Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going

Chen Liang,Si Shi,Qingcai Meng,Dingkong Liang,Shunrong Ji,Bo Zhang,Yi Qin,Jin Xu,Quanxing Ni,Xianjun Yu 생화학분자생물학회 2017 Experimental and molecular medicine Vol.49 No.-

Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth-permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients.

Protective Effects of Gypenosides against Fatty Liver Disease Induced by High Fat and Cholesterol Diet and Alcohol in Rats

Renan Qin,Hong Nie,Jianyu Zhang,Chuyuan Li,Xiaoqi Zhang,Aihua Xiong,Feng Huang,Zhen Yin,Kongyan Li,Wenyu Qin,Mingzhen Chen,Shubing Zhang,Lingyi Liang,Huiye Zhang,Wencai Ye 대한약학회 2012 Archives of Pharmacal Research Vol.35 No.7

In the present study, the protective effects of gypenosides from Gynostemma pentaphyllum on fatty liver disease (FLD) were examined in rats treated with high fat and cholesterol diet and alcohol. Male SD rats were divided into seven groups: control, model, lovastatin, silymarin, gypenosides high-, medium- and low-treatment groups. The latter 6 groups were fed high-fat and cholesterol diet and administered alcohol intragastricly once a day. Body weight was measured every week for 10 weeks, and the hepatic index was measured after 10 weeks. Compared with model group, levels of serum triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), and low density lipoprotein cholesterol (LDL-C) level, malondialdehyde (MDA), serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity, and hepatocyte apoptosis were significantly decreased in gypenosides groups; while serum high density lipoprotein cholesterol (HDL-C), superoxide dismutase (SOD) activity in both serum and hepatic tissue and mRNA and protein level of peroxisome proliferator-activated receptor α (PPAR-α) were significantly increased. Moreover, hepatic steatosis and mitochondrial damage were improved. These results suggested that gypenosides could prevent liver fatty degeneration in fatty liver disease through modulating lipid metabolism, ameliorating liver dysfunction and reducing oxidative stress.

Structure and bioactivity of triterpenoids from the stems of Schisandra sphenanthera

Cheng-Qin Liang,Rong-Hua Luo,Ju-Ming Yan,Yan Li,Xiao-Nian Li,Yi-Ming Shi,Shan-Zhai Shang,Zhong-Hua Gao,Liu-Meng Yang,Yong-Tang Zheng,Wei-Lie Xiao,Hong-Bin Zhang,Han Dong Sun 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.2

Two new triterpenoids, schisphendilactoneA and B (1 and 2), together with three known triterpenoids,were isolated from the stems of Schisandra sphenanthera. Their structures were elucidated by spectroscopic methods,and the absolute configuration of 1 was determined bysingle-crystal X-ray diffraction. Compound 2 showedmoderate inhibitory activity against SW480 cancer cellline, and compound 5 exhibited promising anti-HIV-1activity with EC50 value of 0.52 lg ml-1 and therapeuticindex value of 117.12.

Computed Tomography Manifestations of Histologic Subtypes of Retroperitoneal Liposarcoma

Lu, Jing,Qin, Qin,Zhan, Liang-Liang,Yang, Xi,Xu, Qing,Yu, Jing,Dou, Li-Na,Zhang, Hao,Yang, Yan,Chen, Xiao-Chen,Yang, Yue-Hua,Cheng, Hong-Yan,Sun, Xin-Chen Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.15

Objective: Liposarcoma (LPS) is the most common soft tissue sarcoma and accounts for approximately 20% of all mesenchymal malignancies, often occurring in deep soft tissue of retroperitoneal space. Accurate preoperative diagnosis is therefore necessary. We explored whether computed tomography (CT) could be used to differentiate between the various types of retroperitoneal liposarcoma (RPLS). Method: Forty-seven cases of RPLS, diagnosed surgically and histologically, were analyzed retrospectively. CT features were correlated with postoperative pathological appearance. Results: The study radiologist identified 29, 11, 2, 2 and 3 RPLS as atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL), dedifferentiated liposarcoma (DDL), myxoid/round cell liposarcoma (ML/RCL), pleomorphic liposarcoma (PL) and mixed-type liposarcoma. Analysis of CT scans revealed the following typical findings of the different subtypes of RPLS: ALT/WDL was mainly visible as a well-delineated fatty hypodense tumor with uniform density and integrity margin; DDL was marked by the combination of focal nodular density and hypervascularity. ML/RCL, PL and mixed liposarcoma showed malignant biological behaviour and CT findings need further studies. Conclusions: CT scanning can reveal important details including internal components, margins and surrounding tissues. Based on CT findings, tumor type can be roughly evaluated and biopsy location and therapeutic scheme guided.

Radiosensitivity Enhancement by Arsenic Trioxide in Conjunction with Hyperthermia in the EC-1 Esophageal Carcinoma Cell Line

Cui, Yan-Hui,Liang, Hai-Jun,Zhang, Qing-Qin,Li, Si-Qing,Li, Xiao-Rui,Huo, Xiao-Qing,Yang, Qing-Hui,Li, Wei-Wei,Gu, Jian-Fa,Hua, Qin-Liang,Lu, Ping,Miao, Zhan-Hui Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.4

Objective: To explore the effect on radiosensitivity of arsenic trioxide ($As_20_3$) in conjunction with hyperthermia on the esophageal carcinoma EC-1 cell line. Method: Inhibition of EC-1 cell proliferation at different concentrations of $As_20_3$ was assessed using the methyl thiazolyl blue colorimetric method (MTT method), with calculation of $IC_{50}$ value and choice of 20% of the $IC_{50}$ as the experimental drug concentration. Blank control, $As_20_3$, hyperthermia, radiotherapy group, $As_20_3$ + hyperthermia, $As_20_3$ + radiotherapy, hyperthermia + radiotherapy and $As_20_3$ + hyperthermia + radiotherapy groups were established, and the cell survival fraction (SF) was calculated from flat panel colony forming analysis, and fitted by the 'multitarget click mathematical model'. Flow cytometry (FCM) was used to detect changes in cell apoptosis and the cell cycle. Results: $As_20_3$ exerted inhibitory effects on proliferation of esophageal carcinoma EC-1 cells, with an $IC_{50}$ of 18.7 ${\mu}mol/L$. After joint therapy of $As_20_3$ + hyperthermia + radiotherapy, the results of FCM showed that cells could be arrested in the $G_2$/M phase, and as the ratio of cells in $G_0/G_1$ and S phases decreased, cell death became more pronounced. Conclusion: $As_20_3$ and hyperthermia exert radiosensitivity effects on esophageal carcinoma EC-1 cells, with synergy in combination. Mechanistically, $As_20_3$ and hyperthermia mainly influence the cell cycle distribution of EC-1 esophageal carcinoma cells, decreasing the repair of sublethal damage and inducing apoptosis, thereby enhancing the killing effects of radioactive rays.

Fenofibrate Increases Radiosensitivity in Head and Neck Squamous Cell Carcinoma via Inducing G2/M Arrest and Apoptosis

Liu, Jia,Ge, Yang-Yang,Zhu, Hong-Cheng,Yang, Xi,Cai, Jing,Zhang, Chi,Lu, Jing,Zhan, Liang-Liang,Qin, Qin,Yang, Yan,Yang, Yue-Hua,Zhang, Hao,Chen, Xiao-Chen,Liu, Zhe-Ming,Ma, Jian-Xin,Cheng, Hong-Yan,S Asian Pacific Journal of Cancer Prevention 2014 Asian Pacific journal of cancer prevention Vol.15 No.16

Radiation therapy is an important treatment for head and neck squamous cell carcinoma (HNSCC). However, how to promote radiation sensitivity in HNSCC remains a challenge. This study aimed to investigate the radiosensitizing effects of fenofibrate on HNSCC and explore the underlying mechanisms. HNSCC cell lines CNE-2 and KB were subjected to ionizing radiation (IR), in the presence or absence of fenofibrate treatment. Cell growth and survival, apoptosis and cell cycle were evaluated. In addition, CNE-2 cells were xenografted into nude mice and subjected to IR and/or fenofibrate treatment. The expression of cyclinB and CDK1 was detected by Western blotting. Our results showed that fenofibrate efficiently radiosensitized HNSCC cells and xenografts in mice, and induced apoptosis and G2/M arrest via reducing the activity of the CDK1/cyclinB1 kinase complex. These data suggest that fenofibrate could be a promising radiosensitizer for HNSCC radiotherapy.

Adjuvant Radiotherapy after Breast Conserving Treatment for Breast Cancer:A Dosimetric Comparison between Volumetric Modulated Arc Therapy and Intensity Modulated Radiotherapy

Liu, Zhe-Ming,Ge, Xiao-Lin,Chen, Jia-Yan,Wang, Pei-Pei,Zhang, Chi,Yang, Xi,Zhu, Hong-Cheng,Liu, Jia,Qin, Qin,Xu, Li-Ping,Lu, Jing,Zhan, Liang-Liang,Cheng, Hong-Yan,Sun, Xin-Chen Asian Pacific Journal of Cancer Prevention 2015 Asian Pacific journal of cancer prevention Vol.16 No.8

Background: Radiotherapy is an important treatment of choice for breast cancer patients after breast-conserving surgery, and we compare the feasibility of using dual arc volumetric modulated arc therapy (VMAT2), single arc volumetric modulated arc therapy (VMAT1) and Multi-beam Intensity Modulated Radiotherapy (M-IMRT) on patients after breast-conserving surgery. Materials and Methods: Thirty patients with breast cancer (half right-sided and half left-sided) treated by conservative lumpectomy and requiring whole breast radiotherapy with tumor bed boost were planned with three different radiotherapy techniques: 1) VMAT1; 2) VMAT2; 3) M-IMRT. The distributions for the planning target volume (PTV) and organs at risk (OARs) were compared. Dosimetries for all the techniques were compared. Results: All three techniques satisfied the dose constraint well. VMAT2 showed no obvious difference in the homogeneity index (HI) and conformity index (CI) of the PTV with respect to M-IMRT and VMAT1. VMAT2 clearly improved the treatment efficiency and can also decrease the mean dose and V5Gy of the contralateral lung. The mean dose and maximum dose of the spinal cord and contralateral breast were lower for VMAT2 than the other two techniques. The very low dose distribution (V1Gy) of the contralateral breast also showed great reduction in VMAT2 compared with the other two techniques. For the ipsilateral lung of right-sided breast cancer, the mean dose was decreased significantly in VMAT2 compared with VMAT1 and M-IMRT. The V20Gy and V30Gy of the ipsilateral lung of the left-sided breast cancer for VMAT2 showed obvious reduction compared with the other two techniques. The heart statistics of VMAT2 also decreased considerably compared to VMAT1 and M-IMRT. Conclusions: Compared to the other two techniques, the dual arc volumetric modulated arc therapy technique reduced radiation dose exposure to the organs at risk and maintained a reasonable target dose distribution.

GPH1 is involved in glycerol accumulation in the three-dimensional networks of the nematode-trapping fungus Arthrobotrys oligospora

Qin-Yi Wu,Yue-Yan Zhu,Cheng-Gang Zou,Ying-Qian Kang,Lian-Ming Liang 한국미생물학회 2016 The journal of microbiology Vol.54 No.11

Turgor is very important for the invasive growth of fungal pathogens. Glycerol, a highly osmotic solvent, is considered to play an important role in turgor generation. The nematophagous fungus Arthrobotrys oligospora mainly lives as a saprophyte. In the presence of nematodes, A. oligospora enters the parasitic stage by forming three-dimensional networks (traps) to capture nematodes. In A. oligospora, we found that glycerol accumulated during nematode-induced trap formation. We demonstrated that deleting gph1, which encodes glycogen phosphorylase, decreased the glycerol content, compared with that of a wild-type strain. Although the number of traps induced by nematodes was not affected in the Δgph1 mutant, the capture rate was lower. Meanwhile, deleting gph1 also affected the growth rate and conidiation capacity of the fungus. These results indicate that glycerol derived from GPH1 is essential for the full virulence of A. oligospora against nematodes.

Exogenous Morphine Inhibits Human Gastric Cancer MGC-803 Cell Growth by Cell Cycle Arrest and Apoptosis Induction

Qin, Yi,Chen, Jing,Li, Li,Liao, Chun-Jie,Liang, Yu-Bing,Guan, En-Jian,Xie, Yu-Bo Asian Pacific Journal of Cancer Prevention 2012 Asian Pacific journal of cancer prevention Vol.13 No.4

Morphine is not only an analgesic treating pain for patients with cancer but also a potential anticancer drug inhibiting tumor growth and proliferation. To gain better insight into the involvement of morphine in the biological characteristics of gastric cancer, we investigated effects on progression of gastric carcinoma cells and the expression of some apoptosis-related genes including caspase-9, caspase-3, survivin and NF-${\kappa}B$ using the MGC-803 human gastric cancer cell line. The viability of cells was assessed by MTT assay, proliferation by colony formation assay, cell cycle progression and apoptosis by flow cytometry and ultrastructural alteration by transmission electron microscopy. The influences of morphine on caspase-9, caspase-3, survivin and NF-${\kappa}B$ were evaluated by semi-quantitative RT-PCR and Western blot. Our data showed that morphine could significantly inhibit cell growth and proliferation and cause cell cycle arrest in the G2/M phase. MGC-803 cells which were incubated with morphine also had a higher apoptotic rate than control cells. Morphine also led to morphological changes of gastric cancer cells. The mechanism of morphine inhibiting gastric cancer progression in vitro might be associated with activation of caspase-9 and caspase-3 and inhibition of survivin and NF-${\kappa}B$.

Significant Efficacy of Additional Concurrent Chemotherapy with Radiotherapy for Postoperative Cervical Cancer with Risk Factors: a Systematic Review and Meta-analysis

Qin, Ai-Qiu,Liang, Zhong-Guo,Ye, Jia-Xiang,Li, Jing,Wang, Jian-Li,Chen, Chang-Xian,Song, Hong-Lin Asian Pacific Journal of Cancer Prevention 2016 Asian Pacific journal of cancer prevention Vol.17 No.8

Background: Whether concurrent chemotherapy treatment is superior to radiotherapy alone as an adjuvant regimen for postoperative cervical carcinoma with risk factors remains controversial. Materials and Methods: A literature search strategy examined Pubmed, Embase, the Cochrane Library, the China National Knowledge Internet Web, the Chinese Biomedical Database and the Wanfang Database. Article reference lists and scientific meeting abstracts were also screened. Controlled trials comparing concurrent chemoradiotherapy versus radiotherapy alone in postoperative cervical cancer were included. The methodological quality of non-randomized controlled trials was evaluated using the Newcastle-Ottawa Scale. Randomized controlled studies were evaluated with the Cochrane handbook. A meta-analysis was performed with RevMan 5.3. Results: A total of 1,073 patients from 11 clinical trials were analysed, with 582 patients in the concurrent chemoradiotherapy group and 491 patients in the radiotherapy group. Hazard ratios (HR) of 0.47 (95% CI 0.31-0.72) and 0.50 (95% CI 0.35-0.72) were observed for overall survival and progression-free survival, indicating a benefit from the additional use of concurrent chemotherapy. Subgroup analyses demonstrated that cervical cancer with high risk factors significantly benefitted from concurrent chemotherapy when examining overall survival (HR 0.44, 95% CI 0.28-0.67) and progression-free survival (HR 0.48, 95% CI 0.33-0.70), but patients with intermediate risk factors showed no benefit from concurrent chemotherapy in overall survival (HR 1.72, 95% CI 0.28-10.41) and progression-free survival (HR 1.09, 95% CI 0.19-6.14). No significant differences were observed for grade 3-4 anaemia (risk ratio (RR) 3.87, 95% CI 0.69-21.84), grade 3-4 thrombocytopenia (RR 3.04, 95% CI 0.88-10.58), grade 3-4 vomiting or nausea (RR 1.71, 95% CI 0.27-10.96), or grade 3-4 diarrhoea (RR 1.40, 95% CI 0.69-2.83). Significant differences were observed for grade 3-4 neutropenia in favour of the radiotherapy group (RR 7.23, 95% CI 3.94-13.26). Conclusions: In conclusion, concurrent chemoradiotherapy improves survival in postoperative cervical cancer with high risk factors but not in those with intermediate risk factors.