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Epirubicin up-regulates PARP-1 activity dependent on Kif4A low expression in breast cancer cells

Hui WANG ; Changqing LU ; Bo TIAN ; Qing LI ; Tongbing CHEN

China Oncology.2013;(10):804-812. doi:10.3969/j.issn.1007-3969.2013.10.005

Background and purpose:Chemotherapy is the important way of breast cancer treatment, but the drug-resistance has attracted special attention. The emergence of drug resistance is closely related to the abnormal enhancement of DNA-damage repair. Both Kif4A and PARP-1 are important molecules of DNA repair. The research investigated the function of Kif4A in epirubicin up-regulating the activity of PARP-1 in breast cancer cells and possible significance. Methods:Western blot was used to detect the expression of Kif4A and PARP-1 after treatment with epirubicin in MDA-MB-231 and MCF-7 cells; the expression of PARP-1 and its activity were detected after high expression of Kif4A and treatment with epirubicin;FCM was used to detect cell apoptosis after treatment with epirubicin combined with PARP-1 inhibitor 3-ABA. Results:Epirubicin up-regulated PARP-1 activity and induced low expression of Kif4A in breast cancer cells, both of them showed dose-dependent and time-dependent. After high expression of Kif4A, the activity of PARP-1 was inhibited and the apoptosis of cells increased, epirubicin partially reversed the activity of PARP-1 inhibited by high Kif4A expression. Both of epirubicin and 3-ABA induced cell apoptosis, combination of them further increased cell apoptosis compared with alone used (P<0.05). The results also showed the apoptosis rate of MDA-MB-231 cells induced by epirubicin, PARP-1 inhibitor 3-ABA and high expression Kif4A was higher than that of MCF-7 cells (P<0.05). Conclusion:Epirubicin increases the activity of PARP-1 dependent on the low expression of Kif4A in breast cancer cells. Kif4A might become a novel target for overcoming resistance of epirubicin.

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TanshinoneⅡA inhibites migration and invasion of human gastric cancer SGC7901 cells

Xuefeng ZHAO ; Nan JIA ; Yong LI ; Liqiao FAN ; Dong WANG

China Oncology.2013;(10):793-797. doi:10.3969/j.issn.1007-3969.2013.10.003

Background and purpose:Recently, it was reported that tanshinoneⅡA (TanⅡA) could inhibit proliferation, induce differentiation and apoptosis of human cancer cells. Previous studies also indicated that TanⅡA could inhibit the migration and invasion of osteosarcoma. However, the effects of TanⅡA on the migration and invasion of gastric cancer and the mechanism remains unclear. The aim of this study was to investigate the effect of TanⅡA on gastric cancer cell SGC7901 migration and invasion of in vitro. Methods:After different concentrations (0.5, 1, 2, and 4μg/mL) of TanⅡA treatment for 24, 48, and 72 h respectively, MTT assay were developed to detect the cell proliferation of SGC7901. The wound healing assay and 3D-transwell assay were used to observe the migration and invasion of SGC7901 cells, respectively. Expression of intercellular adhesion molecule 1 (ICAM-1), matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase 2 (TIMP-2) mRNA and protein were measured with real-time PCR and Western blot. Results: 1, 2, and 4 μg/mL Tan ⅡA showed a dose-and time-dependent growth inhibition on SGC7901 cells. 2μg/mL TanⅡA showed a time-dependent migration inhibition of SGC7901 cells. 1, 2, and 4μg/mL TanⅡA could inhibit the invasion of SGC7901 cells. Real-time PCR and Western blot showed a reduction in expression of ICAM-1, MMP-2, and MMP-9, as well as an increase in expression of TIMP-2 (P<0.05).Conclusion:TanⅡA inhibits human gastric cancer SGC7901 cell migration and invasion in vitro. TIMP-2 upregulation and, ICAM-1, MMP-2, MMP-9 downregulation might be one of the mechanisms of anti-tumor of TanⅡA.

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Clinical research progress in preoperative concurrent chemoradiotherapy for advanced adenocarcinoma of the stomach or gastroesophageal junction

Menglong ZHOU ; Yanong WANG

China Oncology.2013;(10):852-856. doi:10.3969/j.issn.1007-3969.2013.10.012

This paper is about the clinical trials of preoperative concurrent chemoradiotherapy for advanced adenocarcinoma of the stomach or gastroesophageal junction reported in recent years. The radiation dose of most trials is 45 Gy. Chemotherapy drugs such as 5-fluorouracil, cisplatin and taxol are concurrently used as sensitizers. A number of trials have induction chemotherapy prior to chemoradiotherpy. The validity is evaluated by R0 resection rate, pathological complete response rate and overall survival rate. The safety is assessed by the adverse reaction, treatment related mortality, and its effect on postoperative complications and mortality. The results showed that preoperative chemoradiotherapy can significantly improve the R0 resection rate and benefit the prognosis of the patients. Meanwhile, the security and impact on operations of preoperative chemoradiotherapy is controllable. The recent researches are mostly in phase II, and more randomized controlled studies are needed. To fully accept the preoperative chemoradiotherapy as a standard treatment, more evidence and long-term efficacy index are indispensible.

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Expression of serum MIP-3α and cystatin A in patients with nasopharyngeal carcinoma and their clinical significance

Jun LI ; Minzhong TANG ; Aiying LU ; Weiming ZHONG ; Jianquan GAO ; Yuming ZHENG ; Hong ZENG ; Wansheng CHEN ; Wei LIANG ; Yonglin CAI

China Oncology.2013;(10):845-851. doi:10.3969/j.issn.1007-3969.2013.10.011

Background and purpose:To date, it mainly depended on imaging examination for detection of residual lesions, recurrence and distant metastasis, evaluation the sensitivity of radiotherapy and chemotherapy, and prognosis in nasopharyngeal carcinoma (NPC). Thus, searching for new tumor markers for NPC early diagnosis and individualized treatment is still merited. This study was aimed to investigate the expressions of serum macrophage inflammatory protein (MIP)-3α and cystatin A in patients with NPC before and after treatment, and to explore two markers’ value in NPC diagnosis, clinicopathological characteristics and clinical outcome assessment. Methods:The serum levels of MIP-3αand cystatin A in 140 primary NPC patients without distant metastasis before and after treatment were detected by enzyme-linked immunosorbent assay (ELISA) and compared with those in 100 healthy controls. Results:The sensitivity of MIP-3αand cystatin A were 92.1%and 42.1%, respectively;and the specificity of MIP-3αand cystatin A were 86.0%and 85.0%, respectively. All 140 NPC patients had complete remission (CR) or partial remission (PR). Serum levels of MIP-3αand cystatin A in pre-treatment patients with NPC were higher than those in post-treatment patients and controls. Serum MIP-3αand cystatin A levels were associated with overall stage of NPC, and MIP-3αwas also associated with T classification of NPC. The serum MIP-3αlevel in NPC with CR after treatment reduced to the level in control group, and that was still significantly higher in NPC with PR than in control group. No significant difference was found in the serum cystatin A level between NPC with CR or PR after treatment and control group. During 1-year follow-up, the post-treatment serum levels of MIP-3αand cystatin A were significantly higher in patients with distant metastasis than in patients without distant metastasis and controls. There was found statistically significant correlation between MIP-3α and cystatin A.Conclusion:MIP-3α may be a potential marker of NPC serological diagnosis. The detection of serum MIP-3αand cystatin A may contribute to the NPC staging and prediction of short-term clinical outcomes.

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The relationship between time to relapse and survival after curative surgery in colorectal cancer patients

Yuanhe WANG ; Jin ZHOU ; Yujia GAO ; Yu TANG ; Xiujuan TAO ; Ying ZHAO

China Oncology.2013;(10):841-844. doi:10.3969/j.issn.1007-3969.2013.10.010

Background and purpose:The risk of recurrence for colorectal cancer after curative surgery is up to 30%-40%. We aimed to evaluate the relationship between time to relapse (TTR) of colorectal cancer with clinical pathological parameters and overall survival after recurrence. Methods:We carried out the analysis of clinical data, pathological examination and follow up information of 375 colorectal cancer patients who admitted to Liaoning Cancer Hospital. Patients were categorized into relapse at<2, 2-5 and>5 years following their initial surgery. Results:TTR was associated with the clinical stage at diagnosis and liver or lung metastasis status. Short TTR (<2 years) was positively associated with survival. However, there was no significant difference in survival between patients who relapsed at 5 years or later compared with those who relapsed between 2 and 5 years. Conclusion:TTR within 2 years is an important predictor of shorter survival for colorectal cancer patients who experienced a relapse.

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The role of 99mTc-MIBI SPECT/CT in predicting response to neoadjuvant chemotherapy with docetaxel-based regimen for locoregionally advanced nasopharyngeal carcinoma

Chengrun DU ; Hongmei YING ; Jingyi CHENG ; Junjun ZHOU ; Jinjin JIANG ; Xiaoshen WANG ; Chaosu HU

China Oncology.2013;(10):834-840. doi:10.3969/j.issn.1007-3969.2013.10.009

Background and purpose:Neoadjuvant chemotherapy with docetaxel was gaining more attention in the treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). The prediction of the sensitivity to neoadjuvant chemotherapy with docetaxel could enable clinicians to individualize treatment protocols for NPC. Recently we found that 99mTc-MIBI imaging in NPC could predict tumor response to chemotherapy with cisplatin plus 5-FU. However, there was no study to support similar findings in NPC patients receiving chemotherapy containing docetaxel. This study was to evaluate the value of double-phase 99mTc-MIBI SPECT/CT in predicting response to neoadjuvant chemotherapy with docetaxel-based regimen for nasopharyngeal carcinoma. Methods:Thirty-one nasopharyngeal carcinoma patients participated in this prospective study. Before treatment, early and delayed single-photon emission computed tomography/compute tomography (SPECT/CT) images were obtained instantly and 2 hours after an intravenous injection of 25-30 mCi 99mTc-MIBI. All patients received neoadjuvant chemotherapy consisting of docetaxel, cisplatin plus 5-FU for two cycles. The relationships between efficacy of neoadjuvant chemotherapy and the early uptake ratio, late uptake ratio and washout rate of 99mTc-MIBI were evaluated.Results:According to the MRI, the early uptake of 99mTc-MIBI (2.67±0.83) in the lesions which were sensitive to chemotherapy was significantly higher compared with that (1.69±0.46) in the insensitive lesions(P=0.003). The difference of the late uptake between the sensitive(1.46±0.39) and the insensitive (1.06±0.62) was also statistically significant (P=0.026). However, the washout rate of 99mTc-MIBI was not significantly different between the two groups (P=0.23). Through ROC curve analysis, the AUC for early uptake of 99mTc-MIBI and late uptake were 0.84. The sensitivity, specificity, positive predictive value and negative predictive value were 74.2%, 87.5%, 95.8%and 46.7%for early uptake when the cut off value of 1.97 was used. Conclusion:The uptake of 99mTc-MIBI in both early phase and late phase could predict the efficacy of neoadjuvant chemotherapy with docetaxel-based regimen.

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Evaluation of K-ras status concordance between primary colorectal cancer and related metastatic sites

Cong TAN ; Shujuan NI ; Weiwei WENG ; Dan HUANG ; Weiqi SHENG ; Peng LIAN

China Oncology.2013;(10):829-833. doi:10.3969/j.issn.1007-3969.2013.10.008

Background and purpose:Metastatic colorectal cancer (mCRC) patients with K-ras mutation won’t benefit in the anti-epidermal growth factor receptor (EGFR) treatments. Thus K-ras mutation analysis is mandatory before this treatment. There is controversy that K-ras mutation analysis should be performed on primaries or related metastases. The aim of our study was to evaluate the concordance of K-ras status between primary and related metastases tumors, thus investigate the validity and rigorousness of clinical K-ras testing. Methods:Seventy-six patients with confirmed mCRC treated in Fudan University Shanghai Cancer Center were enrolled. After DNA extraction and PCR amplification, tumor specimens with paired primary tumors and related metastatic sites were put into sequencing analysis. And the K-ras mutation status in exon 2 was assessed. Results: K-ras mutation was detected in 31 out of 76 primary tumours (40.8%) and also 40.8%of the metastatic sites. But discordance was found between primary tumor and metastasis in 15 cases (19.7%):8 primary tumors had a K-ras mutation with a wild-type metastasis, meanwhile 7 primary tumors were wild type with a K-ras-mutated metastasis. Conclusion:Our study indicated that quite a few mCRC cases have different K-ras status between primary tumors and related metastatic sites, and it’s not very rigorous to choose the anti-EGFR treatments merely according to the primary tumor-K-ras mutation.Further study and consultation are needed on this problem.

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An experimental research of magnetic resonance tumor targeting imaging with Gd labeled human telomerase reverse transcriptase antisense oligonucleotide (Gd-DOTA-hTERT ASON)

Gaohong ZHU ; Bingxiu REN ; Jiangliang WEI ; Yulin SU ; Rui HE ; Wei ZHANG ; Jing CAI ; Bin SONG

China Oncology.2013;(10):821-828. doi:10.3969/j.issn.1007-3969.2013.10.007

Background and purpose:Researches had indicated that about over 85%of malignant tumors highly express telomerase activity. So telomerase has become one of the important methods in the research field of tumor diagnosis and treatment. Nowadays, several reports about malignant tumor which over expresses hTERT targeting imaging with radionuclide labeled hTERT ASON had been published. In these reports, high quality of pictures can hardly be acquired because of poor anatomical and spacial resolution in nuclear imaging itself. Accordingly, in this study, we developed a method of detecting human telomerase in vivo with magnetic resonance imaging (MRI) and evaluate its feasibility. Methods:Firstly, Uniformly phosphorothioate-modified human telomerase reverse transcriptase antisense oligonucleotide (hTERT ASON) was labeled with Gd3+ through the bifunctional chelator 1, 4, 7, 10-tetraazacyclododecane-N, N’, N’’, N’’’-tetraacetic acid (DOTA) and iv vitro experiments were performed to characterize the antisense probes (for biodistribution and cellular uptake, 99mTc-DOTA-ASON was used in stead of Gd-DOTA-ASON). Then Gd-DOTA-ASON was injected intraperitoneally in pulmonary adenocarcinoma A375 nude mice tumor-bearing BALB/c for in vivo imaging using 7.0 T Micro MRI periodically, tumors and their surrounding tissues were defined as region of interest (ROI) to calculate the signal to noise ratio (SNR) of tumor to muscle using Gd-DTPA as control. Finally, immunohistochemical analysis of telomerase activity of each xenograft was operated 2 days after imaging. Results:The binding efficiency of Gd-DOTA-ASON reached was as high as 65%(63.2±2.4, n=6). And it can maintain 61%in fresh human serum and normal saline at 37℃over 24 h;A375 cells showed an uptake of 8.5%when incubated with 99mTc-DOTA-ASON;In comparing with DOTA-ASON and Gd-DTPA, cells transected with Gd-DOTA-ASON had higher SI when performed MRI with T1WI. The hTERT-expressing xenografts were obviously enhanced by Gd-DOTA-ASON at 0.5-6 h after injection and the SNR can reach 2.37, whereas obvious enhancement only could be found within 2 h after injection of Gd-DTPA. Both labeled and non-labeled antisense probes can suppress the activity of telomerase of A375 cells either in vitro or in vitro. Conclusion:Our research offers proof that Gd-DOTA-ASON can be used as tumor specific targeting MR probe for diagnosing malignant tumors with high expression of telomerase.

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Effects of PTEN on the migration and invasion of endometrial carcinoma cells

Yunyun LI ; Wenfeng HE ; Tingting HUANG ; Yang SHEN ; Xiuxia LIU ; Qing CAO

China Oncology.2013;(10):813-820. doi:10.3969/j.issn.1007-3969.2013.10.006

Background and purpose: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) gene is a kind of tumor suppressors, which has been reported to be underexpressed in endometrial carcinoma (EC) tissues by several reports. However, the biological effects and possible mechanisms of PTEN on EC have been known less. In this study, we tried to investigate the effects and possible mechanisms of PTEN on the invasion and migration of endometrial carcinoma cells and to provide a potential target for endometrial carcinoma therapy. Methods:The recombinant plasmid pIRES2-ZsGreen1-PTEN was rebuilt by gene recombination technology;The plasmid was transferred into HEC-1B cells and the cells transfected with pIRES2-ZsGreen1 plasmid were used as control;The expression of PTEN was observed by fluorescence microscope and Western blot assay;Cell migration and invasion was determined by the wound healing assay, transwell migration and invasion assays respectively;The Western blot analysis was performed to detect the expression of ATP-dependent tyrosine kinase (AKT), phosphorylated-AKT (p-AKT) and matrix metalloproteinase-2 (MMP-2). Results:The agarose gel electrophoresis showed a stripe of 1.2 kb which was same to PTEN cDNA;The sequence analysis showed the PCR products owned the same sequence with the coding region of PTEN cDNA in GenBank, suggesting the recombinant plasmid was constructed successfully;The green light of cells observed by fluorescence microscope and the Western blot analysis showed the expression of PTEN was upregulated in the cells transfected with the recombinant plasmid, suggesting the plasmid expressed successfully in HEC-1B cells;The wound healing assay as well as transwell migration assay showed ectopic expression of PTEN suppressed cell migration;The invasive capacity of HEC-1B cells was significantly decreased upon transfection with PTEN plasmid compared to control and untreated groups;Moreover, compared with the control groups, the expression of p-AKT and MMP-2 was downregulated, while there was no significant alteration of the expression of AKT. Conclusion:PTEN could suppress cell migratory and invasive ability of endometrial carcinoma cells by suppressing the phosphorylation of AKT followed by the decrease of MMP-2.

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Experimental study on tumor response to chemotherapy with 18F-SFB-Annexin B1

Yujia ZHENG ; Mingwei WANG ; Jianping ZHANG ; Junyan XU ; Zhongyi YANG ; Jingyi CHENG ; Yongping ZHANG ; Yingjian ZHANG

China Oncology.2013;(10):798-803. doi:10.3969/j.issn.1007-3969.2013.10.004

Background and purpose: One of the main mechanism of chemotherapy is inducing tuomr apoptosis. Molecular imaging can allow noninvasively and dynamically monitor tumor apoptosis in vivo, and help to drug screening and therapeutic evaluation. The purpose of this study was to evaluate the feasibility of 18F-SFB-Annexin B1 in detecting apoptosis at an early phase after chemotheraphy. Methods:Annexin B1 was labeled with 18F using SFB as a chelating agent. Tissue distribution of 18F-SFB-Annexin B1 was studied in healthy mice by the dissection method. W256 tumor-bearing rats were injected with 18F-SFB-Annexin B1 intravenously at 24 h after the treatment of cyclophosphamide (CTX 200 mg/kg) or saline. Then imaging was acquired at 1, 2, 3, and 4 h postinjection on a PET/CT, and the tumor-to-muscle ratio of SUVmax (T/M) and the AI from TUNEL testing were compared. Results: 18F-SFB-Annexin B1 had a radiochemical pruity (RCP)>95%. Biodistribution of this probe showed a predominant uptake in the kidney, then was liver, spleen, and myocardium, rapid clearance from blood and urinary was observed. The radios of T/M were 4.38±0.56, 6.75±1.16, 6.44±1.12, 4.81±0.17, respectively at 1, 2, 3, 4 h post injection of the chemotherapy group, much higher than that of the saline group (2.35±0.14, 2.99±0.55, 3.04±0.41, 2.33±0.47, respectively). The differences between the two groups were significant (F=23.790, 16.913, 14.046, 77.517, respectively, all P<0.05). TUNEL staining revealed that chemotherapy treatment significantly increased the percentage of apoptosis cells with an AI of (21.00±0.04)%in the chemotherapy group, higher than that in the saline group (8.58±0.01)%, the difference was significant (F=21.539, P<0.05). The radios of T/M were significantly correlated with the values of AI (r=0.91, P<0.05). Conclusion: 18F-SFB-Annexin B1 can be used to apoptosis imaging and early therapeutic evaluation in vivo because it can reflect apoptosis at an early stage after chemotheraphy.

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