Xi-Ran He

Acupuncture and Moxibustion for Cancer-related Fatigue: a Systematic Review and Meta-analysis

BACKGROUND Faced with highly prevalent and recalcitrant cancer-related fatigue (CRF), together with the absence of any official guidelines on management, numerous groups have been striving to seek and test alternative therapies including acupuncture and moxibustion. However, different patients have various feedbacks, and the many clinical trials have given rise to varied conclusions. In terms of the therapeutic effect of acupuncture and moxibustion, there exist vast inconsistencies. OBJECTIVE The aim of the study was to evaluate the auxiliary effectiveness of acupuncture and moxibustion in the treatment of CRF, and to provide more reliable evidence to guide clinical practice. METHODS Randomized controlled trials (RCTs) published before December 2012 were all aggregated, focusing on evaluation of acupuncture or moxibustion for CRF. The quality of the included studies was assessed basing on Cochrane handbook 5.1.0, and the available data were analyzed with RevMan software (version 5.2.0). Descriptive techniques were performed when no available data could be used. RESULTS A total of 7 studies involving 804 participants were eligible. With real acupuncture versus sham acupuncture, subjects receiving true acupuncture benefited more in the reduction of fatigue. With real acupuncture versus acupressure or sham acupressure, fatigue level appeared 36% improved in the acupuncture group, but 19% in the acupressure group and only 0.6% with sham acupressure. When real acupuncture plus enhanced routine care was compared with enhanced routine care, the combination group improved mean scores for general fatigue, together with physical and mental fatigue. With real acupuncture versus sham acupuncture or wait list controls, the real acupuncture group displayed significant advantages over the wait list controls at 2 weeks for fatigue improvement and better well-being effects at 6 weeks. When moxibustion plus routine care was compared with routine care alone, the meta-analyses demonstrated the combination had a relatively significant benefit in improving severe fatigue and QLQ-C30. CONCLUSION Up to the search date, there exist few high quality RCTs to evaluate the effect of acupuncture and moxibustion, especially moxibustion in English. Yet acupuncture and moxibustion still appeared to be efficacious auxiliary therapeutic methods for CRF, in spite of several inherent defects of the included studies. Much more high-quality studies are urgently needed.

MicroRNA-33a-3p suppresses cell migration and invasion by directly targeting PBX3 in human hepatocellular carcinoma

MicroRNAs (miRNAs) have been shown to function as either oncogenes or tumor suppressors by negatively regulating target genes involved in tumor initiation and progression. In this study, we demonstrated that down-regulation of miR-33a-3p in human primary hepatocellular cancer (HCC) specimens was significantly associated with metastases and poor survival. Over-expression of miR-33a-3p in HepG2 cells remarkably suppressed not only cell growth, migration and invasion, but also tumor growth and metastases in the chick embryo chorioallantoic membrane (CAM) assay, and down-regulated Pre-B-Cell Leukemia Homeobox 3 (PBX3) expression. Conversely, inhibition of miR-33a-3p in Bel-7402 cells resulted in increased of cell growth, spreading and invasion. Furthermore, rescue experiments by over-expression PBX3 completely eliminated the inhibitory effects of miR-33a-3p on tumor growth and metastasis, both in vitro and in vivo. The luciferase assay showed that 3′-untranslated regions (3′-UTRs) of PBX3 were inhibited significantly by miR-33a-3p, while mutations in the miR-33a-3p pairing residues rescued the luciferase expression. Taken together, our findings suggest that miR-33a-3p suppressed the malignant phenotype while also inhibiting PBX3 expression in hepatocellular cancer, implying that miR-33a-3p may be a promising biomarkers and therapy target for HCC intervention.

Simultaneous determination of gefitinib and its major metabolites in mouse plasma by HPLC–MS/MS and its application to a pharmacokinetics study

Gefitinib (Iressa) is the first oral EGFR tyrosine kinase inhibitor and it brings benefits to non-small cell lung cancer patients with EGFR mutation. In this study, a simple, rapid and credible high performance liquid chromatography-tandem mass spectrometry method was established and validated for the simultaneous quantification of gefitinib and its main metabolites M523595, M537194, M387783 and M608236 in NSCLC tumor-bearing mouse plasma. Sample extraction was done by protein precipitation using acetonitrile containing dasatinib as the internal standard. The chromatography run time was 6min using an Agilent RRHD SB-C18 column with a gradient of acetonitrile and water (0.1% formic acid, v/v). The mass analysis was performed by a triple quadrupole mass spectrometry in positive multiple reaction monitoring mode. The calibration range was 0.5-100ng/mL for M608236 and 1-200ng/mL for other analytes with the correlation coefficients (r(2))≥0.99. For quality control samples, inter- and intra-assay precision was less than 15% and accuracies ranged from 92.6% to 107.58% for all analytes. The extraction recoveries were in the range of 86-105% and no significant matrix effect was observed. This simple and reproducible high-throughput method was successfully applied to the pharmacokinetic study of gefitinib and its major metabolites in mouse.

Marsdenia tenacissima extract overcomes Axl- and Met-mediated erlotinib and gefitinib cross-resistance in non-small cell lung cancer cells

Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations. However, the potential efficacy of MTE in NSCLC cells with resistance mediated by Axl and c-Met, and the related molecular mechanisms need to be elucidated. In this study we evaluated the ability of MTE to restore erlotinib/gefitinib sensitivity in TKI resistant HCC827/ER cells and xenograft mice models. Our results demonstrate that MTE overcomes erlotinib and gefitinib resistance driven by Axl and c-Met in vitro and in vivo. Combination therapy significantly suppressed EGFR downstream molecules and the c-Met and Axl activated bypass signaling pathways. Moreover, we observed that MTE is more efficient at restoring resistance to erlotinib than gefitinib. As the Axl and c-Met mediated bypass pathways share the same downstream signaling cascade as EGFR, simultaneous targeting of these pathways is a promising strategy to overcome acquired resistance of TKIs. Our results demonstrate that MTE treatment attenuates Axl phosphorylation and the associated epithelial-mesenchymal transition, suggesting MTE treatment may be a potential therapeutic strategy for overcoming erlotinib and gefitinib cross-resistance in NSCLC, especially for erlotinib resistance.Tyrosine kinase inhibitors (TKIs) are an effective treatment strategy for non-small cell lung cancer (NSCLC) patients harboring mutations that result in constitutive activation of the epidermal growth factor receptor (EGFR). However, most patients eventually develop resistance to TKIs. This occurs due to additional EGFR mutations or the activation of bypass signaling pathways. In our previous work, we demonstrated that Marsdenia tenacissima extract (MTE) restored gefitinib sensitivity in resistant NSCLC cells with EGFR T790M or K-ras mutations. However, the potential efficacy of MTE in NSCLC cells with resistance mediated by Axl and c-Met, and the related molecular mechanisms need to be elucidated. In this study we evaluated the ability of MTE to restore erlotinib/gefitinib sensitivity in TKI resistant HCC827/ER cells and xenograft mice models. Our results demonstrate that MTE overcomes erlotinib and gefitinib resistance driven by Axl and c-Met in vitro and in vivo. Combination therapy significantly suppressed EGFR downstream molecules and the c-Met and Axl activated bypass signaling pathways. Moreover, we observed that MTE is more efficient at restoring resistance to erlotinib than gefitinib. As the Axl and c-Met mediated bypass pathways share the same downstream signaling cascade as EGFR, simultaneous targeting of these pathways is a promising strategy to overcome acquired resistance of TKIs. Our results demonstrate that MTE treatment attenuates Axl phosphorylation and the associated epithelial-mesenchymal transition, suggesting MTE treatment may be a potential therapeutic strategy for overcoming erlotinib and gefitinib cross-resistance in NSCLC, especially for erlotinib resistance.

Bu Fei Decoction attenuates the tumor associated macrophage stimulated proliferation, migration, invasion and immunosuppression of non-small cell lung cancer, partially via IL-10 and PD-L1 regulation

Macrophages play a pivotal role in tumor microenvironment. Bu-Fei Decoction (BFD) is a classical formula of traditional Chinese medicine (TCM) to alleviate lung cancer related symptoms, whether it has antitumor effect or could influence cancer microenvironment deserves further study. The aim of the present study was to examine the antitumor effect of BFD on non-small cell lung cancer (NSCLC), and to investigate the underlying mechanisms through tumor associated macrophages (TAMs). M2-polarized TAMs were induced by Phorbol 12-myristate 13-acetate (PMA) and interleukin 4 (IL-4). The antitumor activity of BFD in vitro was investigated in A549 and H1975 cells using MTT assay. The in vivo anticancer effect of BFD was evaluated in athymic nude mouse xenograft model. The invasive and migration properties of NSCLC cells were measured using Transwell. The protein expression was assessed using western blotting, ELISA and immunohistochemistry. The gene expression was examined using RT-PCR. TAMs was successfully established. Conditioned medium from TAMs increased cell proliferation, migration and invasion in NSCLC cells (p<0.05). BFD showed dose-dependent inhibitory effect on cell proliferation, migration and invasion abilities induced by TAMs. TAMs and rhIL-10 promoted the mRNA and protein expression of PD-L1 in NSCLC cells (p<0.01). Anti-IL-10 antibodies inhibited the elevated PD-L1 expression induced by TAMs. In vitro, the expression of PD-L1 and IL-10 was inhibited by BFD dose-dependently. In vivo, BFD suppressed A549 and H1975 tumor growth and decreased the expression of IL-10, PD-L1 and CD206. The results showed that TAMs play an important role in tumor progression of NSCLC, which was associated with tumor proliferation, migration, invasion and immunosuppression. Moreover, the antitumor mechanism of BFD is related to interruption of the link between TAMs and cancer cells by inhibiting the expression of IL-10 and PD-L1 in vitro and in vivo. Our results demonstrated BFDs potential as a novel treatment for NSCLC.

Recent highlights of experimental research for inhibiting tumor growth by using Chinese medicine.

To give an overview of contemporary experimental research using Chinese medicine (CM) for the treatment of cancer. As an integral part of mainstream medicine in the People’s Republic of China, CM emphasizes improvements in holistic physical condition instead of merely killing tumor cells, which is consistent with the current medical model that advocates patient-oriented treatment. Great progress has been made in experimental research, and the principle aspects include anti-tumor angiogenesis, inducing apoptosis and differentiation, reversing multidrug resistance, and improving immune function. As a current hot topic in cancer research, tumor microenvironment (TME) highlights the mutual and interdependent interaction between tumor cells and their surrounding tissues, and the CM treatment concept bears a striking resemblance to it. To date, primary points of TME include extracellular matrix remodeling, inflfl ammation, hypoxia, and angiogenesis, but trials using CM with a focus on TME are rare. Despite considerable recent development, experimental research on CM for solving cancer issues appears insufficient. Greater efforts in this field are urgently needed.

Chinese medicine Bu-Fei decoction attenuates epithelial-mesenchymal transition of non-small cell lung cancer via inhibition of transforming growth factor β1 signaling pathway in vitro and in vivo

ETHNOPHARMACOLOGICAL RELEVANCE Traditional Chinese medicine Bu-Fei decoction (BFD) has been utilized to treat patients with Qi deficiency for decades, with the advantages of invigorating vital energy, clearing heat-toxin and moistening lung, etc. According to previous clinical experience and trials, BFD has been found to indeed improve life quality of lung cancer patients and prolong survival time. Nevertheless, little is known on its potential mechanisms so far. Being regarded as a pivotal cytokine in the tumor microenvironment, transforming growth factor β (TGF-β) stands out as a robust regulator of epithelial-mesenchymal transition (EMT), which is closely linked to tumor progression. AIM OF THE STUDY The present study was designed to explore whether BFD antagonized EMT via blocking TGF-β1-induced signaling pathway, and then help contribute to create a relatively steady microenvironment for confining lung cancer. MATERIALS AND METHODS This experiment was performed in lung adenocarcinoma A549 cells both in vitro and in vivo. In detail, the influences mediated by TGF-β1 alone or in combination with different concentrations of BFD on migration were detected by wound healing and transwell assays, and the effects of BFD on cell viability were determined by cell counting kit-8 (CCK-8) assay. TGF-β1, EMT relevant proteins and genes were evaluated by western blotting, confocal microscopy, quantitative real-time polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC) and enzyme-linked immuno sorbent assay (ELISA). Female BALB/C nude mice were subcutaneously implanted A549 cells and given BFD by gavage twice daily for 28 days. The tumor volume was monitored every 4 days to draw growth curve. The tumor weight, expression levels of EMT-related protein in tumor tissues and TGF-β1 serum level were evaluated, respectively. RESULTS BFD only exerted minor effects on A549 cell proliferation and this was in accordance with the in vivo result, which showed that the tumor growth and weight were not be restrained by BFD administration. However, the data elucidated that BFD could dose-dependently suppress EMT induced by TGF-β1 in vitro via attenuating canonical Smad signaling pathway. In the A549 xenograft mouse model, BFD also inhibited protein markers that are associated with EMT and TGF-β1 secretion into serum. CONCLUSIONS Based on these above data, the conclusion could be put forward that BFD probably attenuated TGF-β1 mediated EMT in A549 cells via decreasing canonical Smad signaling pathway both in vitro and in vivo, which may help restrain the malignant phenotype induced by TGF-β1 in A549 cells to some extent.

Recent highlights of Chinese medicine for advanced lung cancer

Owing to its unique superiority in improving quality of life and prolonging survival time among advanced lung cancer patients, Chinese medicine (CM) has, in recent years, received increased attentions worldwide. We utilized a bibliometric statistical method based on MEDLINE/GoPubMed to conduct a comprehensive analysis of the current application status of CM in lung cancer, by including annual and accumulated publications, origin distribution of countries and journals, and keywords with a higher frequency score. Then the relevant clinical trials and mechanistic studies were systematically summarized within the field according to research types. We have raised potential problems and provided potentially useful reference information that could guide similar studies in the future. The basic experimental results are highly consistent with clinical trials, leading us to conclude that CM can offer better overall therapeutic benefits when used in combination with routine Western medicine for patients with advanced lung cancer.

Antitumor effects of Xi Huang pills on MDA‑MB‑231 cells in vitro and in vivo

The management of patients with triple-negative breast cancer is challenging due to the lack of effective therapeutic options, aggressive behavior and relatively poor prognosis. Xi Huang pills (XHP) are a well-known traditional Chinese medicine that demonstrate anticancer activities. The aim of the present study was to investigate the antitumor effects of XHP on MDA-MB-231 cells in vitro and in vivo, and its potential underlying molecular mechanisms. In the present study, an MTT assay was used to evaluate the antiproliferative activity of XHP on MDA-MB-231 cells. In order to investigate the effects further, cell cycle distribution, apoptosis and mitochondrial membrane potential assays were performed, as well as western blot analyses. In addition, a tumor xenograft model was employed to investigate the effects of XHP in vivo. The results of the MTT assay demonstrated that the viability of MDA-MB-231 cells was markedly inhibited by XHP in a dose- and time-dependent manner. The inhibitory effect of XHP on the viability of MDA-MB-231 cells was greater when compared with MCF-10A cells. An increase in apoptosis and loss of mitochondrial membrane potential was observed following 4, 8 and 12 mg/ml XHP treatment of MDA-MB-231 cells. The protein expression levels of cleaved caspase-3 were increased by 1.62-, 2.13- and 2.19-fold, respectively, when compared with the untreated controls, whereas no effects on the expression of B-cell lymphoma 2 (Bcl-2) or Bcl-2-associated X protein (Bax) were observed. The results of the cell cycle distribution assay analysis demonstrated that XHP treatment arrested cells at the G2/M phase. In addition, XHP treatment decreased the expression of cyclin A and increased the expression of p21Cip1. In vivo experiments revealed that XHP inhibited the growth of MDA-MB-231 xenograft tumors without body weight loss, and demonstrated similar effects on the protein expression levels of cleaved caspase 3, cyclin A and p21Cip1 as observed in vitro. In conclusion, the viability of MDA-MB-231 cells was inhibited by XHP in a dose-dependent, time-dependent and cell-selective manner in vitro, and the potential underlying mechanisms may involve apoptosis and cell cycle arrest at the G2/M phase. XHP may induce apoptosis in MDA-MB-231 cells via the intrinsic pathway, which does not involve the Bcl-2/Bax ratio. G2/M phase arrest may have been due to the integrated action of decreased cyclin A expression and increased p21Cip1 expression. In addition, XHP inhibited the growth of xenograft tumors in the absence of body weight loss in vivo.

Taraxacum mongolicum extract induced endoplasmic reticulum stress associated-apoptosis in triple-negative breast cancer cells

BACKGROUND Triple-negative breast cancer (TNBC) is an aggressive and deadly breast cancer subtype with limited treatment options. It is necessary to seek complementary strategies for TNBC management. Taraxacum mongolicum, commonly named as dandelion, is a herb medicine with anti-cancer activity and has been utilized to treat mammary abscess, hyperplasia of mammary glands from ancient time in China, but the scientific evidence and action mechanisms still need to be studied. AIM OF THE STUDY This study was intended to investigate the therapeutic effect and molecular mechanisms of dandelion extract in TNBC cell line. METHODOLOGY Dandelion extract was prepared and purified, and then its chemical composition was determined. Cell viability was evaluated by MTT assay. Analysis of cell apoptosis and cell cycle was assessed by flow cytometry. The expression levels of mRNA and proteins were determined by real-time PCR and Western blotting, respectively. Caspase inhibitor Z-VAD-FMK and CHOP siRNA were used to confirm the cell apoptosis induced by dandelion extract. RESULTS Dandelion extract significantly decreased MDA-MB-231cell viability, triggered G2/M phase arrest and cell apoptosis. Concurrently, it caused a markedly increase of cleaved caspase-3 and PARP proteins. Caspase inhibitor Z-VAD-FMK abolished the apoptosis triggered by dandelion extract. The three ER stress-related signals were strongly induced after dandelion treatment, including increased mRNA expressions of ATF4, ATF6, XBP1s, GRP78 and CHOP genes, elevated protein levels of phosphorylated PERK, eIF-2α, IRE1, as well as the downstream molecules of CHOP and GRP78. MDA-MB-231 cells transfected with CHOP siRNA significantly reduced apoptosis induced by dandelion extract. The underlying mechanisms at least partially ascribe to the strong activation of PERK/p-eIF2α/ATF4/CHOP axis. CONCLUSION ER stress related cell apoptosis accounted for the anti-cancer effect of dandelion extract, and these findings support dandelion extract might be a potential therapeutic approach to treat TNBC.