Structurally novel HDAC inhibitors based on the trans-β-arylacryl tetrahydroisoquinoline scaffold: the design, synthesis, and anti-cancer activity / 药学学报

In this study, a series of 18 histone deacetylases inhibitors (HDACis), derived from our in-house anti-cancer trans-β-arylacryl 1,2,3,4-tetrahydroisoquinoline-based scaffold, were designed, synthesized, and antitumor evaluated. HDAC1 inhibitory activity assay showed that compounds 13d-13f and 13m-13o demonstrated attractive enzymatic activity with IC50 at single-digit nanomolar or subnanomolar level.In addition, 13o exerted superior anti-proliferative activity (A549, IC50 = 0.89 μmol·L-1; HCT116, IC50 = 0.49 μmol·L-1) to that of vorinostat (SAHA).Besides,13e, with the most potent HDAC1 enzymatic activity (IC50 = 3.8 nmol·L-1), also displayed attractive cellular activity (A549, IC50 = 1.74 μmol·L-1; HCT116, IC50 = 2.43 μmol·L-1). The Western blot analysis illustrated that 13e treatment increased the acetylation of H3 and α-tubulin in a dose-dependent manner in A549 cells. In summary, 13e and 13o deserve further functional investigation.

Analysis on the difference between the payment limitations of anti-cancer drugs and the application scope of drug indications / 中国药房

OBJECTIVE To analyze the difference between the payment limitations of anti-cancer drugs and application scope of drug instructions， so as to better implement the payment policy of medical insurance drugs. METHODS The differences between the payment limitations of anti-cancer drugs and application scope of drug instructions in the National Catalogue of Drugs for Basic Medical Insurance， Industrial Injury Insurance and Maternity Insurance （2022） were compared and analyzed； the evidence-based basis of the difference was discussed， and the scope of limited payment was interpreted. RESULTS Totally 118 drugs had payment limitations； limitations scope mainly included limited evidence of gene detection results， limited indications， limited second-line and above treatment， limited payment duration， limited specialist prescription， limited medical institution grade， etc. Among them， 43 drugs had differences between the payment limitations and drug instructions， and the indications of 31 drugs were greater than payment limitations； for seven drugs， the drug indications beyond the payment limitations were recommended by the guidelines. The payment limitations of 75 drugs were consistent with drug instructions. The second-line and multi-line treatment was ineffective or intolerable with first-line drugs. There was a certain relationship between locally advanced， advanced or metastatic tumor and tumor stage， but different tumors had different criteria. Systemic treatment mainly referred to systemic treatment with drug. The results of limited genetic test required that the result was positive or negative. In addition， six kinds of TCM injections were limited to the level of medical institutions； the payment of two drugs did not exceed 12 months； when lenalidomide was combined with isazomide citrate， the medical insurance only paid for one of the drugs. CONCLUSIONS The payment limitations of some anti- cancer drugs are inconsistent with the drug indications. The drug payment limitations should be expanded according to the actual situation of clinical medication and the recommendations of guidelines. At the same time， the payment limitations should be formulated accurately and in detail， thus clinical and medical insurance staff can understand it and fully protect the interests of patients.

Research progress and clinical application of liposomal drug delivery system / 中国药房

With the advantage of high efficiency， low toxicity and targeting， liposomes have become the research hotspot of new drug preparations at home and abroad. In this paper， the research progress in recent years is reviewed from the aspects of preparation methods， classification and clinical application of liposomes. The results showed that in order to obtain more stable and controllable liposomes， scholars improved and optimized the traditional preparation methods and established novel preparation methods such as supercritical fluid methods， freeze-drying method and double-asymmetric centrifugation method. In order to enhance the efficacy and reduce toxicity， the conventional liposomes were optimized to get novel ones such as environmentally sensitive liposomes， long-circulating liposomes and multifunctional liposomes， which had greatly promoted the clinical application of liposomes. For now， liposomes have been used in many fields， such as anti-cancer agents， antimicrobial and vaccines， but most of the new liposomes are still in the early stage of development.

Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy

Gas therapy has been proven to be a promising and advantageous treatment option for cancers. Studies have shown that nitric oxide (NO) is one of the smallest structurally significant gas molecules with great potential to suppress cancer. However, there is controversy and concern about its use as it exhibits the opposite physiological effects based on its levels in the tumor. Therefore, the anti-cancer mechanism of NO is the key to cancer treatment, and rationally designed NO delivery systems are crucial to the success of NO biomedical applications. This review summarizes the endogenous production of NO, its physiological mechanisms of action, the application of NO in cancer treatment, and nano-delivery systems for delivering NO donors. Moreover, it briefly reviews challenges in delivering NO from different nanoparticles and the issues associated with its combination treatment strategies. The advantages and challenges of various NO delivery platforms are recapitulated for possible transformation into clinical applications.

Therapeutic Properties of Flavonoids in Treatment of Cancer through Autophagic Modulation: A Systematic Review / 中国结合医学杂志

Cancers have high morbidity and mortality rates worldwide. Current anticancer therapies have demonstrated specific signaling pathways as a target in the involvement of carcinogenesis. Autophagy is a quality control system for proteins and plays a fundamental role in cancer carcinogenesis, exerting an anticarcinogenic role in normal cells and can inhibit the transformation of malignant cells. Therefore, drugs aimed at autophagy can function as antitumor agents. Flavonoids are a class of polyphenolic secondary metabolites commonly found in plants and, consequently, consumed in diets. In this review, the systematic search strategy was used, which included the search for descriptors "flavonoids" AND "mTOR pathway" AND "cancer" AND "autophagy", in the electronic databases of PubMed, Cochrane Library, Web of Science and Scopus, from January 2011 to January 2021. The current literature demonstrates that flavonoids have anticarcinogenic properties, including inhibition of cell proliferation, induction of apoptosis, autophagy, necrosis, cell cycle arrest, senescence, impaired cell migration, invasion, tumor angiogenesis and reduced resistance to multiple drugs in tumor cells. We demonstrate the available evidence on the roles of flavonoids and autophagy in cancer progression and inhibition. (Registration No. CRD42021243071 at PROSPERO).

Natural Plant-derived Polysaccharides Against Cervical Cancer： A Review / 中国实验方剂学杂志

Cervical cancer is a gynecological malignant tumor with a high incidence in the world. With the insidious onset and lack of obvious symptoms and signs in the early stage， 13% of cervical cancer patients are diagnosed in the advanced stage of the disease， and the 5-year survival rate of metastatic cervical cancer is only 16.5%. So far， surgery and radiotherapy/chemotherapy are still the basic means for the treatment of cervical cancer. However， with the emergence of toxicity， drug resistance， and other side effects， there are still some limitations in the clinical application of these therapies. In recent years， natural compounds represented by polysaccharides have been found to have a significant anti-cervical cancer effect， which has attracted extensive attention from researchers in China and abroad. Widely distributed in the roots， stems， leaves， flowers， and fruits of higher plants， plant-based polysaccharides are important components of natural polysaccharides， as well as multimers with a complex structure and biological response regulators， which have been widely studied in the fields of cancer， cardiovascular， endocrine， and other diseases. This study reviewed the research on the anti-cervical cancer effect and mechanism of natural plant-derived polysaccharides by consulting the literature in the past 20 years to bring breakthroughs in the research and development of anti-cervical cancer new drugs. Through the literature review， the results indicated that natural plant-derived polysaccharides could exert anti-tumor effects by inhibiting cell proliferation， promoting apoptosis， inhibiting invasion and migration， promoting autophagy， arresting cell cycle of cervical cancer cells， regulating epithelial-mesenchymal transition （EMT）， resisting oxidative stress， inhibiting tumor angiogenesis， improving immunomodulatory activity， and regulating signaling pathways. It should be noted that in the current research on natural plant-derived polysaccharides against cervical cancer， the bioavailability of some natural polysaccharides is low and a considerable proportion of the research is limited to the in vitro experiment. Therefore， it is urgent to carry out more clinical experimental studies on the anti-cervical cancer of natural plant-based polysaccharides to obtain a more reliable theoretical and practical basis.

Peptide-drug conjugates for tumor targeted diagnosis and treatment / 药学学报

Cancer is still one of the major diseases threatening human life and health. At present, how to achieve precise diagnosis and treatment of tumors is the biggest challenge in cancer treatment. Prodrugs use the tumor specificity of targeting molecules to deliver anticancer drugs to tumor sites, which can effectively improve drug bioavailability, therapeutic efficacy and safety, and are currently a hot spot in the research and development of anticancer drugs. The targeting molecules of prodrugs mainly include nucleic acid aptamers, polymers, antibodies, polypeptides, etc. Among them, polypeptides have the advantages of good biocompatibility, controllable degradation performance, high in vivo responsiveness, and simple and easy preparation methods, and are widely used. It is used to construct peptide-drug conjugates (PDC) prodrugs to achieve targeted therapy of tumors. In recent years, with the development of phage peptide library technology and peptide standard solid-phase synthesis technology, more and more targeted peptides have been discovered and effectively synthesized and modified, providing strong support for the development of PDC. This review briefly introduces the types and functions of functional peptides and linkers in PDC, and discusses the application of PDC in chemotherapy, immunotherapy and photodynamic therapy in tumor targeted diagnosis and treatment, and finally summarizes the difficulties faced by PDC drug development.

Real-time SERS monitoring anticancer drug release along with SERS/MR imaging for pH-sensitive chemo-phototherapy

In situ and real-time monitoring of responsive drug release is critical for the assessment of pharmacodynamics in chemotherapy. In this study, a novel pH-responsive nanosystem is proposed for real-time monitoring of drug release and chemo-phototherapy by surface-enhanced Raman spectroscopy (SERS). The Fe3O4@Au@Ag nanoparticles (NPs) deposited graphene oxide (GO) nanocomposites with a high SERS activity and stability are synthesized and labeled with a Raman reporter 4-mercaptophenylboronic acid (4-MPBA) to form SERS probes (GO-Fe3O4@Au@Ag-MPBA). Furthermore, doxorubicin (DOX) is attached to SERS probes through a pH-responsive linker boronic ester (GO-Fe3O4@Au@Ag-MPBA-DOX), accompanying the 4-MPBA signal change in SERS. After the entry into tumor, the breakage of boronic ester in the acidic environment gives rise to the release of DOX and the recovery of 4-MPBA SERS signal. Thus, the DOX dynamic release can be monitored by the real-time changes of 4-MPBA SERS spectra. Additionally, the strong T2 magnetic resonance (MR) signal and NIR photothermal transduction efficiency of the nanocomposites make it available for MR imaging and photothermal therapy (PTT). Altogether, this GO-Fe3O4@Au@Ag-MPBA-DOX can simultaneously fulfill the synergistic combination of cancer cell targeting, pH-sensitive drug release, SERS-traceable detection and MR imaging, endowing it great potential for SERS/MR imaging-guided efficient chemo-phototherapy on cancer treatment.

Molecular mechanisms of anti-cancer bioactivities of seaweed polysaccharides / 中草药·英文版

Seaweed is a traditional Chinese medicine homologous to food, in which polysaccharides are responsible for anti-cancer by enhancing immunity, inducing cancer cell apoptosis, inhibiting cancer cell invasion and metastasis or directly scavenging oxidative free radicals that induce cancer cell changes. Among them, regulating immunity and promoting cancer cell apoptosis are intensively studied due to the important role in preventing cancer. Here we reviewed seaweed in the apoptosis-inducing signaling pathways including PI3K/AKT, ROS and JNK and discussed challenges in studying seaweed.

Review of Development of Emerging Clinical Antitumor Therapeutics / 肿瘤防治研究

With the continuous progress of tumor treatment methods in recent years, more and more emerging antitumor drugs have been approved to market and put into clinical use. In addition, some treatments that are in clinical trials such as gene therapy are also continuously making new breakthroughs. In this review, we mainly give a brief introduction to the novel antineoplastic therapies that have been clinically used in recent years, as well as the ones with remarkable efficacy and are expected to be approved for marketing.

A novel second-generation platinum derivative and evaluation of its anti-cancer potential

Abstract Cisplatin is the primary anti-cancer agent for the treatment of most solid tumors. However, platinum-based anti-cancer chemotherapy produces severe side effects due to its poor specificity. There are a broad interest and literature base for a novel mechanism of action on platinum derivatives. Additionally, combining cisplatin with histone deacetylase inhibitors (HDACi) such as 4-hydroxybenzoic acid derivatives showed promising results in treating solid tumors. Here we aimed to conjugate 4-hydroxybenzoic acid with platinum to obtain a novel platinum derivative that can overcome cisplatin resistance. Cis-4-hydroxyphenylplatinum(II)diamine compound was synthesized under mild conditions and characterized. Cytotoxicity assay was performed on SKOV3-Luc and A549-Luc cells. Hemocompatibility and serum protein binding analysis were performed. Treatment potential was evaluated in xenograft tumor models. Biodistribution was tested on tumor-bearing mice via Pt analysis in organs with ICP-MS, ex vivo. In this study, cis-4-hydroxyphenylplatinum (II) diamine was synthesized with a yield of 62%. The MTT assay on A549-Luc and SKOV3-Luc cell lines resulted in IC50 values of 17.82 and 7.81 µM, respectively. While tumor growth was continued in the control group, the tumor volume decreased in the treatment group. All results point to the conclusion that the new compound has the potential to treat solid tumors

In silico evaluation of potential drugs for the treatment of Colorectal Carcinoma

Abstract To evaluate possible new drugs for the treatment of Colorectal Carcinoma (CRC) using in silico tools was the main objective of this study. The method of analysis used was the in silico evaluation of tumor markers and their interaction with selected drugs, through the study of its pharmacokinetic and pharmacodynamic characteristics. A potential therapeutic target pointed out in this study was the Cell Division Cycle 25 B (CDC25B), belonging to the CDC25 phosphatase family. Overexpression of CDC25 phosphatases is often associated with a wide variety of cancers. In addition, CDC25B is an oncogenic protein that induces neoplastic transformation. In CRC, CDC25B is overexpressed to activate the CDC2/cyclin B complex and improve the growth and survival of these tumors. Four drugs were identified for evaluation, with α-amyrin being selected for docking, because it was that had the best characteristics according to the methodology used. The α-amyrin ligand obtained the interaction energy value of -7.6 G (Kcal/mol), while the standard CDC25B ligand obtained -10.0 G (Kcal/mol). TThe results showed that the CDC25B protein was the only structure cocrystallized with α-amyrin and presented favorable outcomes in docking, being a candidate for further studies for its use in the CRC targeted therapy

GB7 acetate,a galbulimima alkaloid from Galbulimima belgraveana,possesses anticancer effects in colorectal cancer cells / 药物分析学报

GB7 acetate is a galbulimima alkaloid obtained from Galbulimima belgraveana.However,information regarding its structure,biological activities,and related mechanisms is not entirely available.A series of spectroscopic analyses,structural degradation,interconversion,and crystallography were performed to identify the structure of GB7 acetate.The MTT assay was applied to measure cell proliferation on human colorectal cancer HCT 116 cells.The expressions of the related proteins were measured by Western blotting.Transmission electron microscopy(TEM),acridine orange(AO)and monodansylcadaverine(MDC)staining were used to detect the presence of autophagic vesicles and autolysosomes.A transwell assay was performed to demonstrate metastatic capabilities.Oxygen consumption rate(OCR)and extracellular acidification rate(ECAR)assays were performed to determine the mitochondrial oxidative phosphorylation(OXPHOS)and glycolysis activity of HCT 116 cells.The data showed that GB7 acetate suppressed the proliferation and colony-forming ability of HCT 116 cells.Pretreatment with GB7 acetate significantly induced the formation of autophagic vesicles and autolysosomes.GB7 acetate upregulated the expressions of LC3 and Thr172 phosphorylated adenosine 5'-monophosphate(AMP)-activated pro-tein kinase α(p-AMPKα),which are key elements of autophagy.In addition,GB7 acetate suppressed the metastatic capabilities of HCT 116 cells.Additionally,the production of matrix metallo-proteinase-2(MMP-2)and MMP-9 was reduced,whereas the expression of E-cadherin(E-cad)was upregulated.Furthermore,GB7 acetate significantly reduced mitochondrial OXPHOS and glycolysis.In conclusion,the structure of the novel Galbulimima alkaloid GB7 acetate was identified.GB7 acetate was shown to have anti-proliferative,pro-autophagic,anti-metastatic,and anti-metabolite capabilities in HCT 116 cells.This study might provide new insights into cancer treatment efficacy and cancer chemoprevention.

Antitumor Effect and Mechanism of Rutin： A Review / 中国实验方剂学杂志

The morbidity and mortality of cancer have been on the rise， making it atop the list of human health threats. It has been a conundrum of global magnitude. As the side effects of chemotherapeutics seriously affect the life quality of cancer patients， it is urgent to find effective anti-cancer drugs with small toxic and side effects. In recent years， the anti-cancer effects of traditional Chinese medicine have attracted the interest of scholars. Owing to the improvement of medical research， an increasing number of anti-cancer components with small toxic and side effects have been extracted from traditional Chinese medicine. Rutin， a unique flavonoid in Chinese medicinals and many plants， proves to inhibit the proliferation of breast cancer， colon cancer， lung cancer， and prostate cancer cells. In addition， rutin alone or in combination with other therapeutic drugs can regulate a variety of signaling pathways and signal mediators of inflammation， apoptosis， autophagy， and angiogenesis， thereby suppressing tumor progression. Moreover， it can also alleviate the drug resistance of tumors and the side effect of chemotherapeutics. Nevertheless， it is limited by the low bioavailability and low solubility， to which nano delivery system turns to be a solution. At the moment， the anti-cancer potential of rutin and the molecular targets of it against various cancers have not been summarized and comprehensively analyzed. Therefore， the authors retrieved articles on the anti-cancer effects of rutin in recent years， summed up the mechanisms and molecular targets， and discussed relevant drug delivery systems and the safety， aiming at laying a theoretical foundation for further development and application of the flavonoid.

Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells

The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).

Research progress on diarrhea induced by molecular-targeted agents / 药学学报

In recent years, the focus of anti-cancer agents has gradually shifted from cytotoxic chemotherapy to molecular-targeted agents that interfere with frequently overexpressed or mutated molecules in cancer cells. Compared with cytotoxic chemotherapy, molecular-targeted therapy is a new biological therapy with higher specificity and lower toxicity, however, the adverse reactions caused by molecular-targeted agents cannot be ignored. Diarrhea is one of the most common adverse drug reactions, which could seriously affect the quality of life and even lead to treatment discontinuation and consequently decreased cancer control. To provide a reference for relevant research and clinical medication, we review the current reports on the incidence, pathogenic mechanism, and management of diarrhea induced by the molecular-targeted agents.

The Positive Impact of Vitamin C (Ascorbic Acid) Utilisation in Cancer Treatment: A Scoping Review of Published Articles From the Perspective of the in Vitro Studies

@#Survival benefit of patients with advanced cancer was reported with intravenous vitamin C administration. Nevertheless, a recent systematic review failed to support the clinically use of vitamin C in cancer patients due to the diversity of interventions and cancer type. This study aimed to provide a scoping review of vitamin C utilisation and its impact on cancer treatment from the perspective of in vitro studies. The review was conducted using predefined search terms in three scientific databases. 44 articles were retrieved with a total of 15 cancer types being studied from 2015 to 2020. The findings were classified into primary and secondary outcome. The primary outcome refers to chief consequences of vitamin C treatment, while the secondary outcome denotes the additional advantages generated as a result of the primary outcome, which occurs both in monotherapy and combination therapy. This review discussed the major mechanism of vitamin C as anti-cancer and its relation with the outcomes.

Peptidomimetic-based antibody surrogate for HER2

Inhibition of human epidermal growth factor receptor 2 mediated cell signaling pathway is an important therapeutic strategy for HER2-positive cancers. Although monoclonal antibodies are currently used as marketed drugs, their large molecular weight, high cost of production and susceptibility to proteolysis could be a hurdle for long-term application. In this study, we reported a strategy for the development of artificial antibody based on

Pharmacologically targeting molecular motor promotes mitochondrial fission for anti-cancer

Mitochondrial shape rapidly changes by dynamic balance of fusion and fission to adjust to constantly changing energy demands of cancer cells. Mitochondrial dynamics balance is exactly regulated by molecular motor consisted of myosin and actin cytoskeleton proteins. Thus, targeting myosin-actin molecular motor is considered as a promising strategy for anti-cancer. In this study, we performed a proof-of-concept study with a natural-derived small-molecule J13 to test the feasibility of anti-cancer therapeutics

New Price Conversion Method of Anti-cancer Drugs under the Buy-and-gift Strategy Based on Survival Data / 中国药房

OBJECTIVE：To provid e a more accurate calculation method for the determination of drug negotiation base price ， pharmacoeconomic calculation and budget impact analysis and calculation in the process of medical insurance access with buy-and-gift strategy. METHODS ：By the model method and literature research ，understanding the existing price conversion methods of the anti-cancer drugs that currently implement the buy-and-gift strategy ，a new method of drug price conversion was explored on the basis of the survival data of patients in different disease states ，and the core idea and calculation process of the algorithm were analyzed by an example. RESULTS ：The new algorithm was combined with the survival data of patients under different disease states. Its calculation process mainly included obtaining the actual duration of medication use per unit cycle and the theoretical amount of medication ，determining the aid model for anti-cancer drugs under buy-and-gift strategy ，converting the actual price. The simulation calculation was carried out under the one-step drug donation mode ，periodic drug donation mode and preferential installment drug donation mode. CONCLUSIONS ：The conversion method of anti-cancer drug price under buy-and-gift strategy based on survival data makes up for the shortcoming that the existing calculation methods are difficult to reflect the actual price of anti-cancer drugs ，and provides a new calculation method for calculating the actual reference price of anti-cancer drugs for medical insurance access.