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Peiqi Zhao,
Hanjie Wang, Man Yu,
Zhenyu Liao,
Xianhuo Wang,
Fei Zhang,
Wei Ji,
Bing Wu,
Jinghua Han,
Haichang Zhang,
Huaqing Wang,
Jin Chang,
Ruifang Niu
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ABSTRACT: A functional drug carrier comprised of folic acid modified lipid-shell and polymer-core nanoparticles (FLPNPs) including poly(D,L-lactide-co-glycolide) (PLGA) core, PEGylated octadecyl-quaternized lysine modified chitosan (PEG-OQLCS) as lipid-shell, folic acid as targeting ligand and cholesterol was prepared and evaluated for targeted delivery of paclitaxel (PTX). Confocal microscopy analysis confirmed the coating of the lipid-shell on the polymer-core. Physicochemical characterizations of FLPNPs, such as particle size, zeta potential, morphology, encapsulation efficiency, and in vitro PTX release, were also evaluated. The internalization efficiency and targeting ability of FLPNPs were demonstrated by flow cytometry and confocal microscopy. PTX loaded FLPNPs showed a significantly higher cytotoxicity than the commercial PTX formulation (Taxol®). The intravenous administration of PTX encapsulated FLPNPs led to tumor regression and improvement of animal survival in a murine model, compared with that observed with Taxol® and biodistribution study showed that PTX concentration in tumor for PTX encapsulated FLPNPs was higher than other PTX formulations. Our data indicate that PTX loaded FLPNPs are a promising nano-sized drug formulation for cancer therapy.
European journal of pharmaceutics and biopharmaceutics: official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V 03/2012; 81(2):248-56. · 3.15 Impact Factor
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ABSTRACT: Since the processes of normal embryogenesis and neoplasia share many of similar pathways, tumor development has been interpreted as an abnormal form of organogenesis. NANOG is a homeodomain-containing transcription factor that functions to maintain self-renewal and proliferation of embryonic stem cells (ESCs). Aberrant expression of NANOG has been observed in many types of human malignancies. However, its potential implication in tumorigenesis has not been fully clarified. In this study, we have employed small interference RNA (RNAi) technology to silence endogenous NANOG expression in breast cancer cells and successfully selected three independent clones with stably inhibited NANOG expression of MCF-7 cells. Functional analysis revealed that down-regulation of NANOG reduced cell proliferation, colony formation and migration ability of MCF-7 cells. Consistently, proliferation of breast cancer MDA-MB-231 cells was also significantly inhibited after the knockdown of NANOG expression. Interestingly, we found that the expression levels of cyclinD1 and c-myc were markedly down-regulated and the cell cycle were blocked at the G0/G1 phases after the knockdown of NANOG, while the expression of cyclinE and signal transducers and activators of transcription3 (STAT3) remained unaffected. In addition, the expression of NANOG and cyclinD1 can be rescued after the transfection of pcDNA3.1 (-)-NANOG expression vector into the three clones. Finally, our chromatin immunoprecipitation (ChIP) experiment showed that NANOG protein can bind to the promoter region of cyclinD1 and regulate cells cycle. Taken together, our findings may not only establish a molecular basis for the role of NANOG in modulating cell cycle progression of breast cancer cells but also suggest a potential target for the treatment of at least some subtypes of breast cancer.
Cancer letters 02/2012; 321(1):80-8. · 4.86 Impact Factor
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ABSTRACT: Targeting therapy is a promising strategy for enhancing the therapeutic potential of chemotherapeutic agents. In this study, we report the construction of a multifunctional drug delivery system, termed folic acid modified and TAT peptide conjugated PEGylated polymeric liposomes (FA-TATp-PLs), which is originally derived from octadecyl-quaternized lysine modified chitosan and cholesterol. Our data revealed that FA-TATp-PLs have a particle size of about 60 nm with a zeta potential of about 30 mV, a low burst release effect within the first day, a sustained release for the next 14 days in vitro as well as an instant cellular uptake by folate receptor-overexpressing KB human nasopharyngeal carcinoma cells. In vitro cytotoxicity of paclitaxel-loaded FA-TATp-PLs in KB cells was superior to that of Taxol(®). Furthermore, a comparable antitumor efficacy of paclitaxel-loaded FA-TATp-PLs and Taxol(®) was observed at the same doses in murine models bearing nasopharyngeal carcinoma. These results demonstrate that the paclitaxel formulation not only exhibits a higher antitumor activity but also significantly reduces the toxicity and improves the bioavailability as compared to that of free paclitaxel for the treatment of nasopharyngeal carcinoma. Taken together, our findings indicate that paclitaxel-loaded FA-TATp-PLs are a promising nano-sized drug formulation for future cancer therapy.
Journal of Drug Targeting 06/2011; 19(5):373-81. · 2.70 Impact Factor
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ABSTRACT: Folic acid and TAT peptide were conjugated on the octadecyl-quaternized, lysine-modified chitosan-cholesterol polymeric liposomes (FA-TATp-PLs) to investigate their potential feasibility for tumor-targeted drug delivery.
FA-TATp-PLs encapsulating paclitaxel or calcein were synthesized and characterized. Cellular uptake of PLs, FA-PLs, TATp-PLs and FA-TATp-PLs was studied by confocal laser scanning microscopy (CLSM) in folate receptor (FR)-positive KB nasopharyngeal epidermal carcinoma cells and FR-deficient A549 lung cancer cells. In vitro and in vivo antitumor activity of paclitaxel-loaded FA-TATp-PLs were also evaluated in KB and A549 cells as well as in a murine KB xenograft model.
Our data showed that 80% paclitaxel released from FA-TATp-PLs in 2 weeks. Different from other various PLs, CLSM analyses showed that FA-TATp-PLs had a significantly high efficient intracellular uptake in both KB and A549 cells. These data revealed the targeting effects of folate decoration, the transmembrane ability of TAT peptide as well as a synergistic interaction between them. In addition, paclitaxel-loaded FA-TATp-PLs exhibited a more superior antitumor effect in vitro and in vivo as compared to that with Taxol.
FA-TATp-PLs possessing both targeting effect and transmembrane ability may serve as a promising carrier for the intracellular delivery of therapeutic agents.
Pharmaceutical Research 09/2010; 27(9):1914-26. · 4.09 Impact Factor
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ABSTRACT: The mutation and reduction of mitochondrial DNA (mtDNA) have been extensively detected in human cancers. The effects of mitochondrial dysfunction are particularly important in breast cancer, because estrogen-mediated metabolites generate large quantities of local reactive oxygen species in the breast, which directly bind to mtDNA and facilitate neoplastic transformation. To further elucidate the molecular roles of mtDNA in breast cancer, we determined the oxidative status of a breast tumor cell line lacking mtDNA (T47D ρ) and analyzed its susceptibility after exposure to various anticancer drugs as well as different proapoptotic signals. Our data showed that T47D ρ cells generated significantly increased levels of lactate with concomitantly reduced oxygen consumption and ATP production compared with the wild-type (WT). The amount of reactive oxygen species generation in ρ cells was lowered to approximately 12% that of parental cells, as evidenced by the oxidation of redox-sensitive probes. Although mtDNA depletion did not affect the expression of superoxide dismutase or its activity, the activities of antioxidant enzymes, catalase and glutathione peroxidase, were significantly higher in ρ cells compared with WT cells. In addition, mtDNA-depleted cells displayed a decreased sensitivity and accumulation of chemotherapeutic drugs (doxorubicin, vincristine, and paclitaxel), potentially because of the upregulated expression of multidrug resistance 1 (MDR1) gene and its product P-glycoprotein. When compared with their WT counterparts, T47D ρ cells were also more resistant to apoptosis induced by varying concentrations of staurosporine and anti-Fas antibody. Altogether, our results indicate the importance of intact mtDNA for maintaining the proper intracellular oxidative status. These data provide evidence for a possible role of mtDNA content reduction in acquiring an apoptosis-resistant phenotype during breast tumor progression and might contribute to effective therapeutic strategies for this common malignancy.
European Journal of Cancer Prevention 08/2009; 18(6):445-57. · 2.13 Impact Factor
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ABSTRACT: Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations. The non-coding displacement (D)-loop, especially a mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310), has been recently identified as a frequent hotspot of mutations in human neoplasia, including breast cancer. To further explore the sequence variations of mitochondrial D-loop region in familial breast cancer and their possible associations with breast cancer risk, PCR-SSCP and direct DNA sequencing methods were used to detect the variants of the mtDNA D-Loop in 23 familial breast cancer patients as well as three high-risk cancer families. Compared to that in sporadic breast tumors (53.3%, 16/30) and healthy blood donors (6.7%, 2/30), we identified a total of 126 sequence alterations in 23/23 (100%) of familial breast cancer patients, including eight novel nucleotide variants. Among these changes, A to G at nt.263, T to C at nt.489, T to C at nt.310, TC insertion at nt.311, CA deletion at nt.522, and C to G at nt.527 were highly frequent ones. In addition, among three high-risk cancer families, we found that individuals affected with breast cancer harbored more mtDNA sequence variants in mtDNA D310 area than other affected family members. Together, our data indicate that sequence variants within the mtDNA D-Loop region are frequent events in Chinese familial breast cancer patients. Some of these nucleotide abnormalities, particularly those in D310 segment, might be involved in the breast carcinogenesis and could be included in a panel of molecular biomarkers for cancer susceptibility early-detection strategy.
Journal of Biomedical Science 08/2008; 15(4):535-43. · 2.01 Impact Factor
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ABSTRACT: The cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein-long form (c-FLIP(L)) is a key regulator of Fas signaling, although owing a dominant-negative homologue of caspase-8, the role of c-FLIP(L) remains controversial. In the present study, two pairs of small interfering RNA (siRNA) directed against c-FLIP(L) were used to assess the effect of c-FLIP(L) on Fas-mediated apoptosis of colon carcinoma in vitro. HT-29 cell line was selected for overexpression of c-FLIP(L) and Fas with RT-PCR and flow cytometry analyses. After electroporation, the mRNA level of c-FLIP(L) was significantly decreased (control siRNA versus c-FLIP(L) siRNA, 77.97+/-5.61% versus 26.22+/-3.79%) and the maximum interfering efficiency was around 66.49% using semi-quantitative RT-PCR analysis. Knockdown of c-FLIP(L) with the specific siRNA sensitized colon carcinoma cells to Fas-mediated apoptosis (control siRNA versus c-FLIP(L) siRNA, 5.68+/-2.11% versus 29.50+/-2.27%) using DNA content analysis and Annexin V-FITC analysis. In conclusion, our study indicated that c-FLIP(L) might be a suppressor of Fas-mediated apoptosis in Fas antigen expressing colon carcinoma and therefore a potential target for novel anticancer therapies.
Cell Biology International 04/2008; 32(3):329-36. · 1.48 Impact Factor
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ABSTRACT: Recent studies revealed high ectopic beta protein 1 (BP1) expression in breast cancer. Remarkably, up to 100% (18/18) of estrogen receptor (ER)-negative tumors and 89% (25/28) of tumors from African American women were BP1-positive. However, the role of BP1 in breast cancer development and its clinical significance still has not been well defined. In the present study, we analyzed the quantitative level of BP1 mRNA in breast carcinomas using real-time polymerase chain reaction and aimed to elucidate its association with tumor characteristics and patient prognosis. Our data showed that BP1 mRNA was expressed at significantly higher levels in tumors with lymph node metastasis, with a high histological grade, and in those that were of ER-negative status. Furthermore, overexpression of BP1 was significantly associated with poor outcome of patients harboring tumors with a high histological grade and negative ER. Using both in vitro and in vivo systems, we also showed that the transcript level of BP1 was positively correlated to the growth rate of breast tumor cells. Taken together, our results support the notion that BP1 might contribute to breast neoplastic transformation or tumor progression and suggest for the first time that BP1 mRNA level has potential as a prognostic predictor for breast cancer.
Cancer Science 02/2008; 99(1):173-8. · 3.33 Impact Factor
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ABSTRACT: Somatic mutations and large-scale depletion in mitochondrial DNA (mtDNA) have been extensively detected in various human cancers. However, it still remains unclear whether the alterations in mtDNA content are related to the clinicopathological parameters and patient prognosis in breast cancer. In the present study, we analyzed the copy number of mtDNA in 59 cases of invasive breast tumors and paired nontumorous tissues using quantitative real-time PCR. Our data showed that the level of mtDNA was significantly decreased in tumor tissues as compared to the adjacent nontumorous counterparts (P = 0.001). The reduced copy number in mtDNA was associated with an older onset age (>or=50 years old, P = 0.035) as well as a higher histological grade (P = 0.012). Survival analysis measured by the Kaplan-Meier curves and the log-rank test indicated that patients with reduced mtDNA content had significantly poorer disease-free survival (DFS, P = 0.0079) and overall survival (OS, P = 0.011) rate. In addition, tumors harboring mutations in displacement (D)-loop region, particularly at the polycytidine stretch (T/N ratio = 64.3 +/- 8.2%) or close to the replication origins of the heavy-strand (T/N ratio = 68.7 +/- 5.5%), had a significantly lower copy number of mtDNA than the ones without D-loop alterations. Together, our results suggested that reduced copy number of mtDNA may be involved in breast neoplastic transformation or progression and mtDNA content might be potentially used as a tool to predict prognosis. Somatic mutation in the D-loop region probably is one of key contributing factors leading to decreased mtDNA level in breast tumors.
International Union of Biochemistry and Molecular Biology Life 07/2007; 59(7):450-7. · 3.51 Impact Factor
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ABSTRACT: In order to investigate the role of mitochondrial DNA (mtDNA) in human breast cancer cell proliferation and apoptosis, a mtDNA-deficient cell line, T47D rho(0), was generated following a long-term exposure to ethidium bromide (EtBr). T47D rho(0) cells showed a marked decrease in mitochondrial membrane potential (DeltaPsi(m)). However, the apoptosis rate of T47D rho(0) cells was the same as that of their parental cells, suggesting that the change in DeltaPsi(m) was insufficient to induce cell death. Electromicroscopy revealed a profound alteration of mitochondrial morphology, which was consistent with the loss of mtDNA and the decrease in DeltaPsi(m). Disruption of mtDNA resulted in a slower proliferation rate in tissue culture and a reduction in anchorage-independent growth. An in vivo assay revealed a severe impairment of tumorigenicity in T47D rho(0) cells, indicating the biological relevance of in vitro studies. Taken together, our results suggest that the integrity of mtDNA plays a critical role in human breast cancer cell proliferation and tumorigenesis.
Toxicology Letters 04/2007; 170(1):83-93. · 3.23 Impact Factor
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ABSTRACT: Beta protein 1 (BP1) gene, a novel member of DLX homeobox gene family, is located in 17q21-22 region and overexpressed in both acute myeloid leukemia and acute T cell lymphocytic leukemia. However, the reports on the function of BP1 in solid tumors are rare. The study was designed to determine the expression of BP1 gene in breast cancer and to analyze its relationship with various clinicopathological factors.
With beta-actin gene as a reference, BP1 mRNA expression was detected in 82 breast cancer tissues and 12 near adjacent tissues and 10 far adjacent tissues using reverse transcription-polymerase chain reaction (RT-PCR).
The expression rates of BP1 in near and far adjacent tissues were 16.67% (2/12) and 0% (0/10), respectively; while the expression rate in breast cancer group was 64.63% (53/82). There were statistically significant differences among the three groups (P< 0.05). Overexpression of BP1 in breast cancer was correlated with histological grade (P< 0.05). Nevertheless, no correlation was found between BP1 expression and other clinicopathological factors, including tumor size, lymph nodal metastasis, family history, pathological type, menarcheal age, primiparous age, number of pregnancy, menopausal status, ER status and PR status (P >0.05).
BP1 gene is of upregulated expression in breast tumors and could be regarded as a new and vital biomarker in breast cancer research.
Ai zheng = Aizheng = Chinese journal of cancer 07/2004; 23(7):855-9.
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ABSTRACT: To investigate the risk factors of lung cancer in Tianjin and to provide evidence for further monitor there of.
A case-control study involving interviews with 193 new cases and 259 controls aged 30 - 76 years was carried out. Structured questionnaires were used to collect information on general condition, living environment, living style, disease and family history, etc. Logistic regression model univariate and multivariate analysis were used to pick out the significant lung cancer risk factors.
By monovariate analysis, risk factors such as smoking, passive smoking, drinking, history of malignancy in family and occupation were found. By multivariate analysis, smoking, passive smoking, higher body mass index (BMI) and average income and living space per capita ten years earlier were ascertained, their operations research (OR) values were 3.302, 1.193, 1.003, 1.067 and 0.913.
Smoking and passive smoking are independent risk factors of lung cancer. Monthly income per person and living space per person 10 years earlier are associated with elevated risk of lung cancer. Higher body mass index has protective effects on lung cancer risk.
Zhonghua zhong liu za zhi [Chinese journal of oncology] 12/2003; 25(6):575-80.
