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The heat shock protein 90 (Hsp90) protein family is a cluster of highly conserved molecules that play an important role in maintaining cellular homeostasis. Hsp90 and its co-chaperones regulate a variety of pathways and cellular functions, such as cell growth, cell cycle control and apoptosis. Hsp90 is closely associated with the occurrence and development of tumors and other diseases, making it an attractive target for cancer therapeutics. Inhibition of Hsp90 expression can affect multiple oncogenic pathways simultaneously. Most Hsp90 small molecule inhibitors are in clinical trials due to their low efficacy, toxicity or drug resistance, but they have obvious synergistic anti-tumor effect when used with histone deacetylase (HDAC) inhibitors, tubulin inhibitors or topoisomerase II (Topo II) inhibitors. To address this issue, the design of Hsp90 dual-target inhibitors can improve efficacy and reduce drug resistance, making it an effective tumor treatment strategy. In this paper, the domain and biological function of Hsp90 are briefly introduced, and the design, discovery and structure-activity relationship of Hsp90 dual inhibitors are discussed, in order to provide reference for the discovery of novel Hsp90 dual inhibitors and clinical drug research from the perspective of medicinal chemistry.
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Objective To design and synthesize the conjugate (compound 1) of chlorin e6 (compound 3) with fluorouracil (5-Fu) as novel pH-responsive dual-mode antitumor photosensitizer by acyl hydrazone bond coupling, based on literature reports that combination of 5-Fu and photosensitizer possess synergistic anti-tumor effect, and investigate its photodynamic antitumor activity and mechanism. Methods Lead compound 3 was obtained by alkali degradation with 25% KOH-CH3OH on pheophorbide a (compound 4) which was prepared through acid hydrolysis of chlorophyll a in crude chlorophyll extracts from silkworm excrement. Reflux reaction of 5-Fu with P2S5 in pyridine formed crude 4-thio-5-fluorouracil which was followed to react with hydrazine hydrate (N2H4·H2O) in CH3OH to give 5-fluorouracil-4-hydrazone (compound 2). Then, treatment of compound 3 i.e. acid alkali degradation product of chlorophyll a in silkworm excrement with EDC·HCl generated its 171- and 152 cyclic anhydride which was followed to directly react with intermediate compound 2 to successfully get title compound 1. In addition, its pH-responsive 5-Fu release and photodynamic antitumor activity and their mechanisms in vitro were investigated. Results Compound 1 could responsively release 5-Fu at pH 5.0, with a cumulative release rate of 60.3% within 24 h. It exhibited much higher phototoxicity against melanoma B16-F10 and liver cancer HepG2 cells than talaporfin and its precursor compound 3, with IC50 value being 0.73 μmol/L for B16-F10 cells and 0.90 μmol/L for HepG2 cells, respectively. Upon light irradiation, it also could significantly induce cell apoptosis and intracellular ROS level and block cell cycle in S phase. Its structure was confirmed by UV, 1H-NMR, ESI-MS and elemental analysis data. Conclusion The conjugate compound 1 of compound 3 and 5-Fu has the advantages of strong PDT anticancer activity, high therapeutic index (i.e. dark toxicity/phototoxicity ratio) and responsively release 5-Fu at pH 5.0 etc. which shows “unimolecular” dual antitumor effects of PDT and chemotherapy and is worthy of further research and development.
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A sesquiterpene natural substance called artemisinin was discovered in Artemisia annua. One of its derivatives， artesunate （ART）， has the properties of economy， immediate effect， low toxicity， and good tolerance. Since it has a quick and powerful killing effect on plasmodium in the erythrocyte phase and can quickly handle clinical seizure and symptoms， it is currently mostly utilized to treat cerebral malaria and other severe instances of malaria. In addition， it has antitumor， antivirus， anti-hepatic fibrosis， anti-inflammatory， antibacterial， hepatocyte protection， immunological modulation， and other pharmacological properties and can inhibit cell proliferation， induce cell apoptosis， and reduce the incidence of sepsis. In many countries， artemisinin-based combination therapies （ACTs）， such as artemether-benflumetol， artesunate-amodiaquine， and artemether-lumefantrine， are the first-line treatments for malaria. Recent research on artesunate by Chinese and international scholars has revealed that compared with monotherapy， artesunate combination therapy offers more benefits in terms of improving pharmacological effects， shortening the duration of medicine， and minimizing adverse effects. Through systematic retrieval of Web of Science Core Collection and integration through CiteSpace （6.2.1） software， this article reviewed the mechanism of artesunate combined with other medications with regard to antimalarial， antitumor， antibacterial， and antiviral features in the previous five years， so as to provide some theoretical basis for rational development and utilization of ART and new drug research and development.
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ObjectiveTo clarify the scientific validity of in vivo pharmacokinetic determination of the whole drug composition in Shenbai nanosuspension in rats， and to provide methodological guidance and theoretical basis for the in vivo study of multi-component complex system of traditional Chinese medicine（TCM） preparations. MethodThe concentration of the overall components， mainly total saponins and total polysaccharides in Shenbai decoction and Shenbai nanosuspension， was determined in rat plasma at different times by area under the absorbance-wavelength curve method（AUAWC）， and the concentration of individual ginsenoside Rg1 was determined by high performance liquid chromatography（HPLC）， and the methodology was verified. The pharmacokinetic parameters of the whole component were compared with those of ginsenoside Rg1 to evaluate the in vivo operational characteristics of the two preparations. ResultThe methodological investigations of AUAWC and HPLC were in accordance with the requirements. AUAWC analysis showed that the overall components in both the decoction group and the nanosuspension group showed a one-compartment model， with half-life（t1/2） of 2.43 h and 2.04 h， respectively. The relative bioavailability of Shenbai nanosuspension was 138.99%. HPLC assay showed that ginsenoside Rg1 in the decoction group and the nanosuspension group showed a two-compartment model， with distribution half-life（t1/2α） of 0.13 h and 2.55 h， and elimination half-life（t1/2β） were 14.28 h and 3.85 h， respectively. The relative bioavailability of Shenbai nanosuspension was 127.49%. Compared with Shenbai decoction， the time to peak（tmax）， peak concentration（Cmax） and area under the drug-time curve（AUC） of the overall components and ginsenoside Rg1 in Shenbai nanosuspension were increased. ConclusionThe established AUAWC can be used for the pharmacokinetic study of the overall components of TCM preparations， which is complementary to the results of individual components measured by HPLC， and can provide useful reference for the in vivo study of new dosage forms of TCM.
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Paridis Rhizoma possesses the functions of clearing heat and detoxifying， alleviating swelling and relieving pain， cooling the liver and calming the convulsion. Saponins are the main active components of Paridis Rhizoma. Studies have shown that total saponins in Paridis Rhizoma have obvious inhibitory effect on solid tumors such as breast cancer， lung cancer， gastric cancer， and liver cancer and non-solid tumors such as leukemia. The saponins may exert the anti-tumor effects by inhibiting the proliferation， migration， and invasion of tumor cells， regulating cell cycle， inducing apoptotic and non-apoptotic death pathways， and regulating metabolism and tumor microenvironment. Furthermore， total saponins in Paridis Rhizoma showed anti-inflammatory， antioxidant， antimicrobial， hemostatic， and uterus-contracting activities. At the same time， they may induce apoptosis of normal cells， inflammation and oxidative stress， and metabolic disorders. In recent years， the reports of liver injury， reproductive injury， gastrointestinal injury， hemolysis， and other adverse reactions caused by total saponins in Paridis Rhizoma have been increasing. Pharmacokinetic studies have shown that there are significant differences in the metabolism of total saponins in Paridis Rhizoma administrated in different ways. Injection has a fast clearance rate， while oral administration may have hepatoenteric circulation. Meanwhile， due to the low solubility and activation of P-glycoprotein （P-gp） molecular pump， the prototype absorption， intestinal permeability， and recovery rate of total saponins in Paridis Rhizoma are poor， which affects the bioavailability. The bioavailability can be improved to some extent by preparing new dosage forms or new drug delivery systems with advanced technology. This paper reviews the pharmacological effect， pharmacokinetics， and adverse reactions of Rhizoma Paridis total saponins by searching the China National Knowledge Infrastructure （CNKI）， VIP， and Web of Science with ''Rhizoma Paridis total saponins'' as the keywords， hoping to provide references for the research， development， and clinical application of such components.
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Bavachinin is a dihydroflavone isolated from dried ripe fruits of Psoralea corylifolia L.，which has various pharmacological activities, such as anti-tumor, anti-virus, anti-diabetes, anti-inflammatory and neuroprotective, and good potential in clinical applications. With the increasing concern about the safety of P. corylifolia applications in clinical, the bavachinin has been found to be one of the main components causing liver injury. In this paper, the pharmacological activities and hepatotoxicity of bavachinin in the recent 20 years were reviewed, in order to provide reference for the further study and clinical application.
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Objective:To explore the establishment and application of ovarian cancer organoids.Methods:Fresh ovarian tumor tissues, obtaining from patients underwent surgery in the First Affiliated Hospital of Nanjing Medical University between October 2021 and March 2022, were collected, enzymatic degraded, digested, and embedded into matrigel to establish organoids. A total of 32 ovarian cancer samples were collected. Hematoxylin eosin (HE) staining and immunofluorescence (IF) procedure were used to verify the morphological structure of organoids and their expression of molecular markers. 3D cyto-live or dead assay was used to detecte the live or dead cells in organoids. Carboplatin with a concentration ranging from 5 to 80 μmol/L (5, 10, 20, 40, 80 μmol/L) was added to organoids to calculate the 50% inhibitory concentration (IC 50) in different organoids. Results:(1) Organoids from a total of 32 patients were established, of which 18 cases could be passaged stably in the long term in vitro, while 14 could be passaged in the short time. The average amplification time of long-term passage in vitro was over 3 months, and the longest reached 9 months. (2) In HE staining, significant nuclei atypia and local micropapillary structures were observed in organoids. IF staining revealed that ovarian cancer organoids expressed molecular markers similar to primary tumor tissues, such as Pan cytokeratin (Pan-CK), p53, paired box gene 8 (PAX8), and Wilms tumor gene 1 (WT1). (3) In 3D cyto-live or dead assay, a large number of apoptotic cells were observed inside and around the organoids after added carboplatin. The sensitivity to carboplatin varied in 18 organoids could amplify in the long term, with an average IC 50 of (29.5±15.8) μmol/L. Moreover, IC 50 values of 4 organoids derived from patients received neoadjuvant chemotherapy were much higher than the 14 organoids which did not received neoadjuvant chemotherapy [(48.7±11.3) μmol/L vs (24.0±12.1) μmol/L; t=3.429, P=0.022]. Conclusions:Organoids recapitulate ovarian cancers in vitro and could be stably passaged. Organoids derived from patients received neoadjuvant chemotherapy have higher resistance to carboplatin.
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Objective:To analyze the related factors of neurotoxicity induced by oxaliplatin chemotherapy in patients with colorectal cancer and its prevention and treatment strategies.Methods:A total of 300 patients with colorectal cancer treated with oxaliplatin in Zhejiang Cancer Hospital from January 2018 to December 2020 were randomly selected for baseline collection using the convenience sampling method. The occurrence of oxaliplatin-induced peripheral neurotoxicity (OIPN) was statistically analyzed. The factors that affect the occurrence of OIPN were analyzed using univariate analysis.Results:There was a significant difference in OIPN score between patients of different genders, between patients who had different education levels, between patients who had different occupations, and between patients who lived in different long-term residence places ( t = 7.29, 3.39, 2.53, 18.11, all P < 0.05). There was no significant difference in OIPN score between patients adhering to different religion's beliefs, between patients married and not, between patients who lived with and without members, between patients who paid medical costs and not, and between patients who had a previous history of smoking and not ( t = 3.25, 0.37, 0.69, 2.39, 0.15, all P > 0.05). There was a significant difference in OIPN score between patients with different tumor-node-metastasis stages, between patients who received medication via different administration routes, and between patients who received different times of oxaliplatin administration ( t = 8.40, 3.34, 3.49, all P < 0.05). Conclusion:Medical staff should pay attention to the occurrence of OIPN in patients with colorectal cancer treated with oxaliplatin, focus on the patient's factors related to the disease, and take correct and effective coping strategies promptly to reduce the adverse reactions, improve the quality of life, and ensure the therapeutic effect.
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The phenomenon of off-label use of antitumor drugs in the treatment of malignant tumors is relatively common. Although it is conducive to the development of clinical medical practice, but it is still necessary to pay attention to ethical issues such as medication risks and inadequate implementation of informed consent. Therefore, to effectively avoid ethical risks and standardize the rational use of off-label antitumor drugs, this paper proposed that pharmacists should actively participate in the process of off-label use of antitumor drugs, improve the evidence level of evidence-based medicine, implement patients’ right to informed consent, and improve the hospital’s supervision system of off-label drug use, so as to ensure the reasonable and legal use of drugs by patients.
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Cancer and cardiovascular diseases are the two major causes of death worldwide. The application of anti-tumor drugs has significantly improved the prognosis of patients, the cardiovascular toxicity caused by the application of them has become an important factor affecting the survival and prognosis of cancer patients. Therefore, the prevention and treatment of cardiovascular toxicity related to cancer treatment is increasingly important. The cardiovascular toxicity associated with anti-tumor drugs exhibits different clinical manifestations and involves multiple pathological mechanisms. This article reviews the current research progress from the perspective of the characteristics, molecular mechanisms and prevention and treatment strategies of cardiovascular toxicity caused by cancer drugs.
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Cholangiocarcinoma is a bile duct adenocarcinoma derived from the bile duct epithelium. Current treatment strategies for cholangiocarcinoma include surgery, chemotherapy, and radiotherapy. Surgical treatment is the first choice for all subtypes of cholangiocarcinoma. However, cholangiocarcinoma has the characteristics of high malignancy, easy recurrence after surgery, and low 5-year survival rates. Recent studies have found that many traditional Chinese medicines exhibit excellent anti-tumor effects in the treatment of various cancers, including cholangiocarcinoma. These medicines have advantages, such as low prices and abundant reserves, and are considered as an effective and safe complementary and alternative therapy for the treatment of cholangiocarcinoma. This article aims to review the effects of traditional Chinese medicine on cholangiocarcinoma from different aspects and levels in recent years. Results will provide new ideas for the prevention and treatment of cholangiocarcinoma.
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@#Based on our previous work, the study herein designed and synthesized eight glycoconjugates of natural product harmine (14a-14h)by introducing a cyclohexylmethyloxyl group at its C7 position and coupling a methyl-2-amino-β-D-glucopyranoside to the N9 position through different lengths of alkyl chains.In vitro anti-tumor activity screening and structure-activity relationship studies showed that the antitumor activity of the conjugates increased with the lengthening of the alkyl chain in the linker.Compound 14h exhibited significantly better proliferative inhibitory activity against MDA-MB-231 breast cancer cells than harmine.As compared to harmine, the introduction of the carbohydrate moiety improved the water solubility of compound 14h and enhanced its tumor cell selectivity through the Warburg effect.Mechanism of action studies revealed that compound 14h induced apoptosis and G0/G1 cell cycle arrest in MDA-MB-231 cells, and inhibited tumor cell migration by interfering with epithelial-mesenchymal transition process.This study provides a new approach for the development of antitumor drugs based on harmine.
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The most toxic DNA damage is DNA double strand breaks (DSBs), which are mainly repaired by non-homologous end joining (NHEJ). DNA-dependent protein kinase (DNA-PK) belongs to phosphatidylinositol-3-kinase-related protein kinase family (PIKK) and plays a key role in NHEJ. DNA-PK is overexpressed in a variety of cancer cells and is related to the occurrence, development and drug resistance of malignant tumors. In this article, the representative DNA-PK inhibitors with anticancer effects are reviewed, in order to provide a reference to discovery novel DNA-PK inhibitors.
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Cancer is the most important leading cause of death worldwide, with about 10 million deaths caused by cancer in 2020. In situ gel drug delivery systems have attracted much attention in the field of pharmacy and biotechnology due to their good histo-compatibility, excellent injectability, high drug delivery capacity, slow-release drug delivery, and less influence by the in vivo environment. Meanwhile, in situ gel can be combined with chemotherapy, photo-thermal therapy, chemokinetic therapy, immunotherapy and so on to deliver drugs into the tumor site in a less invasive way without surgical operation, forming a semi-solid gel reservoir in the tumor site to realize in situ tumor combined therapy. In this paper, the author summarized the research progress of anti-tumor in situ gel delivery system in the past 10 years, introduced its commonly used polymer materials, classification principles and specific application examples, and finally summarized and discussed the key issues, in order to provide reference for the development of new anti-tumor drug delivery system in the future.
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Dihydrofolate reductase (DHFR) is a well-known key target in the treatment of tumors, bacterial infections, and parasitic infections; and it plays a critical role in the biosynthesis of cellular DNA. DHFR inhibitors interfere with one-carbon metabolism by inhibiting substrate binding to DHFR, thereby inhibiting cell proliferation. Research on DHFR inhibitors has continued since the 1940s. To date, a variety of DHFR inhibitors have come into the market, primarily used for anti-tumor, antibacterial, antiparasitic, and anti-inflammatory therapy. This review summarizes the research progress of DHFR inhibitors with antitumor or antibacterial effects in recent years based on the classification of single-target and dual-target and looks forward to the opportunities and challenges faced by the work in this field.
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To discover new structural hits, based on the important role of pyrazole ring and fragment of pyridinone carboxylic acid in drug design, novel title pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives (10a-10p) were designed and synthesized, the structures were confirmed by spectral data and elemental analyses. The antibacterial and antitumor activities were evaluated by the measured minimum inhibitory concentration (MIC) values against the tested four strains and half inhibitory concentration (IC50) values against the tested four cancer cells, respectively. The results displayed markedly poor antibacterial activity and observably potent antitumor activity. In particularly, the title difluorophenyl (10d, 10e, 10f), pyridyl (10j), ethyl (10k) and cycloproyl (10l) compounds exhibited comparable activity against Capan-1 and A549 cells to that of the comparison doxorubicin. Thus, pyrazolo[3,4-b]pyridine-4-one-5-carboxylic acid derivatives as promising antitumor hits need to be developed.
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Inositol requiring enzyme 1 alpha (IRE1α), a widespread transmembrane protein in mammals, is an endoplasmic reticulum stress (ER stress) receptor. Among the three signaling pathways of the unfolded protein response (UPR), the IRE1α pathway is the most conservative. And there is a growing body of evidence that the occurrence and development of tumors is closely related to the over-expression of IRE1α. Therefore, the study of the IRE1α inhibitors is of great significance to the discovery of new anti-tumor drugs and has been attracting more and more attention. In the hope of providing ideas for the research of targeting IRE1α for cancer therapy, this paper reviewed the data of representative IRE1α inhibitors, including inhibitory activity, the mechanism of action, structural characteristics, and so on.
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As a natural product with a long history of medicinal use, parthenolide has aroused great interest of chemists and biologists. Existing studies have shown that it has anti-inflammatory, antitumor and other pharmacological activities, and also revealed its action on NF-κB signaling pathway, DNMT1 enzyme and Wnt/β-catenin signaling pathway. But its biological targets remain to be elucidated systematically. Proteolysis Targeting Chimeras (PROTAC) provides a new strategy for target discovery of natural products, which can be used to explore the panorama of protein changes in cells through proteomic investigation, so as to analyze their potential targets. Based on this idea, current study designed and synthesized 20 parthenolide-derived degraders. After measured their antitumor activity in vitro, selected compounds were carried out the proteomic experiment. Finally, 139 down-regulated differentially expressed proteins were identified and the discovery of parthenolide interacting protein was preliminarily explored.
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Chinese medicine self-assembly nano-strategies（CSAN） is to utilize the self-assembly property of Chinese medicine components， so that the Chinese medicine components can self-assemble to form structurally stable nano-preparations through non-covalent interactions. The formation of Chinese medicine self-assembly nano-preparations is often a synergistic result of a variety of non-covalent interactions， and many Chinese medicine monomers are susceptible to self-assembly due to their structural characteristics， and the phenomenon of self-assembly of Chinese medicine is also common in the decoction of single or compound Chinese medicine， which has attracted the attention of researchers. It is found that CSAN can improve the solubility and bioavailability of active components in Chinese medicine， which is of positive significance for the development and application of insoluble components of Chinese medicine. The self-assembly phenomenon of Chinese medicine decoction is closely related to the therapeutic efficacy， and the study of self-assembly phenomenon of Chinese medicine will bring a new perspective for the explanation of the mechanism of Chinese medicine decoction. At the same time， traditional Chinese medicine（TCM） has unique advantages in the field of anti-tumor. The application of CSAN in the field of oncology can not only exert the anti-tumor effect of the active components of Chinese medicine directly， but also act as a natural nano-carrier to carry chemotherapy drugs for combination chemotherapy， improve the targeting of drugs， enhance the anti-tumor efficacy， and reduce the side effects of chemotherapy， which has excellent anti-tumor potential. The preparation method of Chinese medicine self-assembly nano-preparations is simple， low cost， and has better safety than traditional nano-preparations， which is conducive to the promotion of the clinical transformation of nano-preparations， and also helps to provide new strategies and perspectives for promoting the modernization of TCM. Therefore， based on a large number of researches in this field in recent years， this paper reviewed the formation mechanism， different assembly forms， formation conditions and stability of Chinese medicine self-assembly nano-preparations by searching databases such as China national knowledge infrastructure（CNKI）， PubMed， WanFang data and VIP， and summarized the application of CSAN in different tumor therapies， providing a reference for further research on CSAN.
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Malignant tumors are one of the main causes of human death worldwide and pose a serious threat to human health. The current treatment methods are mainly the combination of chemotherapeutics， surgery， radiotherapy， or hormone therapy. The treatment process has limitations such as multidrug resistance， non-selective targeting of cancer cells， and drug toxicity. With the development and application of traditional Chinese medicine （TCM）， Chinese medicine has the characteristics of multi-angle and multi-mechanism coordination and slight toxic and side effects. It can effectively inhibit tumor proliferation， differentiation， and metastasis， and avoid drug resistance， serving as the focus of current tumor treatment research. Hedysari Radix， one of the genuine medicinal materials in Gansu province， is a tonic Chinese medicine with a wide range of pharmacological effects such as anti-inflammation， immune regulation， anti-oxidation， prevention and treatment of diabetic complications. In the majority of the ancient works on herbs of the past dynasties， Hedysari Radix was included under the item of Astragali Radix and used as Astragali Radix. Hedysari Radix is superior to Astragali Radix in enhancing immunity， scavenging free radicals， and resisting liver fibrosis. Studies have found that the effective components of Hedysari Radix have a prominent anti-tumor effect and a significant inhibitory effect on various malignant tumors such as liver cancer， bladder cancer， gastric cancer， breast cancer， and colorectal cancer. They can also combine with clinical anti-cancer drugs to reduce the toxic and side effects of chemotherapy drugs and improve the tolerance of patients during chemotherapy. On the basis of current research， this study summarized the mechanism of Hedysari Radix active components in inducing cell apoptosis， blocking cell cycle， inhibiting tumor cell proliferation， migration， and invasion， regulating micro mRNA （miRNA）， inducing cell autophagy， enhancing immune regulation， as well as reducing toxicity and enhancing efficiency and sensitization with clinical chemotherapeutics， and systematically explained the anti-tumor mechanism of Hedysari Radix active components， aiming to provide a basic reference for the further exploration of the anti-tumor mechanism of Hedysari Radix and the further development and utilization of its effective components.