共查询到20条相似文献,搜索用时 46 毫秒
1.
Karagiannis P Singer J Hunt J Gan SK Rudman SM Mechtcheriakova D Knittelfelder R Daniels TR Hobson PS Beavil AJ Spicer J Nestle FO Penichet ML Gould HJ Jensen-Jarolim E Karagiannis SN 《Cancer immunology, immunotherapy : CII》2009,58(6):915-930
Trastuzumab (Herceptin), a humanized IgG1 antibody raised against the human epidermal growth factor receptor 2 (HER2/neu), is the main antibody in clinical use against breast cancer. Pre-clinical evidence and clinical studies indicate that trastuzumab employs several anti-tumour mechanisms that most likely contribute to enhanced survival of patients with HER2/neu-positive breast carcinomas. New strategies are aimed at improving antibody-based therapeutics like trastuzumab, e.g. by enhancing antibody-mediated effector function mechanisms. Based on our previous findings that a chimaeric ovarian tumour antigen-specific IgE antibody showed greater efficacy in tumour cell killing, compared to the corresponding IgG1 antibody, we have produced an IgE homologue of trastuzumab. Trastuzumab IgE was engineered with the same light- and heavy-chain variable-regions as trastuzumab, but with an epsilon in place of the gamma-1 heavy-chain constant region. We describe the physical characterisation and ligand binding properties of the trastuzumab IgE and elucidate its potential anti-tumour activities in functional assays. Both trastuzumab and trastuzumab IgE can activate monocytic cells to kill tumour cells, but they operate by different mechanisms: trastuzumab functions in antibody-dependent cell-mediated phagocytosis (ADCP), whereas trastuzumab IgE functions in antibody-dependent cell-mediated cytotoxicity (ADCC). Trastuzumab IgE, incubated with mast cells and HER2/neu-expressing tumour cells, triggers mast cell degranulation, recruiting against cancer cells a potent immune response, characteristic of allergic reactions. Finally, in viability assays both antibodies mediate comparable levels of tumour cell growth arrest. These functional characteristics of trastuzumab IgE, some distinct from those of trastuzumab, indicate its potential to complement or improve upon the existing clinical benefits of trastuzumab. 相似文献
2.
John Gordon Bruno 《In vitro cellular & developmental biology. Animal》2010,46(2):107-113
Nucleic acid aptamers are regarded as rivals for antibodies and as such are being investigated for their therapeutic potential.
In the present work, it is shown that two different high-affinity DNA aptamers developed previously by Ferreira et al. against
MUC1 antigen (designated MUC1-5TR-1 and MUC1-S1.3/S2.2) on MCF7 breast cancer cells can be linked to the first component of
complement (C1q) via a biotin–streptavidin system and induce significant killing of MCF7 cells in vitro. Cell viability was
assessed by Trypan blue uptake and absorbance at 590 nm of stained cells following buffer washes and lysis in 1% SDS. While
the killing effect is demonstrable versus various controls, dependent on aptamer dose, and reproducible, it appears to kill
maximally about half of treated MCF7 cells. Possible reasons for the marginal killing effect include antigenic shedding in
vitro and membrane-bound complement regulatory proteins (mCRPs) on the cell surface such as CD46, CD55, and CD59 which act
to inhibit complement-mediated lysis of cells. Future in vitro research could benefit from application of mCRP-specific aptamers
in combination with anti-MUC1 aptamers to overcome surface protective mechanisms while attacking the plasma membrane of MCF7
cells or other MUC1-expressing cancer cells. However, in vivo such a combination could have deleterious effects on normal
MUC1-expressing cells as well. 相似文献
3.
《生物化学与生物物理学报:疾病的分子基础》2023,1869(2):166618
Trastuzumab has an impressive level of efficacy as regards antineoplasticity, however it can cause serious cardiotoxic side effects manifested by impaired cardiac contractile function. Although several pharmacological interventions, including melatonin and metformin, have been reported to protect against various cardiovascular diseases, their potential roles in trastuzumab-induced cardiotoxicity remain elusive. We hypothesized that either melatonin or metformin co-treatment effectively attenuates trastuzumab-mediated cardiotoxicity through attenuating the impaired mitochondrial function and mitochondrial dynamics. Male Wistar rats were divided into control (normal saline, n = 8) and trastuzumab group (4 mg/kg/day for 7 days, n = 24). Rats in the trastuzumab group were subdivided into 3 interventional groups (n = 8/group), and normal saline, or melatonin (10 mg/kg/day), or metformin (250 mg/kg/day) were orally administered for 7 consecutive days. Cardiac parameters were determined, and biochemical investigations were carried out on blood and heart tissues. Trastuzumab induced left ventricular (LV) dysfunction by increasing oxidative stress, inflammation, and apoptosis. It also impaired cardiac mitochondrial function, dynamics, and autophagy. Treatment with either melatonin or metformin equally attenuated trastuzumab-induced cardiac injury, indicated by a marked reduction in inflammation, oxidative damage, cardiac mitochondrial injury, mitochondrial dynamic imbalance, autophagy dysregulation, and apoptosis, leading to improved LV function, as demonstrated by increased LV ejection fraction. Melatonin and metformin conferred equal levels of cardioprotection against trastuzumab-induced cardiotoxicity, which may provide novel and promising approaches for management of cardiotoxicity induced by trastuzumab. 相似文献
4.
Yunting Lin Ruitao Lu Jingmei Hou Grace Guoying Zhou Wenmin Fu 《Experimental cell research》2021,398(1):112382
Radiotherapy is a conventional approach for anti-cancer treatment, killing tumor cells through damaging cellular DNA. While increasing studies have demonstrated that tumors generated the tolerance to radiation and tumor immune system was found to be correlated to radiotherapy resistance. Therefore, it is critical to identify potential immune factors associated with the efficacy of radiotherapy. Here in this study, we evaluated the sensitivities of different tumor cells to radiation and determined HEp-2 cells as the radio-resistant tumor cells for further investigation. IFNgamma as a key regulator of host immune response showed the potential to sensitize tumors to ionizing radiation (IR). Besides, IFNgamma-induced CXC chemokine ligand 10 (CXCL10) was found to be necessary for effective IR-induced killing of cultured HEp-2 cells. Increased clonogenic survival was observed in CXCL10-depleted HEp-2 cells and CXCL10-KO cells. Additionally, the loss of CXCL10 in HEp-2 cells showed less progression of the G0/G1 phase to G2/M when exposed to IR (8 Gy). Local IR (20 Gy) to nude mice bearing HEp-2 tumors significantly reduced tumor burden, while fewer effects on tumor burden in mice carrying CXCL10-KO tumors were observed. We furtherly evaluated the possible roles the chemokine receptor CXCR3 plays in mediating the sensitivity of cultured HEp-2 cells to IR. Altered expression of CXCR3 in HEp-2 cells affected IR-induced killing of HEp-2 cells. Our data suggest the IFNgamma-activated CXCL10/CXCR3 axis may contribute to the effective radiation-induced killing of HEp-2 cells in vitro. 相似文献
5.
Adolfo Sánchez-Blanco Alberto G Rodríguez-Matellán Mariana Reis-Sobreiro Beatriz Sáenz-Narciso Juan Cabello William A Mohler 《Cell cycle (Georgetown, Tex.)》2014,13(21):3375-3389
Drugs capable of specifically recognizing and killing cancer cells while sparing healthy cells are of great interest in anti-cancer therapy. An example of such a drug is edelfosine, the prototype molecule of a family of synthetic lipids collectively known as antitumor lipids (ATLs). A better understanding of the selectivity and the mechanism of action of these compounds would lead to better anticancer treatments. Using Caenorhabditis elegans, we modeled key features of the ATL selectivity against cancer cells. Edelfosine induced a selective and direct killing action on C. elegans embryos, which was dependent on cholesterol, without affecting adult worms and larvae. Distinct ATLs ranked differently in their embryonic lethal effect with edelfosine > perifosine > erucylphosphocholine >> miltefosine. Following a biased screening of 57 C. elegans mutants we found that inactivation of components of the insulin/IGF-1 signaling pathway led to resistance against the ATL edelfosine in both C. elegans and human tumor cells. This paper shows that C. elegans can be used as a rapid platform to facilitate ATL research and to further understand the mechanism of action of edelfosine and other synthetic ATLs. 相似文献
6.
Anticancer peptides are polycationic amphiphiles capable of preferentially killing a wide spectrum of cancer cells relative to noncancerous cells. Their primary mode of action is an interaction with the cell membrane and subsequent activation of lytic effects; however, the exact mechanism responsible for this mode of action remains controversial. Using zeta potential analyses we demonstrate the interaction of a small anticancer peptide with membrane model systems and cancer cells. Electrostatic interactions have a pivotal role in the cell killing process, and in contrast to the antimicrobial peptides action cell death occurs without achieving full neutralization of the membrane charge. 相似文献
7.
May Kung Sutherland Changpu Yu Timothy S Lewis Jamie B Miyamoto Carol A Morris-Tilden Mechthild Jonas Jennifer Sutherland Albina Nesterova Hans-Peter Gerber Eric L Sievers Iqbal S Grewal Che-Leung Law 《MABS-AUSTIN》2009,1(5):481-490
Despite therapeutic advances, the long-term survival rates for acute myeloid leukemia (AML) are estimated to be 10% or less, pointing to the need for better treatment options. AML cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Thus, the in vitro and in vivo anti-tumor activities of lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, were investigated. In vitro assays were used to assess the ability of lintuzumab to mediate effector functions and to decrease the production of growth factors from AML cells. SCID mice models of disseminated AML with the multi-drug resistance (MDR)-negative HL60 and the MDR+, HEL9217 and TF1-α, cell lines were developed and applied to examine the in vivo antitumor activity. In vitro, lintuzumab significantly reduced the production of TNFα-induced pro-inflammatory cytokines and chemokines by AML cells. Lintuzumab promoted tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities against MDR− and MDR+ AML cell lines and primary AML patient samples. At doses from 3 to 30 mg/kg, lintuzumab significantly enhanced survival and reduced tumor burden in vivo, regardless of MDR status. Survival of the mice was dependent upon the activity of resident macrophages and neutrophils. The results suggest that lintuzumab may exert its therapeutic effects by modulating the cytokine milieu in the tumor microenvironment and through effector mediated cell killing. Given that lintuzumab induced meaningful responses in a phase 1 clinical trial, the preclinical antitumor activities defined in this study may underlie its observed therapeutic efficacy in AML patients. 相似文献
8.
The complement system is composed of soluble factors in plasma that enhance or “complement” immune-mediated killing through innate and adaptive mechanisms. Activation of complement causes recruitment of immune cells; opsonization of coated cells; and direct killing of affected cells through a membrane attack complex (MAC). Tumor cells up-regulate complement inhibitory factors – one of several strategies to evade the immune system. In many cases as the tumor progresses, dramatic increases in complement inhibitory factors are found on these cells. This review focuses on the classic complement pathway and the role of major complement inhibitory factors in cancer immune evasion as well as on how current protein engineering efforts are being employed to increase complement fixing or to reverse complement resistance leading to better therapeutic outcomes in oncology. Strategies discussed include engineering of antibodies to enhance complement fixation, antibodies that neutralize complement inhibitory proteins as well as engineered constructs that specifically target inhibition of the complement system. 相似文献
9.
Ramar Thangam Palani Gunasekaran Krishnasamy Kaveri Gnanaiah Sridevi Shenbagamoorthy Sundarraj Manickam Paulpandi Soundarapandian Kannan 《Process Biochemistry》2012,47(8):1243-1249
Animal venoms and toxins are potential bioresources that have been known to mankind as a therapeutic tool for more than a century through folk and traditional medicine. The purified “disintegrin protein” (64 kDa) from the venom of the Indian cobra snake (Naja naja) exhibited cytotoxic effects of various types of human cancer cell lines such as breast cancer (MCF-7), lung cancer (A549) and liver cancer (HepG2). In vitro cytotoxicity, DNA fragmentation, an apoptotic assay and a cell cycle analysis were performed to evaluate the anticancer activity of disintegrin against the above cell lines. The IC50 value of disintegrin was determined to be 2.5 ± 0.5 μg/mL, 3.5 ± 0.5 μg/mL, and 3 ± 0.5 μg/mL for the MCF-7, A549 and HepG2 cell lines respectively. Moreover, the increased distribution of G0/G1 and S phase led to decreased populations of cells in the G2/M phase of MCF-7, HepG2 and A549 cells. 相似文献
10.
Shen G Huang H Zhang A Zhao T Hu S Cheng L Liu J Xiao W Ling B Wu Q Song L Wei W 《Cancer immunology, immunotherapy : CII》2011,60(3):339-348
It was well studied that ErbB2 (HER2/p185(her2/neu)) overexpression in human malignant cancers correlates with poor prognosis and chemo-resistance. Although Trastuzumab (Herceptin) has been widely used in patients with ErbB2-overexpressing metastatic breast cancer, many patients either do not respond to Trastuzumab therapy or progress within 1 year of initiating Trastuzumab treatment. Previously, we reported a novel tumor-inhibitory antibody chA21, which recognized ErbB2 extracellular domain with an epitope distinct from other tumor-inhibitory anti-ErbB2 antibodies. Here, we report that chA21 combined with Paclitaxel or Trastuzumab significantly enhances the tumor-inhibition effects on ErbB2-overexpressing breast and ovarian cancer in xenograft mice. Moreover, the study reveals that the effects by chA21 to cause an enhanced inhibition on cancer cell proliferation and angiogenesis was highly associated with the intrinsic ability of chA21 to down-regulate ErbB2 receptor, inhibit downstream MAPK and PI3K-AKT signal transduction and activate natural killer cells. Our findings show that chA21 may represent a unique anti-ErbB2 antibody with potentials as therapeutic candidate alone or combination with other anti-ErbB2 reagents in cancer therapy. 相似文献
11.
12.
《MABS-AUSTIN》2013,5(5):481-490
Despite therapeutic advances, the long-term survival rates for acute myeloid leukemia (AML) are estimated to be 10% or less, pointing to the need for better treatment options. AML cells express the myeloid marker CD33, making it amenable to CD33-targeted therapy. Thus, the in vitro and in vivo anti-tumor activities of lintuzumab (SGN-33), a humanized monoclonal anti-CD33 antibody undergoing clinical evaluation, were investigated. In vitro assays were used to assess the ability of lintuzumab to mediate effector functions and to decrease the production of growth factors from AML cells. SCID mice models of disseminated AML with the multi-drug resistance (MDR)-negative HL60 and the MDR+, HEL9217 and TF1-α, cell lines were developed and applied to examine the in vivo antitumor activity. In vitro, lintuzumab significantly reduced the production of TNF-α-induced pro-inflammatory cytokines and chemokines by AML cells. Lintuzumab promoted tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) activities against MDR- and MDR+ AML cell lines and primary AML patient samples. At doses from 3 to 30 mg/kg, lintuzumab significantly enhanced survival and reduced tumor burden in vivo, regardless of MDR status. Survival of the mice was dependent upon the activity of resident macrophages and neutrophils. The results suggest that lintuzumab may exert its therapeutic effects by modulating the cytokine milieu in the tumor microenvironment and through effector mediated cell killing. Given that lintuzumab induced meaningful responses in a phase 1 clinical trial, the preclinical antitumor activities defined in this study may underlie its observed therapeutic efficacy in AML patients. 相似文献
13.
Kenneth T. Bogen 《人类与生态风险评估》2001,7(4):811-827
Ecologic U.S. county data suggest negative associations between residential radon exposure and lung cancer mortality (LCM) that are inconsistent with clearly positive ones revealed by individual data on underground miners. If this inconsistency is due to competing effects of induced cell killing vs. mutations in alpha-radiation exposed bronchial epithelium, then linear extrapolation from miner data may overestimate typical residential radon risks. To investigate the plausibility of this hypothesis, a biologically based “cytodynamic 2-stage” (CD2) cancer-risk model was fit to combined 1950 to 1954 age-specific person-year data on white females of age 40+ y in 2821 U.S. counties (~90% never-smokers), and on five cohorts of underground miners who never smoked, conditional on a realistic rate of alpha-radiation-induced killing of human lung cells, and on linear-no-threshold dose-response relations for both processes assumed to affect cancer risk (alpha-induced mutations and cell killing). As summarized previously (Bogen, K.T., Hum. Exper. Toxicol. 17:691-6, 1998), a good CD2 fit was obtained that involved biologically plausible parameter values and (without further optimization) also predicted inverse dose-rate effects observed in the nonsmoking miners. The present paper reports mathematical details of the CD2 model used, as well as additional modeling results involving the same combined data set. The results obtained are consistent with the hypotheses that low-level radon exposure is nonlinearly related to LCM risk, and that current linear no-threshold extrapolation models overestimate LCM risk associated with relatively low residential radon concentrations (<~200?Bq m?3). Testing this hypothesis would require more extensive individual-level epidemiological data relating residential radon exposures to LCM than are currently available. 相似文献
14.
Xingyuan Shi Xueping Luo Ting Chen Wei Guo Chanjin Liang Sihan Tang Jianming Mo 《Journal of cellular and molecular medicine》2021,25(5):2563-2571
Lung cancer is one of the major cause for high-death rate all over the world, due to increased metastasize and difficulties in diagnosis. Naringenin is naturally occurring flavonoid found in various fruits including tomatoes, citrus fruit and figs. Naringenin is known to have several therapeutic effects including anti-atherogenic, antimicrobial, anti-inflammatory, hepatoprotective, anticancer and anti-mutagenic. The present study was aimed to analyse the naringenin induced anti-proliferative and apoptosis effects in human lung cancer cells. Cells were treated with various concentrations of naringenin (10, 100 & 200 µmol/L) for 48 hours. Cisplatin (20 µg/mL) was used as positive control. Cell viability, apoptosis, migration and mRNA, and protein expression of caspase-3, matrixmetallo proteinases-2 (MMP-2) and MMP-9 were determined. The cell viability was 93.7 ± 7.5, 51.4 ± 4.4 and 32.1 ± 2.1 at 10, 100 and 200 µmol/L of naringenin respectively. Naringenin significantly increased apoptotic cells. The 100 and 200 µmol/L of naringenin significantly suppressed the larger wounds of cultured human cancer cells compared with the untreated lung cancer cells. Naringenin increased d the expression of caspase-3 and reduced the expression of MMP-2 and MMP-9. Taking all these data together, it is suggested that the naringenin was effective against human lung cancer proliferation, migration and metastasis. 相似文献
15.
Idit Dotan Philip J. R. Roche Miltiadis Paliouras Elliot J. Mitmaker Mark A. Trifiro 《PloS one》2016,11(2)
Background
The incidence of papillary thyroid carcinoma (PTC) has risen steadily over the past few decades as well as the recurrence rates. It has been proposed that targeted ablative physical therapy could be a therapeutic modality in thyroid cancer. Targeted bio-affinity functionalized multi-walled carbon nanotubes (BioNanofluid) act locally, to efficiently convert external light energy to heat thereby specifically killing cancer cells. This may represent a promising new cancer therapeutic modality, advancing beyond conventional laser ablation and other nanoparticle approaches.Methods
Thyroid Stimulating Hormone Receptor (TSHR) was selected as a target for PTC cells, due to its wide expression. Either TSHR antibodies or Thyrogen or purified TSH (Thyrotropin) were chemically conjugated to our functionalized Bionanofluid. A diode laser system (532 nm) was used to illuminate a PTC cell line for set exposure times. Cell death was assessed using Trypan Blue staining.Results
TSHR-targeted BioNanofluids were capable of selectively ablating BCPAP, a TSHR-positive PTC cell line, while not TSHR-null NSC-34 cells. We determined that a 2:1 BCPAP cell:α-TSHR-BioNanofluid conjugate ratio and a 30 second laser exposure killed approximately 60% of the BCPAP cells, while 65% and >70% of cells were ablated using Thyrotropin- and Thyrogen-BioNanofluid conjugates, respectively. Furthermore, minimal non-targeted killing was observed using selective controls.Conclusion
A BioNanofluid platform offering a potential therapeutic path for papillary thyroid cancer has been investigated, with our in vitro results suggesting the development of a potent and rapid method of selective cancer cell killing. Therefore, BioNanofluid treatment emphasizes the need for new technology to treat patients with local recurrence and metastatic disease who are currently undergoing either re-operative neck explorations, repeated administration of radioactive iodine and as a last resort external beam radiation or chemotherapy, with fewer side effects and improved quality of life. 相似文献16.
Valeria V. Costantino Sabrina F. Mansilla Juliana Speroni Celina Amaya Darío Cuello-Carrión Daniel R. Ciocca Horacio A. Priestap Manuel A. Barbieri Vanesa Gottifredi Luis A. Lopez 《PloS one》2013,8(1)
Sesquiterpene lactones (SLs) are plant-derived compounds that display anti-cancer effects. Some SLs derivatives have a marked killing effect on cancer cells and have therefore reached clinical trials. Little is known regarding the mechanism of action of SLs. We studied the responses of human cancer cells exposed to various concentrations of dehydroleucodine (DhL), a SL of the guaianolide group isolated and purified from Artemisia douglasiana (Besser), a medicinal herb that is commonly used in Argentina. We demonstrate for the first time that treatment of cancer cells with DhL, promotes the accumulation of DNA damage markers such as phosphorylation of ATM and focal organization of γH2AX and 53BP1. This accumulation triggers cell senescence or apoptosis depending on the concentration of the DhL delivered to cells. Transient DhL treatment also induces marked accumulation of senescent cells. Our findings help elucidate the mechanism whereby DhL triggers cell cycle arrest and cell death and provide a basis for further exploration of the effects of DhL in in vivo cancer treatment models. 相似文献
17.
Hiranmoy Das Zhihui Wang M. Khalid Khan Niazi Reeva Aggarwal Jingwei Lu Suman Kanji Manjusri Das Matthew Joseph Metin Gurcan Vittorio Cristini 《PloS one》2013,8(4)
Molecular-focused cancer therapies, e.g., molecularly targeted therapy and immunotherapy, so far demonstrate only limited efficacy in cancer patients. We hypothesize that underestimating the role of biophysical factors that impact the delivery of drugs or cytotoxic cells to the target sites (for associated preferential cytotoxicity or cell signaling modulation) may be responsible for the poor clinical outcome. Therefore, instead of focusing exclusively on the investigation of molecular mechanisms in cancer cells, convection-diffusion of cytotoxic molecules and migration of cancer-killing cells within tumor tissue should be taken into account to improve therapeutic effectiveness. To test this hypothesis, we have developed a mathematical model of the interstitial diffusion and uptake of small cytotoxic molecules secreted by T-cells, which is capable of predicting breast cancer growth inhibition as measured both in vitro and in vivo. Our analysis shows that diffusion barriers of cytotoxic molecules conspire with γδ T-cell scarcity in tissue to limit the inhibitory effects of γδ T-cells on cancer cells. This may increase the necessary ratios of γδ T-cells to cancer cells within tissue to unrealistic values for having an intended therapeutic effect, and decrease the effectiveness of the immunotherapeutic treatment. 相似文献
18.
The structure, and assumed parameter values, of a recent dynamic population model for tsetse (Diptera: Glossinidae) render
it unable to fit published data on tsetse control programs using odor-baited targets, insecticide-treated cattle and the sterile
insect technique (SIT). The underlying problem is a mismatch between the small size of the mapped cells (1 ha) and the long
time-step, which allows flies to move only once every 5 days, and then only to an adjacent cell. Assumed rates of tsetse dispersal
and killing by odor-baited targets are consequently at least an order of magnitude lower than observed in the field. Suggestions
that Glossina pallidipes could be eradicated more rapidly with SIT, than using hundreds of targets per km2, is contradicted both by the field data and by three other independent modeling studies. 相似文献
19.
Wei Tan Wei Zhou Hong-gang Yu He-Sheng Luo Lei Shen 《Biochemical and biophysical research communications》2013,430(1):250-255
DNA methyltransferase (DNMT) inhibitor zebularine has been reported to potentiate the anti-tumor effect by reactivating the expression of tumor suppressor genes and apoptosis-related genes in various malignant cells. However, the apoptotic signaling pathway in gastric cancer cells induced by zebularine is not well understood. In the study, the effects of zebularine on the growth and apoptosis of gastric cancer cells were investigated by MTT assay, Hoechst assay, Western blot analysis, flow cytometric analysis of annexin V-FITC/PI staining, and TUNEL assay. Zebularine was an effective inhibitor of human gastric cancer cells proliferation in vitro and in vivo. The effects were dose dependent. A zebularine concentration of 50 μM accounted for the inhibition of cell proliferation of 67% at 48 h. The treatment with zebularine upregulated Bax, and decreased Bcl-2 protein. Caspase-3 was activated, suggesting that the apoptosis is mediated by mitochondrial pathways. Moreover, zebularine injection successfully inhibited the tumor growth via apoptosis induction which was demonstrated by TUNEL assay in xenograft tumor mouse model. These results demonstrated that zebularine induced apoptosis in gastric cancer cells via mitochondrial pathways, and zebularine might become a therapeutic approach for the treatment of gastric cancer. 相似文献
20.
Folate receptors are targets of various strategies aimed at efficient delivery of anti-cancer drugs. Folate receptors also play a role in the uptake of antifolate drugs which are used for therapeutic intervention in leukemia. Therefore, it is important to identify compounds which regulate expression of folate receptors in leukemic cells. The present study examined if curcumin could modulate the uptake and cytotoxicity of the antifolate drug methotrexate, in KG-1 leukemic cells. This is the first report to show that curcumin (10–50 μM) causes a significant, dose-dependent, 2–3 fold increase in uptake of radiolabelled folic acid and methotrexate into KG-1 cells both at 24 h and 48 h of treatment. Interestingly, pre-treatment of KG-1 leukemic cells with curcumin (10 μM and 25 μM) also caused a statistically significant enhancement in the cytotoxicity of methotrexate. We performed Real Time Quantitative RT-PCR to confirm the upregulation of FRβ mRNA in curcumin treated cells. Immunocytochemistry and Western blotting showed that curcumin caused increased expression of folate receptor βin KG-1 cells. Our data show that the mechanism of curcumin action involves up-regulation of folate receptor β mRNA and protein in KG-1 cells. Therefore, combination of non-toxic concentrations of curcumin and methotrexate, may be a viable strategy for therapeutic intervention for leukemias using a folate receptor-targeted drug delivery system. 相似文献