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1.
We discussed the role of DNA topoisomerase I (topo I) inhibitor, which is now widely used in clinical practice, in cisplatin-resistant ovarian cancer. Our study showed the synergistic actions between cisplatin and 7-ethyl-10-hydroxycamptothecin (SN-38), an active metabolite of 7-ethyl-10-[4-(1-pyperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), in two cisplatin-resistant cancer cell lines, HeLa/CDDP and KFr cells, but not in each parent cell line, HeLa and KF cells. Furthermore, HeLa/CDDP cells had a collateral sensitivity to SN-38. The levels of topo I protein in the cisplatin-resistant cells did not differ from those of their parent cell lines and were unaffected by exposure to cisplatin. In contrast, topo I enzymatic activity was 2-4 fold higher in the cisplatin-resistant cell lines compared with their respective parent cell lines. A significant correlation between the sensitivity for SN-38 and topo I activity human clear cell carcinoma cell lines, which are known as intrinsically ciasplatin-resistant cancer, was observed. Next, we examined the relationship between topo I activity and sensitivity to second-line chemotherapy consisting of cisplatin and CPT-11. A total of 30 patients with ovarian cancer who had initially undergone chemotherapy consisting of cisplatin, doxorubicin, and cyclophosphamide (CAP) and exhibited measurable lesions were entered in the study. Tumor samples were obtained in the period between the initial and the second-line chemotherapy. Of those 30 patients, 18 responded to second-line chemotherapy and 12 did not. Topo I activity in tumor samples of responder was significantly greater than that of in nonresponders. In 8 cases whose samples could be obtained before and after CAP, topo I activity significantly increased after CAP therapy. Consequently, the combination therapy with cisplatin and CPT-11 may be effective for patients with cisplatin-resistant ovarian cancer. In addition, topo I enzymatic activity may be a predictor of the sensitivity for topo I inhibitor.  相似文献   

2.
W Xu  S Wang  Q Chen  Y Zhang  P Ni  X Wu  J Zhang  F Qiang  A Li  O D R?e  S Xu  M Wang  R Zhang  J Zhou 《Cell death & disease》2014,5(2):e1055
Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis-diamminedichloridoplatinum(II) (DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitin-proteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.  相似文献   

3.
Takano M  Kudo K  Goto T  Yamamoto K  Kita T  Kikuchi Y 《Human cell》2001,14(4):267-271
Cisplatin has played a key-role in the management of ovarian cancer patients. Since the mechanisms of cisplatin-resistance have been reported to be multifactorial, it is quite difficult to predict effectiveness of cisplatin-based chemotherapy. In the present study, we have screened abnormal chromosomal regions in cisplatin-resistant and paclitaxel-resistant human ovarian cancer cell lines using comparative genomic hybridization (CGH). Increased copy number at 6q21-25 and decreased copy number at 7q21-36 and 10q12-15 were observed in the cisplatin-resistant cell line. Increased copy number at 7q11.2-21 was observed in paclitaxel-resistant cell lines. Messenger RNA of MDR1 located on chromosomal region of 7q11.2-21 was overexpressed in the paclitaxel-resistant cell lines and recognized as a potential mechanism of acquired paclitaxel-resistance. In CGH analyses of 28 primary epithelial ovarian cancer patients, gains of 1q21-22 (p = 0.0183) and 13q12-14 (p = 0.0407) were observed in significantly high abundance in the cisplatin-resistant tumor group, compared with the cisplatin-sensitive tumor group. These genetic alterations were suggested to be potential indicators for drug resistance.  相似文献   

4.
Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival. In this study we hypothesized that methylation of key genes mediates cisplatin resistance. We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line. We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis. We then created a xenograft model with SCC-25/CP and determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control. To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients. Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles. When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile. The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro and in vivo models of HNSCC. Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain. Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.  相似文献   

5.
Multidrug resistance is a major obstacle to successful treatment of oral squamous cell carcinoma (OSCC). Lately, we found a novel human gene named tongue cancer chemotherapy resistance-associated protein1 (TCRP1) in the tongue cancer multi-drug resistance cell line (Tca8113/PYM) established by us. In this study, we focus on recombinant expression, purification, and biochemical characterization of TCRP1. After molecular cloning and purification of the gene encoding the 24-kDa protein, a mouse polyclonal antibody against TCRP1 was prepared, and the specialty of the antibody was confirmed by Western blot. The cell proliferation was evaluated by MTS assay and DNA damage was determined by comet assay, the results indicated that this protein especially mediated the cell's resistance to cisplatin; it was associated with its role of providing protection against DNA damage. We also found that TCRP1 expression was increased in cisplatin-resistant carcinoma cell lines (Tca/PYM and A549/DDP), but not in cisplatin-sensitive MDR cell lines (MCF-7/5-Fu), compared with their parental counterparts by Western blot analysis. Immunofluorescence and immunohistochemical analysis showed TCRP1 is mainly expression in cytoplasmic, the Mann-Whitney U test exhibited that TCRP1 positive patients predicted the worst sensitive with cisplatin of OSCC patients. All these findings suggest that TCRP1 is a novel cisplatin-resistant protein which is mainly localized in the cytoplasm and can mediate cisplatin resistance against DNA damage; the expression level of TCRP1 in patients with OSCC may be useful as an indicator of therapeutic efficacy of the sensitivity to cisplatin.  相似文献   

6.
Resistance to cisplatin-based chemotherapy is responsible for therapeutic failure of many common human cancers including cancer of head and neck (HNC). Mechanisms underlying cisplatin resistance remain unclear. In this study, we identified neurofilament light polypeptide (NEFL) as a novel hypermethylated gene associated with resistance to cisplatin-based chemotherapy in HNC. Analysis of 14 HNC cell lines revealed that downregulation of NEFL expression significantly correlated with increased resistance to cisplatin. Hypermethylation of NEFL promoter CpG islands was observed in cell lines as examined by bisulfite DNA sequencing and methylation-specific PCR (MSP) and tightly correlated with reduced NEFL mRNA and protein expression. Furthermore, in patient samples with HNC (n = 51) analyzed by quantitative MSP, NEFL promoter hypermethylation was associated with resistance to cisplatin-based chemotherapy [relative risk (RR), 3.045; 95% confidence interval (CI), 1.459-6.355; P = 0.007] and predicted diminished overall and disease-free survival for patients treated with cisplatin-based chemotherapy. Knockdown of NEFL by siRNA in the highly cisplatin-sensitive cell line PCI13 increased (P < 0.01) resistance to cisplatin. In cisplatin-resistant O11 and SCC25cp cells, restored expression of NEFL significantly increased sensitivity to the drug. Furthermore, NEFL physically associated with tuberous sclerosis complex 1 (TSC1), a known inhibitor of the mTOR pathway, and NEFL downregulation led to functional activation of mTOR pathway and consequentially conferred cisplatin resistance. This is the first study to show a role for NEFL in HNC chemoresistance. Our findings suggest that NEFL methylation is a novel mechanism for HNC chemoresistance and may represent a candidate biomarker predictive of chemotherapeutic response and survival in patients with HNC.  相似文献   

7.
Protein quantification in a complex protein mixture presents a daunting task in biochemical analysis. Antibody-based immunoassays are traditional methods for protein quantification. However, there are issues associated with accuracy and specificity in these assays, especially when the changes are small (e.g., <2-fold). With recent developments in mass spectrometry, monitoring a selected peptide, thus protein, in a complex biological sample has become possible. In this study, we demonstrate a simple mass spectrometry-based method for selective measurement of a moderately low abundant protein, superoxide dismutase 1 (SOD1), in cisplatin-sensitive and cisplatin-resistant human ovarian cancer cells. Selected-reaction-monitoring (SRM) technology was employed to specifically analyze the target peptides in a pair of human ovarian cancer cell lines: 2008/2008-C13*5.25 (cisplatin-sensitive/cisplatin-resistant, respectively). The observed 1.47-fold higher expression in the resistant cell line is consistent with findings by other approaches. This robust liquid chromatography/mass spectrometry (LC/MS) method provides a powerful tool for targeted proteomic verification and/or validation studies.  相似文献   

8.
Prolonged wild-type p53 protein accumulation and cisplatin resistance   总被引:2,自引:0,他引:2  
The major limitation for the chemotherapeutic use of DNA-damaging agent cisplatin is the development of resistance in initially responsive tumors. One of the main pathways regulating cell survival following DNA damage is the p53 pathway. In this study we compared the cisplatin-induced response of p53 protein and its downstream targets p21WAF-1 and Mdm2 in the cisplatin-sensitive ovarian carcinoma cell line A2780 and its cisplatin-resistant derivative CP70. A higher dose of cisplatin and a longer exposure time was required to achieve the same level of p53, p21WAF-1, and Mdm2 protein accumulation in the cisplatin-resistant CP70 cells versus cisplatin-sensitive A2780 cells. A significant difference between the two cell lines was observed in cisplatin-induced stabilization of p53 protein. The p53 half-life increased 31-fold in CP70 cells compared to only 6-fold in A2780 cells. In contrast, there was no difference in p21WAF-1 half-life between the two cell lines. These results demonstrate that in A2780 and CP70 cells resistance to cisplatin correlates with prolonged p53 protein stabilization and accumulation.  相似文献   

9.
10.
Although cisplatin is a very effective anticancer agent against several types of cancer including ovarian cancer, the mechanisms of acquired resistance are not fully understood. By chronically exposing cisplatin to ovarian cancer cell lines, we established two cisplatin-resistant cell lines OV433 and TOV112D. Our results indicate that the mechanisms underlying their cisplatin resistance are distinct. In OV433 cells, cisplatin resistance is associated with increased expression of mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP-1). By knocking down MKP-1 expression by siRNA or inhibiting MKP-1 expression by its pharmacological inhibitor triptolide, cisplatin-resistant OV433 cells became cisplatin-sensitive and subsequently increased cisplatin-induced apoptosis. In TOV112D cells, on the other hand, acquired cisplatin resistance is associated with increased levels of Bcl-2 protein. By inhibiting the activity of Bcl-2 protein with its pharmacological inhibitor gossypol or knocking down Bcl-2 expression by siRNA, cisplatin-resistant TOV112D cells became cisplatin-sensitive and subsequently increased cisplatin-induced apoptosis. Therefore, our data suggest that the mechanisms of acquired cisplatin resistance vary among ovarian cancer cells, which involve up-regulation of molecules associated with the cell survival pathways.  相似文献   

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