Chemoresistance-related Proteins Research Articles

Vismodegib Potentiates Marine Antimicrobial Peptide Tilapia Piscidin 4-Induced Cytotoxicity in Human Non-Small Cell Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is a common cancer with several accepted treatments, such as chemotherapy, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, and immune checkpoint inhibitors. Nevertheless, NSCLC cells often become insensitive to these treatments, and therapeutic resistance is a major reason NSCLC still has a high mortality rate. The induction of therapeutic resistance in NSCLC often involves hedgehog, and suppression of hedgehog can increase NSCLC cell sensitivity to several conventional therapies. In our previous work, we demonstrated that the marine antimicrobial peptide tilapia piscidin 4 (TP4) exhibits potent anti-NSCLC activity in both EGFR-WT and EGFR-mutant NSCLC cells. Here, we sought to further explore whether hedgehog might influence the sensitivity of NSCLC cells to TP4. Our results showed that hedgehog was activated by TP4 in both WT and EGFR-mutant NSCLC cells and that pharmacological inhibition of hedgehog by vismodegib, a Food and Drug Administration-approved hedgehog inhibitor, potentiated TP4-induced cytotoxicity. Mechanistically, vismodegib acted by enhancing TP4-mediated increases in mitochondrial membrane potential and intracellular reactive oxygen species (ROS). MitoTempo, a specific mitochondrial ROS scavenger, abolished vismodegib/TP4 cytotoxicity. The combination of vismodegib with TP4 also reduced the levels of the antioxidant proteins catalase and superoxide dismutase, and it diminished the levels of chemoresistance-related proteins, Bcl-2 and p21. Thus, we conclude that hedgehog regulates the cytotoxic sensitivity of NSCLC cells to TP4 by protecting against mitochondrial dysfunction and suppressing oxidative stress. These findings suggest that combined treatment of vismodegib and TP4 may be a promising therapeutic strategy for NSCLC.

Impacts of hyperthermic chemotherapeutic agent on cytotoxicity, chemoresistance-related proteins and PD-L1 expression in human gastric cancer cells

Objective: Gastric cancer with peritoneal metastasis is considered to be final stage gastric cancer. One current treatment approach for this condition is combined cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the therapeutic mechanisms of HIPEC remain largely undescribed. Method: In order to assess the cellular effects of HIPEC in vitro, we treated AGS human gastric adenocarcinoma cells with or without 5-fluorouracil (5-Fu) at 37 °C or at 43 °C (hyperthermic temperature) for 1 h followed by incubation at 37 °C for 23 h. The impacts of hyperthermia/5-Fu on apoptosis, cell survival signals, oxidative stress, chemoresistance-related proteins and programmed death-ligand 1 (PD-L1) expression were measured. Results: Our results showed that hyperthermia potentiates 5-Fu-mediated cytotoxicity in AGS cells. Furthermore, the combination of 5-Fu and hyperthermia reduces levels of both phosphorylated STAT3 and STAT3, while increasing the levels of phosphorylated Akt and ERK. In addition, 5-Fu/hyperthermia enhances reactive oxygen species and suppresses superoxide dismutase 1. Chemoresistance-related proteins, such as multidrug resistance 1 and thymidylate synthase, are also suppressed by 5-Fu/hyperthermia. Interestingly, hyperthermia enhances 5-Fu-mediated induction of glycosylated PD-L1, but 5-Fu-mediated upregulation of PD-L1 surface expression is prevented by hyperthermia. Conclusion: Taken together, our findings provide insights that may aid in the development of novel therapeutic strategies and enhanced therapeutic efficacy of HIPEC.

HOTAIR mediates cisplatin resistance in nasopharyngeal carcinoma by regulating miR-106a-5p/SOX4 axis

ABSTRACT This study explored the function and mechanisms of HOX transcript antisense RNA (HOTAIR) in the drug resistance of nasopharyngeal carcinoma (NPC). Quantitative PCR, Western blotting, MTT assay, flow cytometry, Transwell assay, and luciferase assay were performed. HOTAIR expression levels were upregulated in cisplatin (DDP)-resistant NPC tissues and cells. Knockdown of HOTAIR in DDP-resistant NPC cells increased cell sensitivity of DDP, as well as decreased cell viability, expression of chemoresistance-related proteins, migration and invasion, increased cell apoptosis. In addition, downregulation of microRNA 106a-5p (miR-106a-5p) expression and upregulation of SRY-box transcription factor 4 (SOX4) expression were observed in DDP-resistant NPC tissues and cells. MiR-106a-5p targets HOTAIR and SOX4; thus, silencing of HOTAIR significantly increased miR-106a-5p expression. The overexpression of miR-106a-5p significantly reversed the increase in SOX4 expression induced by HOTAIR lentivirus (Lv-HOTAIR). Knockdown of SOX4 reduced the drug resistance of DDP caused by the silencing of miR-106a-5p expression. In summary, HOTAIR enhanced DDP resistance in NPC cells by regulating the miR-106a-5p/SOX4 axis.

Quantitative phosphoproteomic analysis reveals chemoresistance-related proteins and signaling pathways induced by rhIL-6 in human osteosarcoma cells

BackgroundIL-6 plays a pivotal role in resistance to chemotherapeutics, including lobaplatin. However, the underlying mechanisms are still unclear. This study was to investigate the changes in phosphoproteins and their related signaling pathways in the process of IL-6-induced chemoresistance to lobaplain in osteosarcoma cells.MethodsWe performed a quantitative phosphoproteomic analysis of the response of SaOS-2 osteosarcoma cells to recombinant human IL-6 (rhIL-6) intervention prior to lobaplatin treatment. The cells were divided into the control group (Con), the lobaplatin group (Lob), and the rhIL-6-and-lobaplatin group (IL-6). Three biological replicates of each group were included. The differentially expressed phosphoproteins were subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Netphos 3.1 was used for the prediction of kinases, and STRING was used for the visualization of protein–protein interactions. The conserved motifs surrounding the phosphorylated residues were analyzed using the motif-x algorithm. Western blot analysis was performed to verify the differential expression of p-FLNC, its predicted kinase and the related signaling pathway. The results of the bioinformatic analysis were validated by immunohistochemical staining of clinical specimens.ResultsIn total, 3373 proteins and 12,183 peptides, including 3232 phosphorylated proteins and 11,358 phosphorylated peptides, were identified and quantified. Twenty-three significantly differentially expressed phosphoproteins were identified in the comparison between the IL-6 and Lob groups, and p-FLNC ranked second among these phosphoproteins. GO and KEGG analyses revealed the pivotal role of mitogen-activated protein kinase signaling in drug resistance induced by rhIL-6. Four motifs, namely, -SPxxK-, -RxxSP-, -SP-, and -SPK-, demonstrated higher expression in the IL-6 group than in the Lob group. The western blot analysis results verified the higher expression of p-FLNC, AKT1, and p-ERK and the lower expression of p-JNK in the IL-6 group than in the Con and Lob groups. The immunohistochemical staining results showed that p-FLNC, AKT1 and p-ERK1/2 were highly expressed in platinum-resistant clinical specimens but weakly expressed in platinum-sensitive specimens, and platinum-resistant osteosarcoma specimens demonstrated weak expression of p-JNK.ConclusionsThis phosphoproteomic study is the first to reveal the signature associated with rhIL-6 intervention before lobaplatin treatment in human osteosarcoma cells. p-FLNC, AKT1, and MAPK signaling contributes to resistance to lobaplatin in osteosarcoma SaOS-2 cells and may represent molecular targets to overcome osteosarcoma chemoresistance.

ID4 Promotes Breast Cancer Chemotherapy Resistance via CBF1-MRP1 Pathway.

Chemo-resistance is considered a key problem in triple negative breast cancer (TNBC) chemotherapy and as such, an urgent need exists to identify its exact mechanisms. Inhibitor of DNA binding factor 4 (ID4) was reported to play diverse roles in different breast cancer molecular phenotypes. In addition, ID4 was associated with mammary carcinoma drug resistance however its functions and contributions remain insufficiently defined. The expression of ID4 in MCF-7, MCF-7/Adr and MDA-MB-231 breast cancer cell lines and patients' tissues were detected by RT-PCR, western blot and immunohistochemistry. Furthermore, TCGA database was applied to confirm these results. Edu and CCK8 assay were performed to detect the proliferation and drug resistance in breast cancer cell lines. Transwell and scratch migration assay were used to detected metastasis. Western blot, TCGA database, Immunoprecipitation (IP), Chromatin Immunoprecipitation (ChIP) and Luciferase reporter assay were used to investigate the tumor promotion mechanisms of ID4. In this study, we report that the expression levels of ID4 appeared to correlate with breast cancers subtype differentiation biomarkers (including ER, PR) and chemo-resistance related proteins (including MRP1, ABCG2, P-gp). Down-regulation of ID4 in MCF-7/Adr and MDA-MB-231 breast cancer cell lines significantly suppressed cell proliferation and invasion, however enhanced Adriamycin sensitivity. We further demonstrated that the oncogenic and chemo-resistant effects of ID4 could be mediated by binding to CBF1 promoter region though combination with MyoD1, and then the downstream target MRP1 could be activated. We reveal for the first time that ID4 performs its function via a CBF1-MRP1 signaling axis, and this finding provides a novel perspective to find potential therapeutic targets for breast cancer chemotherapy.

The LQB-223 Compound Modulates Antiapoptotic Proteins and Impairs Breast Cancer Cell Growth and Migration.

Drug resistance represents a major issue in treating breast cancer, despite the identification of novel therapeutic strategies, biomarkers, and subgroups. We have previously identified the LQB-223, 11a-N-Tosyl-5-deoxi-pterocarpan, as a promising compound in sensitizing doxorubicin-resistant breast cancer cells, with little toxicity to non-neoplastic cells. Here, we investigated the mechanisms underlying LQB-223 antitumor effects in 2D and 3D models of breast cancer. MCF-7 and MDA-MB-231 cells had migration and motility profile assessed by wound-healing and phagokinetic track motility assays, respectively. Cytotoxicity in 3D conformation was evaluated by measuring spheroid size and performing acid phosphatase and gelatin migration assays. Protein expression was analyzed by immunoblotting. Our results show that LQB-223, but not doxorubicin treatment, suppressed the migratory and motility capacity of breast cancer cells. In 3D conformation, LQB-223 remarkably decreased cell viability, as well as reduced 3D culture size and migration. Mechanistically, LQB-223-mediated anticancer effects involved decreased proteins levels of XIAP, c-IAP1, and Mcl-1 chemoresistance-related proteins, but not survivin. Survivin knockdown partially potentiated LQB-223-induced cytotoxicity. Additionally, cell treatment with LQB-223 resulted in changes in the mRNA levels of epithelial-mesenchymal transition markers, suggesting that it might modulate cell plasticity. Our data demonstrate that LQB-223 impairs 3D culture growth and migration in 2D and 3D models of breast cancer exhibiting different phenotypes.

Ependymomas overexpress chemoresistance and DNA repair-related proteins.

BackgroundAfter surgery and radiation, treatment options for ependymoma are few making recurrence a challenging issue. Specifically, the efficacy of chemotherapy at recurrence is limited. We performed molecular profiling on a cohort of ependymoma cases in order to uncover therapeutic targets and to elucidate the molecular mechanisms contributing to treatment resistance.ResultsThis ependymoma cohort showed minimal alterations in gene amplifications and mutations but had high expression rates of DNA synthesis and repair enzymes such as RRM1 (47%), ERCC1 (48%), TOPO1 (62%) and class III β-tublin (TUBB3) (57%), which are also all associated with chemoresistance. This cohort also had high expression rates of transporter proteins that mediate multi-drug resistance including BCRP (71%) and MRP1 (43%). Subgroup analyses showed that cranial ependymomas expressed the DNA synthesis enzyme TS significantly more frequently than spinal lesions did (57% versus 15%; p = 0.0328) and that increased TS expression was correlated with increased tumor grade (p = 0.0009). High-grade lesions were also significantly associated with elevated expression of TOP2A (p = 0.0092) and TUBB3 (p = 0.0157).Materials and MethodsWe reviewed the characteristics of 41 ependymomas (21 cranial, 20 spinal; 8 grade I, 11 grade II, 22 grade III) that underwent multiplatform profiling with immunohistochemistry, next-generation sequencing, and in situ hybridization.ConclusionsEpendymomas are enriched with proteins involved in chemoresistance and in DNA synthesis and repair, which is consistent with the meager clinical effectiveness of conventional systemic therapy in ependymoma. Adjuvant therapies that combine conventional chemotherapy with the inhibition of chemoresistance-related proteins may represent a novel treatment paradigm for this difficult disease.

The molecular mechanisms of chemoresistance in cancers.

Overcoming intrinsic and acquired drug resistance is a major challenge in treating cancer patients because chemoresistance causes recurrence, cancer dissemination and death. This review summarizes numerous molecular aspects of multi-resistance, including transporter pumps, oncogenes (EGFR, PI3K/Akt, Erk and NF-κB), tumor suppressor gene (p53), mitochondrial alteration, DNA repair, autophagy, epithelial-mesenchymal transition (EMT), cancer stemness, and exosome. The chemoresistance-related proteins are localized to extracellular ligand, membrane receptor, cytosolic signal messenger, and nuclear transcription factors for various events, including proliferation, apoptosis, EMT, autophagy and exosome. Their cross-talk frequently appears, such as the regulatory effects of EGFR-Akt-NF-κB signal pathway on the transcription of Bcl-2, Bcl-xL and survivin or EMT-related stemness. It is essential for the realization of the target, individualized and combine therapy to clarify these molecular mechanisms, explore the therapy target, screen chemosensitive population, and determine the efficacy of chemoreagents by cell culture and orthotopic model.

Sensitization to docetaxel in prostate cancer cells by green tea and quercetin

Chemotherapy with docetaxel (Doc) is a standard treatment for metastatic and castration-resistant prostate cancer. However, chemoresistance and side effects of Doc limit its clinical success. We investigated whether natural products green tea (GT) and quercetin (Q), a flavonoid from apples and onions, will enhance the efficacy of Doc in androgen-independent (AI) prostate cancer cells. Two cell lines including LAPC-4-AI and PC-3 were treated in vitro with 40 μM of (−)-epigallocatechin gallate (EGCG), 5 μM of Q, 2 or 5 nM of Doc alone or in combination. The mixture of EGCG+Q+Doc increased the antiproliferative effect by threefold in LAPC-4-AI cells and eightfold in PC-3 cells compared to Doc alone. EGCG, Q and Doc in combination significantly enhanced cell cycle arrest at G2/M phase and increased apoptosis in both LAPC-4-AI and PC-3 cells compared to Doc alone. The mixture increased the inhibition of PI3K/Akt and the signal transducer and activator of transcription (Stat) 3 signaling pathways compared to Doc alone, and decreased the protein expression of multidrug resistance-related protein. In addition, the combination with EGCG and Q increased the inhibition of tumor cell invasion and colony formation in both LAPC-4-AI and PC-3 cells compared to Doc alone, and decreased the percentage of CD44+/CD24− stem-like LAPC-4-AI cells. In summary, GT and Q enhanced the therapeutic effect of Doc in castration-resistant prostate cancer cells through multiple mechanisms including the down-regulation of chemoresistance-related proteins. This study provides a novel therapeutic modality to enhance the efficacy of Doc in a nontoxic manner.

Protein profiling predicts the response to anthracycline and taxanes based neo-adjuvant chemotherapy in breast cancer

Neo-adjuvant chemotherapy for breast cancer substantially benefits patients who achieve pathological response. However, clinical or pathological response information can only be obtained a period of time after chemotherapy. The identification of novel bio-markers or the application of new technique that can be used to predict treatment response before chemotherapy would allow therapy to be tailored on an individual patient basis. The purpose of this study is to identify the chemo-sensitivity and chemo-resistance related proteins using antibody microarray profiling, and to develop a multi-protein predictive model for breast cancer. Total protein was extracted from core needle biopsy samples obtained from 15 patients before treatment with neo-adjuvant TA (combination of taxanes and anthracycline) chemotherapy. Protein profiling was analyzed by antibody microarray. 10 patients were used as training set to develop the predictive model using the software PAM(prediction analysis of microarray). Another 5 patients were used as a validation set to test the model. In cross-validation, the molecular predictive model showed an accuracy of 90%, in independent validation, the model classified the cases with an accuracy of 80%. In conclusion, the proteomic predictive model has the potential to predict pathological response to neo-adjuvant TA chemotherapy.

A long-time survivor of alpha-fetoprotein-producing gastric cancer successfully treated by fluoropyrimidine-based chemotherapy: a case study.

A 67-year-old male with advanced gastric cancer and lymph node metastasis as well as a tumor embolus in the portal vein was treated by S-1/cisplatin therapy. The serum alpha-fetoprotein levels were elevated to 836ng/ml at the first visit. After one course of chemotherapy, the patient showed stable disease; the serum level of alpha-fetoprotein also decreased to 626ng/ml after a transient increase, and therefore reduction surgery was performed. A total gastrectomy with a distal pancreatectomy, splenectomy, and regional lymph node dissection was performed. The resected specimen was diagnosed to be alpha-fetoprotein-producing gastric cancer. There were no metastatic foci in the resected lymph nodes, presumably due to the preoperative chemotherapy. S-1/cisplatin therapy was continued after the operation to treat the remaining tumor embolus in the portal vein. After one course of this therapy, the tumor embolus disappeared. However, a lymph node measuring 1.5cm in diameter appeared in the hepatoduodenal ligament. Therefore, the chemotherapy was changed to paclitaxel monotherapy. After 2 courses of paclitaxel monotherapy, the lymph node swelled, and thus 5'-deoxy-5-fluorouridine was added to the paclitaxel regimen. After 5 courses of this regimen, the lymph node swelling disappeared without any other new lesions and a total of 21 courses were performed. The patient remained stable for over 8years without recurrence. The expression of chemoresistance-related proteins was retrospectively analyzed by immunohistochemistry to evaluate the chemoresistance. The ortate phosphoribosyltransferase expression was strongly positive, and the good outcome in this case may have been associated with this result.

Expression of chemoresistance-related proteins in α-fetoprotein-producing adenocarcinoma of the digestive organs

alpha-fetoprotein-producing adenocarcinoma of the digestive organs (APAD) is known to show a poor prognosis. To clarify the characteristics of chemoresistance in APAD, three proteins of fluoropyrimidine chemotherapy association [dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and thymidylate synthase (TS)] and one protein of cisplatin association [metallothionein (MT)] were immunohistochemically evaluated. Tissue samples were taken from 12 AFP-positive gastric cancers and 94 AFP-negative gastric cancers. Four AFP-positive cancer xenografts (one colonic, two pancreatic, and one biliary tract) and 17 AFP-negative cancer xenografts were also examined. In gastric cancers, high expression of TP was observed in 30% of AFP-negative tumors but in none of AFP-positive tumors (p=0.03). High expression of MT was found in 30% of AFP-negative tumors but in only one of the AFP-positive tumors. The TP-low and MT-low phenotype was noted in 92% of AFP-positive tumors and in 46% of AFP-negative tumors (p=0.004). None of the AFP-positive cancer xenografts revealed high TP expression and only one showed high MT expression. In the cellular level, TP and MT were scarcely co-expressed with AFP in either gastric cancer or xenograft series, using double immunostaining and serial sectioning techniques. There were no significant differences in the expression of DPD and TS between AFP-positive group and -negative group. However, DPD was frequently co-expressed with AFP in poorly differentiated medullary areas of the AFP-positive gastric cancers. The data presented herein suggest that APAD should be sensitive to cisplatin, but resistant to capecitabine and 5'-deoxyfluorouridine, fluoropyrimidines which are converted to 5-fluorouracil by TP. S-1, a fluoropyrimidine containing a strong DPD inhibitor, may be effective for AFP-positive gastric cancers with poorly differentiated medullary growth pattern.

Multichimiorésistance du mélanome uvéal

In spite of important progress in the local treatment of uveal melanoma, the most frequent primitive intraocular tumor, 15%-30% of patients still die because of tumor metastasis. This tumor is characterized by constitutive chemoresistance, thwarting any attempt to control it using the usual chemotherapy protocols. The chemoresistance of uveal melanoma is mainly due to the typical multidrug resistance phenotype (MDR), which is linked to overexpression of membrane proteins that actively extrude anticancer drugs from the cell. Typical MDR is particularly complex in this tumor since several chemoresistance-related proteins are simultaneously produced. The negative prognostic significance of the overexpression of P-glycoprotein, the main representative among the typical MDR-related proteins, was shown in uveal melanoma. The atypical MDR phenotype, which refers to other chemoresistance mechanisms such as resistance to apoptosis also contributes to the chemoresistance of uveal melanoma. Thanks to the recent progress in molecular biology, the chemosensitization strategies of gene therapy approaches, which aim at weakening the pathological activity of MDR genes in cancer cells, are currently on the rise. This approach will disrupt current therapeutic strategies and necessarily improve and standardize the methods used to characterize the chemoresistance profile of this cancer. Indeed, we will have to know the genes to be targeted for each melanoma in order to induce cell chemosensitivity.

Fractionated Irradiation Leads to Restoration of Drug Sensitivity in MDR Cells that Correlates with Down-regulation of P-gp and DNA-Dependent Protein Kinase Activity

We showed that the drug sensitivity of multidrug-resistant (MDR) cells could be enhanced by fractionated irradiation. The molecular changes associated with fractionated radiation-induced chemosensitization were characterized. Irradiated cells of the multidrug-resistant CEM/MDR sublines (CEM/MDR/IR1, 2 and 3) showed a loss of P-glycoprotein (P-gp) and concurrent reduction of Ku DNA binding and DNA-PK activities with decreased level of Ku70/80 and increased level of DNA-PKcs, and these changes were followed by an increased susceptibility to anticancer drugs. These irradiated MDR cells also exhibited the reduction of other chemoresistance-related proteins, including BCL2, NF-kappaB, EGFR, MDM2 and Ku70/80, and the suppression of HIF-1alpha expression induced by hypoxia. In contrast, fractionated irradiation increased the levels of these proteins and induced drug resistance in the parental drug-sensitive CEM cells. These results suggest that the chemoresistance-related proteins are differentially modulated in drug-sensitive and MDR cells by fractionated irradiation, and the optimized treatment with fractionated radiation could lead to new chemoradiotherapeutic strategies to treat multidrug-resistant tumors.

Multivariate analysis for prognostic significance of histologic subtype, GST-pi, MDR-1, and p53 in stages II-IV ovarian cancer

It has been suggested that histologic subtype of ovarian cancer is a factor that determines the chemoresponsiveness of tumor. In this study, we wanted to clarify the prognostic significance of histologic subtype and its correlation to expression of chemoresistance-related proteins (CRPs) in ovarian cancer. A total of 93 stage II-IV ovarian cancers, where the proportion of serous, endometrioid, mucinous, and clear cell subtype was 61.3%, 14.0%, 7.5%, and 17.2%, respectively, were investigated for glutathione S-transferase-pi (GST-pi), MDR (multidrug resistance)-1, and p53 expression using immunohistochemistry. GST-pi expression was detected in 62.4% of the tumors and was not related to histologic subtype of tumor. MDR-1 expression was observed in 12.9% of the tumors tested and was more frequently detected in clear cell adenocarcinomas than other histologic subtypes of tumor (10/ 16 vs. 2 / 77, P < 0.001). P53 expression was found in 49.1% of serous, 53.8% of endometrioid, and 50% of mucinous adenocarcinomas. In contrast, none of 16 clear cell adenocarcinomas showed positive p53 staining. In univariate analysis, no direct correlations were found between CRPs and overall survival. Histology of mucinous/clear cell tumors (P = 0.0063), as well as FIGO stage III/IV (P = 0.0091) and residual tumor >or= 2 cm (P = 0.0045), was found to have independent prognostic value in multivariate analysis. In conclusion, histologic subtype proved to be the significant independent prognostic factor in addition to FIGO stage and residual tumor in stage II-IV ovarian cancer. GST-pi, MDR-1, and p53 expression pattern is closely related to histologic subtype of ovarian cancer, although they are not significant predictors of survival.

Multivariate analysis for prognostic significance of histologic subtype, GST-pi, MDR-1, and p53 in stages II-IV ovarian cancer

It has been suggested that histologic subtype of ovarian cancer is a factor that determines the chemoresponsiveness of tumor. In this study, we wanted to clarify the prognostic significance of histologic subtype and its correlation to expression of chemoresistance-related proteins (CRPs) in ovarian cancer. A total of 93 stage II-IV ovarian cancers, where the proportion of serous, endometrioid, mucinous, and clear cell subtype was 61.3%, 14.0%, 7.5%, and 17.2%, respectively, were investigated for glutathione S-transferase-pi (GST-pi), MDR (multidrug resistance)-1, and p53 expression using immunohistochemistry. GST-pi expression was detected in 62.4% of the tumors and was not related to histologic subtype of tumor. MDR-1 expression was observed in 12.9% of the tumors tested and was more frequently detected in clear cell adenocarcinomas than other histologic subtypes of tumor (10/ 16 vs. 2 / 77, P &lt; 0.001). P53 expression was found in 49.1% of serous, 53.8% of endometrioid, and 50% of mucinous adenocarcinomas. In contrast, none of 16 clear cell adenocarcinomas showed positive p53 staining. In univariate analysis, no direct correlations were found between CRPs and overall survival. Histology of mucinous/clear cell tumors (P = 0.0063), as well as FIGO stage III/IV (P = 0.0091) and residual tumor ≥ 2 cm (P = 0.0045), was found to have independent prognostic value in multivariate analysis. In conclusion, histologic subtype proved to be the significant independent prognostic factor in addition to FIGO stage and residual tumor in stage II-IV ovarian cancer. GST-pi, MDR-1, and p53 expression pattern is closely related to histologic subtype of ovarian cancer, although they are not significant predictors of survival.

Prognostic value of immunoexpression of the chemoresistance-related proteins in ependymomas: an analysis of 76 cases.

Intracranial ependymomas are the third most common primary brain tumor in children. A variety of chemotherapy protocols have been introduced for the treatment of ependymoma although overall these have not contributed to patients outcome. To our knowledge, data on the prognostic value of immunoexpression of the chemoresistance-related proteins (ChRPs) in ependymomas are absent. Seventy-six patients with intracranial ependymomas who received combined treatment were studied retrospectively. Tumor specimens were immunohistochemically examined with antibodies to metallothioneins (MT), glutathione S-transferase pi (GST pi) and P-glycoprotein (P-GP). The results demonstrated significant preponderance of expression of all the above-mentioned ChRPs for the low-grade tumors. The progression-free survival time was found to be significantly shorter for immunonegative tumors in both tumor grades. Multivariate analysis using a Cox hazard model revealed that recurrence-free survival time is significantly associated with tumor grade, and MT and P-GP expression. Risk of recurrence increased for the high-grade ependymomas (hazard ratio 2.85; P = 0.004), and decreased for the MT-positive tumors (hazard ratio -2.72; P = 0.005) and for the P-GP-positive tumors (hazard ratio -2.02; P = 0.02). The obtained results allow one to conclude that ChRPs expression is closely associated with low-grade ependymomas and immunohistochemical findings may be estimated as a predictor for local tumor progression.

Tumor Response to Neoadjuvant Chemotherapy Correlates with the Expression of P-Glycoprotein and PCNA but Not GST-π in the Tumor Cells of Cervical Carcinoma

Objective.To identify the clinicopathological and chemoresistant factors predicting the response to neoadjuvant chemotherapy and the patient prognosis in high-risk cervical carcinomas.Methods.We retrospectively reviewed 47 patients with locally advanced or bulky cervical carcinoma treated with two courses of intraarterial infusion of cisplatin, doxorubicin, mitomycin C, and 5-fluorouracil (5-FU), followed by radical hysterectomy at our hospital between 1988 and 1995. Expressions of the chemoresistance-related proteins, such as P-glycoprotein, glutathioneS-transferase π (GST-π), and proliferating cell nuclear antigen (PCNA) in the tumor cells, were examined by immunohistochemistry using pretreatment biopsy specimens. These results were compared with the chemotherapeutic response, which was evaluated by magnetic resonance imaging (MRI) and histopathology. Outcome of the patients was also studied.Results.Chemotherapeutic effect of either complete (CR) or partial (PR) response on MRI was obtained in 36 of the 47 (86%) patients. Poor response to chemotherapy was significantly correlated with P-glycoprotein expression (P< 0.005) and low PCNA labeling (P< 0.05), but not GST-π expression in the tumor cells. Independent prognostic factors for patient survival were parametrial involvement and lymph node metastasis. Neither the expression of GST-π nor PCNA was correlated with the patient survival.Conclusion.Assessment of the expression of P-glycoprotein and PCNA is potentially useful for the prediction of tumor response to neoadjuvant chemotherapy for cervical carcinomas.