Synergistic Anti-Tumor Effect of Toosendanin and Paclitaxel on Triple-Negative Breast Cancer via Regulating ADORA2A-EMT Related Signaling.

Triple negative breast cancer (TNBC) is an aggressive cancer with very poor prognosis. Combination therapy has proven to be a promising strategy for enhancing TNBC treatment efficacy. Toosendanin (TSN), a plant-derived triterpenoid, has shown pleiotropic effects against a variety of tumors. Herein, it is evaluated whether TSN can enhance the efficacy of paclitaxel (PTX), a common chemotherapeutic agent, against TNBC. It is found that TSN and PTX synergistically suppress the proliferation of TNBC cell lines such as MDA-MB-231 and BT-549, and the combined treatment also inhibits the colony formation and induces cell apoptosis. Furthermore, this combination shows more marked migratory inhibition when compared to PTX alone. Mechanistic study shows that the ADORA2A pathway in TNBC is down-regulated by the combination treatment via mediating epithelial-to-mesenchymal transition (EMT) process. In addition, the combined treatment of TSN and PTX significantly attenuates the tumor growth when compared to PTX monotherapy in a mouse model bearing 4T1 tumor. The results suggest that combination of TSN and PTX is superior to PTX alone, suggesting that it may be a promising alternative adjuvant chemotherapy strategy for patients with TNBC, especially those with metastatic TNBC.

Brusatol suppresses the tumor growth and metastasis of colorectal cancer via upregulating ARRDC4 expression through modulating PI3K/YAP1/TAZ Pathway.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly diagnosed cancers with high metastasis and lethality. Arrestin domain-containing 4 (ARRDC4) is involved in inhibiting cancer glycolytic phenotypes. Brusatol (BR), extracted from Bruceae Fructus, exerts good anti-cancer effects against a number of cancers. PURPOSE: In the present study, we aimed to explore the efficacy of BR on inhibiting CRC metastasis and elucidate the underlying mechanisms involving the upregulation of the ARRDC4 expression. METHODS: Cell viability, colony formation, wound healing and transwell assay were used to detect the anti-proliferative and anti-metastatic effects of BR against CRC in vitro. Microarray analysis was performed to find out differential genes in CRC cells after treatment with BR. Analysis of the CRC patients tumor samples and GEPIA database were first conducted to identify the expression of ARRDC4 on CRC. Stable overexpression and knockdown of ARRDC4 CRC cells were established by lentiviral transfection. The role of ARRDC4 in mediating the anti-metastatic effects of BR on CRC was measured using qRT-PCR, western blotting, immunohistochemical and immunofluorescence analysis. Orthotopic xenograft and pulmonary metastasis mouse models of CRC were established to determine the anti-cancer and anti-metastatic effects of ARRDC4 and BR. RESULTS: BR markedly suppressed the cell proliferation, migration, invasion and inhibited tumor growth and tumor metastasis. Microarray analysis demonstrated that BR treatment markedly increased the gene expression of ARRDC4 in CRC cells. ARRDC4 was significantly repressed in CRC in the clinical samples and GEPIA analysis. ARRDC4 overexpression plus BR produced better inhibitory effects on CRC metastasis than BR treatment alone, while ARRDC4 knockdown could partially eliminate the inhibitory effects of BR against CRC metastasis. BR exerted anti-metastatic effects against CRC via upregulating ARRDC4 and inhibiting epithelial-mesenchymal transition (EMT) processing through modulating PI3K/Hippo pathway. CONCLUSION: This study reported for the first time that BR is a potent ARRDC4 agonist, and is worthy of further development into a new therapeutic strategy for CRC.

The Adjunctive Effect of Acupuncture for Advanced Cancer Patients in a Collaborative Model of Palliative Care: Study Protocol for a 3-Arm Randomized Trial.

BACKGROUND: Cancer is the second leading cause of death before the age of 70. Improved cancer survival has put increasing demands on cancer care. Palliative care is the specialized multi-disciplinary care providing relief from the pain, symptoms, and stress of serious illness. The study aims to evaluate the adjunctive effect of acupuncture for advanced cancer patients in a collaborative model of palliative care. METHODS/DESIGN: This is a single-blinded, randomized, sham-controlled trial. One hundred twenty advanced cancer patients undergoing palliative care will be randomized in a ratio of 2:1:1 to manual acupuncture plus standard care group (ASC), sham acupuncture plus standard care group (SSC), and standard care group (SC). Patients in ASC and SSC will receive 9 sessions of acupuncture or sham acupuncture for 3 weeks, and will be followed up for 2 months. The primary measure is the change from baseline score of the Edmonton Symptom Assessment System at 3 weeks. The secondary measures include the Brief Fatigue Inventory, Hospital Anxiety and Depression Scale, Insomnia Severity Index, Numeric Rating Scale, and European Organization for Research and Treatment of Cancer Quality of Life 15 items Questionnaire for Palliative Care. DISCUSSION: The finding of this trial will provide high-quality evidence on the adjunctive effect of acupuncture to standard care on advanced cancer patients undergoing palliative care. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04398875 (https://www.clinicaltrials.gov/ct2/show/NCT04398875), Registered on 21 May 2020.

Herb-drug interactions between androgenic Chinese herbal medicines and androgen receptor antagonist on tumor growth: Studies on two xenograft prostate cancer animal models.

Our previous study revealed that Epimedii Folium (EF) and Codonopsis Radix (CNR) significantly promoted tumor growth on a subcutaneous mouse model of prostate cancer (PCa) via enhancing the mRNA and protein expressions of androgen receptor (AR), while Astragali Radix (AGR) inhibited tumor growth via suppressing the protein expression of AR. In the present study, we aimed to investigate the potential interactions between EF, CNR or AGR and AR antagonist (abiraterone acetate [ABI]) on the tumor growth using subcutaneous and orthotopic PCa mouse models. EF, CNR, AGR and ABI were intragastrically given to mice once every 2 days for 4 weeks. The pharmacokinetics of ABI were evaluated in the plasma of rats when combined with EF, CNR, or AGR. Our results demonstrated that EF or CNR could weaken the anti-tumor effects of ABI via increasing the AR expression involving activation of the PI3K/AKT and Rb/E2F pathways and decreasing the bioavailability of ABI, while AGR could enhance the anti-tumor effects of ABI through suppressing the AR expression via inhibiting the activations of PI3K/AKT and Rb/E2F pathways and increasing the bioavailability of ABI. These findings imply that cautions should be exercised when prescribing EF and CNR for PCa patients.

Moxibustion for alleviating side effects of chemotherapy or radiotherapy in people with cancer.

BACKGROUND: Moxibustion, a common treatment in traditional Chinese medicine, involves burning herbal preparations containing Artemisia vulgaris on or above the skin at acupuncture points. Its intended effect is to enhance body function, and it could reduce the side effects of chemotherapy or radiotherapy and improve quality of life (QoL) in people with cancer. OBJECTIVES: To assess the effects of moxibustion for alleviating side effects associated with chemotherapy, radiotherapy or both in people with cancer. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE via Ovid, Embase via Ovid and AMED (Allied and Complementary Medicine Database) from their inception to February 2018. We also searched databases in China including the Chinese BioMedical Literature Database (CBM), Chinese Medical Current Contents (CMCC), TCMonline, Chinese Dissertation Database (CDDB), China Medical Academic Conference (CMAC) and Index to Chinese Periodical Literature from inception to August 2017. Registries for clinical trials and other resources were also searched. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing moxibustion treatment, including moxa cone and moxa stick, versus sham, no treatment or conventional treatment. DATA COLLECTION AND ANALYSIS: Two review authors (HWZ and FC) independently extracted data on study design, participants, treatment and control intervention, and outcome measures, and they also assessed risk of bias in the included studies. We performed meta-analyses, expressing dichotomous outcomes as risk ratios (RR) and continuous outcomes as mean differences (MD), with 95% confidence intervals (CI). MAIN RESULTS: We included 29 RCTs involving 2569 participants. Five RCTs compared moxibustion versus no treatment, 15 compared moxibustion plus conventional treatment versus conventional treatment, one compared moxibustion versus sham moxibustion, and eight compared moxibustion versus conventional medicine. The overall risk of bias was high in 18 studies and unclear in 11 studies. Studies measured outcomes in various ways, and we could rarely pool data.Moxibustion versus no treatment: low-certainty evidence from single small studies suggested that moxibustion was associated with higher white blood cell counts (MD 1.77 × 109/L; 95% CI 0.76 to 2.78; 80 participants, low-certainty evidence) and higher serum haemoglobin concentrations (MD 1.33 g/L; 95% CI 0.59 to 2.07; 66 participants, low-certainty evidence) in people with cancer, during or after chemotherapy/radiotherapy, compared with no treatment. There was no evidence of an effect on leukopenia (RR 0.50, 95% CI 0.10 to 2.56; 72 participants, low-certainty evidence) between study groups. The effects on immune function (CD3, CD4, and CD8 counts) were inconsistent.Moxibustion versus sham moxibustion: low-certainty evidence from one study (50 participants) suggested that moxibustion improved QoL (measured as the score on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30)) compared with sham treatment (MD 14.88 points; 95% CI 4.83 to 24.93). Low-certainty evidence from this study also showed reductions in symptom scores for nausea and vomiting (MD -38.57 points, 95% CI -48.67 to -28.47) and diarrhoea (MD -13.81, 95% CI -27.52 to -0.10), and higher mean white blood cell count (MD 1.72 × 109/L, 95% CI 0.97 to 2.47), serum haemoglobin (MD 2.06 g/L, 95% CI 1.26 to 2.86) and platelets (MD 210.79 × 109/L, 95% CI 167.02 to 254.56) when compared with sham moxibustion.Moxibustion versus conventional medicines: low-certainty evidence from one study (90 participants) suggested that moxibustion improved WBC count eight days after treatment ended compared with conventional medicines (MD 0.40 × 109/L; 95% CI 0.15 to 0.65). Low-certainty evidence from two studies (235 participants) suggested moxibustion improved serum haemoglobin concentrations compared with conventional medicines (MD 10.28 g/L; 95% CI 4.51 to 16.05).Moxibustion plus conventional treatment versus conventional treatment alone: low-certainty evidence showed that moxibustion plus conventional treatment was associated with lower incidence and severity of leukopenia (WHO grade 3 to 4) (RR 0.14, 95% CI 0.01 to 2.64; 1 study, 56 participants), higher QoL scores on the EORTC QLQ-C30 (MD 8.85 points, 95% CI 4.25 to 13.46; 3 studies, 134 participants, I² = 26%), lower symptom scores for nausea and vomiting (RR 0.43, 95% CI 0.25 to 0.74; 7 studies, 801participants; I² = 19%), higher white blood cell counts (data not pooled due to heterogeneity), higher serum haemoglobin (MD 3.97 g/L, 95% CI 1.40 to 6.53; 2 studies, 142 participants, I² = 0%). There was no difference in platelet counts between the two groups (MD 13.48 × 109/L; 95% CI -16.00 to 42.95; 2 studies, 142 participants; I² = 34%).Most included studies did not report related adverse events, such as burning or allergic reactions. AUTHORS' CONCLUSIONS: Limited, low-certainty evidence suggests that moxibustion treatment may help to reduce the haematological and gastrointestinal toxicities of chemotherapy or radiotherapy, improving QoL in people with cancer; however, the evidence is not conclusive, and we cannot rule out benefits or risks with this treatment. High-quality studies that report adverse effects are needed.

Apoptosis and Anti-cancer Drug Discovery: The Power of Medicinal Fungi and Plants.

The purpose of this account is to review the compounds capable of eliciting mitochondria-mediated apoptosis in cancer cells produced by medicinal fungi and plants. The medicinal fungi discussed encompass Cordyceps, Ganoderma species, Coriolus versicolor and Hypsizygus marmoreus. The medicinal plants discussed comprise Astragalus complanatus, Dendrobium spp, Dioscorea spp, Glycyrrhiza spp, Panax notoginseng, Panax ginseng, and Momordica charantia. These compounds have the potential of development into anticancer drugs.

A systematic review on natural medicines for the prevention and treatment of Alzheimer's disease with meta-analyses of intervention effect of ginkgo.

We performed a systematic review to evaluate the efficacy of natural medicines for the treatment of Alzheimer's disease (AD) in randomized controlled trials (RCTs). Disease-specific and intervention terms were searched in MEDLINE, EMBASE, the Cochrane Library and PsycINFO to identify RCTs for the AD intervention of natural medicines, and searched for literatures in English language. The RCTs compared natural medicines and either placebo or orthodox medication in AD patients. The quality of literature was evaluated by Jadad's score and the Cochrane assessing tool to reduce the risk of bias. Meta-analysis and the heterogeneity of results across the trials were performed. Out of the literatures, 21 clinical reports were included in this review that satisfied the particular selection criteria. Apart from Ginkgo, other treatments we came across had minimal benefits and/or the methodological quality of the available trials was poor. The meta-analyses showed that Ginkgo had better outcomes than the placebo, with the standardized mean difference (SMD) between Ginkgo and the placebo on cognition being -1.62 (95% CI: -2.69 to -0.56) and on activities of daily living being -1.55 (95% CI: -2.55 to -0.55), with the existence of significant heterogeneity across studies. The meta-analysis for assessing the prevention effect of Ginkgo against AD suggested that risk ratio (RR) is 1.06 (95% CI: 0.92 to 1.22) between Gingko and the placebo, with no significant heterogeneity across studies (test for heterogeneity, p = 0.49). Our results suggest that Ginkgo may help established AD patients with cognitive symptoms but cannot prevent the neurodegenerative progression of the disease.

Lessons learnt from evidence-based approach of using chinese herbal medicines in liver cancer.

This paper is a systematic review of evidence-based studies of the effectiveness of Chinese herbal medicine (CHM) in the treatment of liver cancer. After a detailed analysis of the literature, five animal studies and four human clinical trials met the criteria for inclusion. Analysis revealed that results of the clinical trials, whilst encouraging, need to be interpreted with caution as problems with study designs may lead to apparent benefits being attributable to various forms of bias. However, as each of the CHM agents used in these studies appeared to be potentially beneficial, further well-designed and controlled randomized clinical trials are warranted. The second part of this review focused on the lessons learned from the relationships between Traditional Chinese Medicine (TCM) theory, TCM Syndrome Differentiation, and modern scientific understanding of mechanisms of action of CHM agents. The understanding of TCM Syndrome Differentiation may allow identification of different patterns of disharmony and may provide important guidance to the prescription of CHM. Furthermore, quality control using both biological and chemical fingerprinting of CHM is important to ensure batch-to-batch consistency to deliver sustained therapeutic benefit. Also, careful assessment of herb-drug interactions is paramount for safety and integrative use of western chemotherapeutic and CHM agents.

The yin-yang of DNA damage response: roles in tumorigenesis and cellular senescence.

Senescent cells are relatively stable, lacking proliferation capacity yet retaining metabolic activity. In contrast, cancer cells are rather invasive and devastating, with uncontrolled proliferative capacity and resistance to cell death signals. Although tumorigenesis and cellular senescence are seemingly opposite pathological events, they are actually driven by a unified mechanism: DNA damage. Integrity of the DNA damage response (DDR) network can impose a tumorigenesis barrier by navigating abnormal cells to cellular senescence. Compromise of DDR, possibly due to the inactivation of DDR components, may prevent cellular senescence but at the expense of tumor formation. Here we provide an overview of the fundamental role of DDR in tumorigenesis and cellular senescence, under the light of the Yin-Yang concept of Chinese philosophy. Emphasis is placed on discussing DDR outcome in the light of in vivo models. This information is critical as it can help make better decisions for clinical treatments of cancer patients.

Rhynchophylline Protects Cultured Rat Neurons against Methamphetamine Cytotoxicity.

Rhynchophylline (Rhy) is an active component isolated from species of the genus Uncaria which has been used for the treatment of ailments to the central nervous system in traditional Chinese medicine. Besides acting as a calcium channel blocker, Rhy was also reported to be able to protect against glutamate-induced neuronal death. We thus hypothesize that Rhy may have neuroprotective activity against methamphetamine (MA). The primary neurons were cultured directly from the cerebral cortex of neonatal rats, acting as in vitro model in the present study. The neurotoxicity of MA and the protective effect of Rhy were evaluated by MTT assay. The effects of MA, Rhy or their combination on intracellular free calcium concentration ([Ca(2+)](i)) were determined in individual neocortical neurons by the Fluo-3/AM tracing method. The MTT assay demonstrated that MA has a dose-dependent neurotoxicity in neuronal cultures. The addition of Rhy prior to the exposure to MA prevented neuronal death. Time course studies with the Fluo-3/AM probe showed that Rhy significantly decreased neuronal [Ca(2+)](i) which was elevated by the exposure to MA. Our results suggested that Rhy can protect the neuronal cultures against MA exposure and promptly attenuate intracellular calcium overload triggered by MA challenge. This is the first report demonstrating an inhibitory effect of Rhy against MA impairment in cultured neurons in vitro.

[Report of the 10th Annual Meeting of the Chinese society of Clinical Oncology].

The 10th Annual Meeting of the Chinese Society of Clinical Oncology (CSCO) was held on 19-23 September 2007 in Harbin. The theme of this conference was "putting standard multidisciplinary cancer management into practice" and special reports of standard multidisciplinary management on various cancers were presented. Over 3 500 clinical oncologists and scientists participated in the 2007 CSCO Annual Meeting where more than ten international top experts were invited to exchange valuable experiences with the delegates. The programs consisted of Education Session, Satellite Symposium and Meet the Professor Session. The latest research results were presented as oral presentations and posters at the congress. Several hotspots were particularly highlighted in this report, including innovative radiotherapy and chemotherapy methods, researches on molecular targets and clinical trials of targeted therapy, such as endostatin, volociximab, cetuximab, bevacizumab and temozolomide. The remarkable research results of anti-cancer Chinese medicine, cancer screening and prognosis were also introduced. This article tries to call the attention to some hot topics in the program that are both new and noteworthy, and it may serve as a highlight of this important international cancer research meeting for clinical oncologists and scientists.

[Integrated therapy and research progress in molecular therapy for intracranial tumor].

Intracranial tumor is the most common primary neoplasm in the central nervous system, it is a complex, heterogeneous and hard to cure disease. Current treatments include gross resection of the tumor, radiotherapy, chemotherapy, immunotherapy and Chinese medicine treatment. Despite valiant efforts, prognosis remains dismal. The thrust of an integrated approach to increase disease-free survival and improve quality-of-life is urgently required. In the era of molecular targeted therapy, recent promising diagnostic and therapeutic strategies have resulted from advancement in understanding molecular brain tumor biology, neuroimaging, neurosurgical treatment, radiotherapy, combined chemotherapy and molecular therapy. This review outlines the current status of diagnosis and therapeutic intervention in intracranial tumor. The article discusses the perspective of molecular therapy. This approach includes new technologies, such as genomics, proteomics, nanomedicine and metabolomics.

In vitro and in vivo immunomodulating and immunorestorative effects of Astragalus membranaceus.

Astragalus membranaceus is a common traditional Chinese medicinal plant widely used as a tonic to enhance the body's natural defense mechanisms. In this study, bioactive fractions were isolated from the roots of Astragalus membranaceus. One of these fractions, designated as AI, was found to be the most potent with respect to its mitogenicity on murine splenocytes. Effects of AI on both specific and nonspecific immunity in mouse models were examined. Results showed that AI could exhibit mitogenic and co-mitogenic activities on mouse splenocytes, both in vitro and in vivo. Experiments in human cell culture demonstrated that AI was also active on human lymphocytes. It was found that AI was mitogenic to T cell depleted population but virtually inactive on B cell depleted population. Intraperitoneal injection of AI into mice markedly augmented the antibody response to sheep red blood cells. Besides, both the influx of macrophages into the peritoneal cavity and the phagocytic activity of macrophages were found to be enhanced by AI in vivo. On the other hand, AI could significantly increase the interleukin-2 receptor expression on mouse splenocytes in vitro. In terms of immunorestorative activity, it was found that AI could restore the lymphocyte blastogenic response of the older mice to values that are normally found in the younger mice. Moreover, administration of AI in vivo could partially restore the depressed immune functions in tumour-bearing mice and cyclophosphamide-treated mice. Collectively, the results clearly showed that AI could exhibit immunomodulating and immunorestorative effects, both in vitro and in vivo.

Application of proteomics in Chinese medicine research.

Proteomics technologies can be applied to simultaneously study the function, organization, diversity, and dynamic variety of a cell or a whole tissue. The integrative approach of proteomics is in line with the holistic concept and practices of traditional Chinese medicine (TCM). In this review, the technologies of proteomics, their adoption leverages the depth and breadth of TCM research are introduced. This article presents some examples to illustrate the use of proteomics technologies in the study of pharmacological effects and their action mechanisms relevant to TCM. Proteomics technologies could be used to screen the target molecules of the TCM actions, identify new bioactive components, and elucidate the underlying mechanisms of their effects. With proteomics approaches, it was found that the Siwu decoction could regulate the protein expression of the bone marrow of blood (Xue) deficient mice, including some proteins and enzymes involved in the hemopoiesis system. Ganoderma lucidum spores might promote the survival and axon regeneration of injured spinal motor neurons in rats by regulating the expression levels of proteins involved in the energy and tissue regeneration system. Polygonatum zanlanscianense Pamp exhibited cytotoxicity towards human myeloblast leukemia HL-60 cells through multiple apoptosis-including pathways. Panax ginseng might be beneficial to patients suffering from diabetes mellitus and its complications by alleviating inflammation. Taken together with a discussion on the challenges and perspectives, this paper provides an overview of the recent developments of proteomics technologies in TCM research, and contends that proteomics will play an important role in the modernization and internationalization of TCM.