanism of acquired drug resistance, as well as combination therapy under research.
Chemotherapeutic agents, also known as cytotoxic anticancer agents, inhibit the cancer cell proliferation via interrupting DNA replication, transcription and microtubule stability etc. Chemotherapeutic agents have been used in clinical cancer treatment for decades. Recently, with the tremendous advancement in immunooncology, chemotherapeutic agents have aroused renewed interest for their great potential to sensitize tumor cells to immunotherapy. Meanwhile, it is worth noting that the effects of chemotherapeutic agents on the immune system involve multiple aspects with complex mechanisms. Currently, there still lacks guidance for the combined use of chemotherapy and immunotherapy, and the clinical benefits remain obscure, impelling a better under-standing of the impact of chemotherapeutic agents on the antitumor immunity. This article reviews the mechanistic insights into chemotherapy-modulated antitumor immune responses, with major focus on the direct effect on immune cells and the immunogenic remodeling of tumor cells. The review is particularly interested in the chemo-therapy-trigged signaling that contributes to the immunogenic cell death. This review may provide useful insights into the immunomodulatory effects of chemotherapeutic agents and the implications in exploring therapeutic oppor-tunities of chemotherapy in cancer immunotherapy.
Chemotherapy resistance is the main cause of poor prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC). Pyroptosis is one of the anti-tumor mechanisms by chemotherapy drugs. Studies have shown that DEP-domain containing mTOR-interacting protein (DEPTOR) is correlated with sorafenib and gefitnib resistance, which is discovered as a naturally negative regulator of mammalian/mechanistic target of rapamicin (mTOR). In this study, DEPTOR knockdown (shDEPTOR) lentivirus was used to establish the stable DEPTOR knockdown ESCC cell lines. The results showed that knockdown of DEPTOR reduced chemosensitivity to cisplatin in ESCC cells in vitro. The lower expression of DEPTOR caused less extensive morphological characteristics of pyroptosis than that was observed in sh-con cells with the treatment of cisplain. Further studies showed that knockdown of DEPTOR induced downregulation of Caspase-1 expression and reduction of Caspase-1 activation, thereby inhibiting the activation of the classical pathway of pyroptosis. This paper demonstrates that DEPTOR can improve cisplatin chemosensitivity in ESCC cells via inducing Caspase-1-mediated pyroptosis.
Calcium-binding protein S100A9 is closely related to inflammation and tumor invasion, and is one of the specific markers of myeloid-derived suppressor cells (MDSC). In this study, a recombinant polypeptide vaccine CTB-S100A9 targeting mouse calcium-binding protein S100A9 was constructed by fusion cholera toxin B subunit (CTB) with S100A9 gene. The CTB-S100A9 fusion protein was expressed in E coli. and purified by Ni+ affinity chromatography. Vaccinate the purified recombinant CTB-S100A9 protein supplemented with aluminum hydroxide adjuvant can break the autoimmune tolerance and produce high titer of S100A9 antibody in mice. Moreover, the S100A9 antibody produced by CTB-S100A9 vaccination is more specific and does not cross-react with S100A8. In the mouse 4T1 breast cancer model, CTB-S100A9 vaccination not only has significant tumor prevention effects, but also has significant tumor therapeutic effects. In addition, CTB-S100A9 significantly inhibited lung metastasis in 4T1 mice breast cancer model. Further analysis by flow cytometry showed that CTB-S100A9 vaccination can significantly reduce the tumor induced Treg cells and granulocyte-derived MDSC in 4T1 mice model, and reverse the tumor immunosuppressive environment, thereby promote the anti-tumor efficacy. The animal experiments in this study were carried out under the animal care guidelines approved by the Animal Ethics Committee of the Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine. This study shows that CTB-S100A9 is a good recombinant vaccine that targets the tumor immune-suppression environment and has great potential for the future clinical application.
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