Targeted immunotherapy to cancer stem cells: A novel strategy of anticancer immunotherapy.

Cancer is a major disease that endangers human health. Cancer drug resistance and relapse are the two main causes contributing to cancer treatment failure. Cancer stem cells (CSCs) are a small fraction of tumor cells that are responsible for tumorigenesis, metastasis, relapse, and resistance to conventional anticancer therapies. Therefore, CSCs are considered to be the root of cancer recurrence, metastasis, and drug resistance. Novel anticancer strategies need to face this new challenge and explore their efficacy against CSCs. Recently, immunotherapy has made rapid advances in cancer treatment, and its potential against CSCs is also an interesting area of research. Meanwhile, immunotherapy strategies are novel therapeutic modalities with promising results in targeting CSCs. In this review, we summarize the targeting of CSCs by various immunotherapy strategies such as monoclonal antibodies(mAb), tumor vaccines, immune checkpoint inhibitors, and chimeric antigen receptor-T cells(CAR-T) in pre-clinical and clinical studies. This review provides new insights into the application of these immunotherapeutic approaches to potential anti-tumor therapies in the future.

[Cloning and functional analysis of flavanone synthase â ¡ from Dendrobium huoshanense].

Flavonoid C-glycosides are a class of natural products that are widely involved in plant defense responses and have diverse pharmacological activities. They are also important active ingredients of Dendrobium huoshanense. Flavanone synthase Ⅱ has been proven to be a key enzyme in the synthesis pathway of flavonoid C-glycosides in plants, and their catalytic product 2-hydroxyflavanone is the precursor compound for the synthesis of various reported flavonoid C-glycosides. In this study, based on the reported amino acid sequence of flavanone synthase Ⅱ, a flavanone synthase Ⅱ gene(DhuFNSⅡ) was screened and verified from the constructed D. huoshanense genome localization database. Functional validation of the enzyme showed that it could in vitro catalyze naringenin and pinocembrin to produce apigenin and chrysin, respectively. The open reading frame(ORF) of DhuFNSⅡ was 1 644 bp in length, encoding 547 amino acids. Subcellular localization showed that the protein was localized on the endoplasmic reticulum. RT-qPCR results showed that DhuFNSⅡ had the highest expression in stems, followed by leaves and roots. The expression levels of DhuFNSⅡ and other target genes in various tissues of D. huoshanense were significantly up-regulated after four kinds of abiotic stresses commonly encountered in the growth process, but the extent of up-regulation varied among treatment groups, with drought and cold stress having more significant effects on gene expression levels. Through the identification and functional analysis of DhuFNSⅡ, this study is expected to contribute to the elucidation of the molecular mechanism of the formation of quality metabolites of D. huoshanense, flavonoid C-glycosides, and provide a reference for its quality formation and scientific cultivation.

A strategy combining chemical analysis and network pharmacology to investigate the mechanism of Xiao'er Qingre Zhike Oral solution in cough.

Xiao'er Qingre Zhike Oral Solution (XQZS) is a commonly used TCM formula to treat cough in children in China. Its complicated composition renders its chemical analysis and mechanism elucidation difficult. To evaluate the bioactive components and mechanism of XQZS against cough, we used a combination strategy of chemical analysis and network pharmacology. A UHPLC/Q-Orbitrap-MS method was established for the identification and qualitative analysis of components of XQZS, and a total of 33 components were unambiguously identified. Aiming at identifying the components, network pharmacology revealed 107 potential targets related to cough. Using protein-protein interactions analysis, nine core targets were selected. Several cough-related pathways were enriched using the Kyoto Encyclopedia of Genes and Genomes, including neuroactive ligand-receptor interaction, serotonergic synapse and dopaminergic synapse. The herb-compound-target-pathway network indicated that PTGS2 (COX-2) was the core target of XQZS against cough. To demonstrate the inhibition effects of the major components against the key target, a COX-2 inhibitor screening assay was used. Compounds P2, P4, P23 and P49 exhibited promising inhibition effects on COX-2 at 20 µm, with inhibitory rates of 55.80-69.87%. In conclusion, this study demonstrates that XQZS may alleviate cough via the inhibition of PTGS2 (COX-2) and the regulation of the serotonergic synapse pathway. The chemical analysis and network pharmacology integrated evaluation provided an efficient strategy for discovering the key pharmacological mechanism of XQZS.

[Comparison of planting modes of Dendrobium huoshanense and analysis of advantages of simulated cultivation].

Dendrobium huoshanense is a precious medicinal plant belonging to Dendrobium of Orchidaceae. It is a special medicinal material and extremely scarce in Huoshan county, Anhui province. At present, D. huoshanense has been greatly protected, which also makes it possible to industrialize relying on tissue culture and artificial cultivation technology. Three main planting methods were utilized for cultivating D. huoshanense including facility cultivation, under forest cultivation and simulative habitat cultivation. Firstly, the three cultivation modes and technical characteristics of D. huoshanense were compared and analyzed, and it was found that the ecological environment of D. huoshanense cultivated in the simulated environment was closer to that of wild D. huoshanense. Secondly, based on comparing the characters and quality of three cultivation modes, the results showed that the shape of D. huoshanense cultivated in simulated environment was more similar to that of "grasshopper thigh" recorded in Bencao Jing Jizhu, and its quality was better than that of facilities and under forest cultivation. The comprehensive benefit comparison of three modes showed that the simulated cultivation had high income, the lowest input-output ratio and significant economic benefit. The quality of cultivated D. huoshanense was further evaluated from four aspects of "excellent environment" "excellent shape" "high quality" "excellent effect", which summarized the comprehensive advantages of simulative habitat cultivation of D. huoshanense as follows: the original habitat and site environment of simulated wild D. huoshanense, the closer shape to the wild, the more content of main medicinal components, and higher economic benefit and better efficacy. The quality of D. huoshanense was improved by the use of simulative habitat cultivation, which has practical significance to guide its large-scale cultivation.

Metronomic gemcitabine targeted tumor vascular microenvironment decreases the population of CD133(+) cells in hepatocarcinoma xenografts.

Recently, compelling evidence shows that cancer stem-like cells (CSLC) are thought to be critical for initiation and propagation of many types of cancers. Most of CSLC are dependent upon the vascular microenvironments that promote their long-term growth and self-renewal. However, it is not known if when we disrupted their vascular microenvironments, CSLC would be eliminated. Considering these possibilities, we have investigated the influence of different chemotherapy regimens on the CSLC population of hepatocarcinoma xenografts model. The mouse models of hepatocarcinoma were treated with different therapeutic regimens: low-dose metronomic (LDM) regimens, combination therapies of Bolus dose and low-dose metronomic regimens, for the purpose of comparison, a conventional cytotoxic schedule of maximum tolerated dose (MTD) chemotherapy using gemcitabine (GEM). All therapies produced a significant tumor growth delay. LDM GEM and Bolus+LDM GEM significantly reduced the tumor spheres, whereas MTD GEM had no effect on the tumor spheres. Furthermore, Bolus+LDM GEM could more significantly decrease both the population of CSLC and the levels of viable endothelial progenitor cells (EPC). Overall, our data indicate that Bolus+LDM GEM is a potent treatment regimen for inhibiting angiogenesis, attacking the tumor vascular microenvironments, and decreasing the population of CSLC. Targeting the unique microenvironment of CSLC may be the key to effective cancer therapy, and shows great promise for the clinical practice.

New insights into metronomic chemotherapy-induced immunoregulation.

Chemotherapy is the mainstay of treatment in mid-advanced tumors. Considering their toxicity on hematopoietic cells, chemotherapeutics are often considered as immunosuppressive inducers. However, recently accumulating data indicate that some chemotherapeutic agents with specific administration schedules also display some positive immunological effect to contribute to tumor elimination. For instance, metronomic chemotherapy could promote tumor eradication not only by inhibiting tumor angiogenesis but also by selectively eliminating immunosuppressive cells and improving anti-tumor immune responses. In this review, we summarize what is currently known regarding metronomic chemotherapy-induced immunoregulation. Understanding of the molecular mechanisms of metronomic chemotherapy-induced immunoregulation may yield invaluable information for the optimal design of immunochemotherapies.

Cancer stem cells niche: a target for novel cancer therapeutics.

Nowadays, cancer has been a frequent disease, and the first or second most common cause of death worldwide. Despite a better understanding of the biology of cancer cells, the therapy of most cancers has not significantly changed for the past four decades. It is because conventional chemotherapies and/or radiation therapies are usually designed to eradicate highly proliferative cells. Mounting evidence has implicated that cancer is a disease of stem cells. Cancer stem cells (CSC) are often relatively quiescent, and therefore may not be affected by therapies targeting rapidly dividing cells. Like normal stem cells (NSC) residing in a "stem cell niche" that maintains them in a stem-like state, CSC also require a special microenvironment to control their self-renewal and undifferentiated state. The "CSC niche" is likely to be the most crucial target in the treatment of cancer. In this article, we summarize the current knowledge regarding CSC and their niche microenvironments. Understanding of CSC's origin, molecular profile, and interaction with their microenvironments, this could be a paradigm shift in the treatment of cancer, away from targeting the blast cells and towards the targeting of the CSC, thus improving therapeutic outcome.

WITHDRAWN: Treatment of combining antiangiogenic therapy and cytotoxic chemotherapy reduce the cancer stem-like cell fraction in hepatocarcinoma xenografts.

This article has been withdrawn consistent with Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). The Publisher apologizes for any inconvenience this may cause.

[Effect of extract of Ginkgo biloba on doxorubicin-associated cardiotoxicity in patients with breast cancer].

OBJECTIVE: To study the effect of extract of Ginkgo biloba (Egb761) on doxorubicin-associated cardiotoxicity in patients with breast cancer (BC). METHODS: Sixty BC patients in stage IV were randomly assigned to two groups, the control group was treated with chemotherapy, using 4 cycles of PA protocol alone and the treated group with the same chemotherapy and Egb761. Changes in electrocardiogram (ECG), myocardial enzyme spectrum (MES) and ultrasono-cardiogram (USCG) before and after treatment were observed. RESULTS: After treatment, the incidence of abnormal ECG was lower in the treated group than in the control group (6.7% vs 30.0%); significant differences were found between the two groups in the parameters of MES (P< 0.05); USCG showed significant difference between the two groups in left ventricular diastolic diameter (LVDd), left ventricular systolic diameter (LVDs), ratio of early and late diastolic transmitral peak flow velocity (E/A) and fractional shortening (FS), while there was no significant difference in ejection fraction (EF). CONCLUSION: Egb761 is an ideal drug for preventing and reducing the acute doxorbincin-induced cardiotoxicity; it could also be helpful for alleviating the chronic cardiotoxicity.

Tumor-initiating stem cells in liver cancer.

It is widely accepted that cancer is a disease of stem cells. Definite evidence suggests that tumors harbor a small population of cancer stem cells (CSC) that both give rise to the bulk of the tumor and are tumorigenic in experimental models. Mounting evidence suggests that these cells are responsible for regrowth of a tumor following unsuccessful treatment and for the establishment of metastases. The concept of CSC has been demonstrated in several human cancers including leukemia, breast, prostate, lung, pancreas, colon and brain tumors. Recently, several studies have demonstrated that liver cancer, like other tumors, are derived from a small population of liver cancer stem/progenitor cells. Although still controversial, Liver CSC will likely become the most crucial target in the treatment of liver cancer, and a thorough understanding of its origin, molecular profile and particularly of how the Liver CSC differs from the normal stem cells, might allow it to be targeted selectively and eliminated, thus improving therapeutic outcome. In this review we will summarize the recent evidence for Liver CSC, the relationship between normal and liver stem cells, and the possibility that transformation of different cell types in the liver may generate different types of liver cancers.