Schilling D.,TU Munich |
Schilling D.,Helmholtz Center Munich |
Garrido C.,French Institute of Health and Medical Research |
Garrido C.,Anticancer Center Georges Francois Leclerc |
And 4 more authors.
Cancer Letters | Year: 2017
The inhibition of heat shock protein 90 (Hsp90) is a promising strategy to increase the radiosensitivity of tumor cells. However, Hsp90 inhibition induces the expression of Hsp70 which is a prominent cytoprotective protein. Therefore, dual targeting of Hsp70 and Hsp90 might be beneficial to increase the radiosensitivity of tumor cells. Hsp70 inhibiting peptide aptamers have been shown to increase the sensitivity of tumor cells to apoptosis induced by different anticancer drugs. Herein, we studied the radiosensitizing activity of the Hsp70 inhibiting peptide aptamer A17 in combination with the Hsp90 inhibitor NVP-AUY922. Whereas A17 significantly increased apoptosis induction by NVP-AUY922 it did not significantly affect the radiosensitivity of human lung and breast cancer cells. However, Hsp70 inhibition by the aptamer A17 potentiated the radiosensitizing effects of the Hsp90 inhibitor NVP-AUY922. Mechanistically we speculate that an increased number of DNA double strand breaks and an enhanced G2/M arrest might be responsible for the increased radiosensitization in A17 expressing tumor cells. Therefore, the simultaneous inhibition of Hsp90 and Hsp70 combined with radiotherapy might provide a promising anti-cancer strategy. © 2017 Elsevier B.V.
Collura A.,French Institute of Health and Medical Research |
Collura A.,University Pierre and Marie Curie |
Lagrange A.,French Institute of Health and Medical Research |
Lagrange A.,University Pierre and Marie Curie |
And 64 more authors.
Gastroenterology | Year: 2014
Background & Aims Patients with colorectal tumors with microsatellite instability (MSI) have better prognoses than patients with tumors without MSI, but have a poor response to 5-fluorouracil-based chemotherapy. A dominant-negative form of heat shock protein (HSP)110 (HSP110DE9) expressed by cancer cells with MSI, via exon skipping caused by somatic deletions in the T17 intron repeat, sensitizes the cells to 5-fluorouracil and oxaliplatin. We investigated whether HSP110 T17 could be used to identify patients with colorectal cancer who would benefit from adjuvant chemotherapy with 5-fluorouracil and oxaliplatin. Methods We characterized the interaction between HSP110 and HSP110DE9 using surface plasmon resonance. By using polymerase chain reaction and fragment analysis, we examined how the size of somatic allelic deletions in HSP110 T17 affected the HSP110 protein expressed by tumor cells. We screened 329 consecutive patients with stage II-III colorectal tumors with MSI who underwent surgical resection at tertiary medical centers for HSP110 T17. Results HSP110 and HSP110DE9 interacted in a 1:1 ratio. Tumor cells with large deletions in T17 had increased ratios of HSP110DE9:HSP110, owing to the loss of expression of full-length HSP110. Deletions in HSP110 T17 were mostly biallelic in primary tumor samples with MSI. Patients with stage II-III cancer who received chemotherapy and had large HSP110 T17 deletions (≥5 bp; 18 of 77 patients, 23.4%) had longer times of relapse-free survival than patients with small or no deletions (≤4 bp; 59 of 77 patients, 76.6%) in multivariate analysis (hazard ratio, 0.16; 95% confidence interval, 0.012-0.8; P =.03). We found a significant interaction between chemotherapy and T17 deletion (P =.009). Conclusions About 25% of patients with stages II-III colorectal tumors with MSI have an excellent response to chemotherapy, due to large, biallelic deletions in the T17 intron repeat of HSP110 in tumor DNA. © 2014 by the AGA Institute.
Marcion G.,French Institute of Health and Medical Research |
Marcion G.,University of Burgundy |
Seigneuric R.,French Institute of Health and Medical Research |
Seigneuric R.,University of Burgundy |
And 12 more authors.
Cell Stress and Chaperones | Year: 2015
The human inducible heat shock protein 70 (hHsp70), which is involved in several major pathologies, including neurodegenerative disorders and cancer, is a key molecular chaperone and contributes to the proper protein folding and maintenance of a large number of protein structures. Despite its role in disease, the current structural knowledge of hHsp70 is almost exclusively based on its Escherichia coli homolog, DnaK, even though these two proteins only share ~50 % amino acid identity. For the first time, we describe a complete heterologous production and purification strategy that allowed us to obtain a large amount of soluble, full-length, and non-tagged hHsp70. The protein displayed both an ATPase and a refolding activity when combined to the human Hsp40. Multi-angle light scattering and bio-layer interferometry analyses demonstrated the ability of hHsp70 to homodimerize. The role of the C-terminal part of hHsp70 was identified and confirmed by a study of a truncated version of hHsp70 that could neither dimerize nor present refolding activity. © 2014, The Author(s).
de Magistris L.,Dijon University Hospital |
Paquette B.,Besancon University Hospital Center |
Orry D.,Anticancer Center Georges Francois Leclerc |
Facy O.,Dijon University Hospital |
And 8 more authors.
International Journal of Colorectal Disease | Year: 2016
Background: Septic complications after colorectal surgery are frequent and sometimes life threatening. It is well known that inflammation impairs the healing process. It has been suggested that preoperative ongoing inflammation could increase the risk of postoperative infections. This study aimed to elucidate the role of preoperative inflammation on postoperative infectious complications and to understand if, through biological markers, it is possible to identify preoperatively patients at higher risk of infection. Methods: A prospective, observational study was conducted in three centers from November 2011 to April 2014. Consecutive patients undergoing elective colorectal surgery with anastomosis were included. Any ongoing infection was an exclusion criterion. C-reactive protein, albumin, prealbumin, and procalcitonin plasma levels were measured preoperatively. Postoperative infections were recorded according to the definitions of the Centers for Diseases Control. The areas under the receiver operating characteristic curve were analyzed and compared to assess the accuracy of each preoperative marker. Results: Four-hundred and seventy two patients were analyzed. Infectious complications occurred in 118 patients (25 %) and mortality in 6 patients (1.3 %). In the univariate analysis, preoperative C-reactive protein and albuminemia were found significantly associated with postoperative infectious complications (P = 0.008 and P = 0.0002, respectively). Areas under the ROC curve for preoperative C-reactive protein and albuminemia were 0.57and 0.62, respectively. Conclusions: This study confirms the association between preoperative inflammatory activity, hypoalbuminemia, and the onset of infections after surgery. Trials aiming to decrease the inflammatory activity before surgery in order to prevent postoperative complications are warranted. © 2016 Springer-Verlag Berlin Heidelberg
Burgy O.,French Institute of Health and Medical Research |
Burgy O.,Equipe Heat Shock Proteins Labellisee Par la Ligue Nationale Contre le Cancer |
Burgy O.,University of Burgundy |
Wettstein G.,French Institute of Health and Medical Research |
And 32 more authors.
Science Translational Medicine | Year: 2016
Bleomycin (BLM) is a potent anticancer drug used to treat different malignancies, mainly lymphomas, germ cell tumors, and melanomas. Unfortunately, BLM has major, dose-dependent, pulmonary toxicity that affects 20% of treated individuals. The most severe form of BLM-induced pulmonary toxicity is lung fibrosis. Deglyco-BLM is a molecule derived from BLM in which the sugar residue D-mannosyl-L-glucose disaccharide has been deleted. The objective of this study was to assess the anticancer activity and lung toxicity of deglyco-BLM. We compared the antitumor activity and pulmonary toxicity of intraperitoneally administrated deglyco-BLM and BLM in three rodent models. Pulmonary toxicity was examined in depth after intratracheal administration of both chemotherapeutic agents. The effect of both drugswas further studied in epithelial alveolar cells in vitro.Wedemonstrated in rodent cancer models, including a human Hodgkin's lymphoma xenograft and a syngeneic melanoma model, that intraperitoneal deglyco-BLM is as effective as BLM in inducing tumor regression. Whereas the antitumor effect of BLM was accompanied by a loss of body weight and the development of pulmonary toxicity, deglyco-BLM did not affect body weight and did not engender lung injury. Both molecules induced lung epithelial cell apoptosis after intratracheal administration, but deglyco-BLM lost the ability to induce caspase-1 activation and the production of ROS (reactive oxygen species), transforming growth factor-β1, and other profibrotic and inflammatory cytokines in the lungs of mice and in vitro. Deglyco-BLM should be considered for clinical testing as a less toxic alternative to BLM in cancer therapy. Copyright 2016 by the American Association for the Advancement of Science; all rights reserved.
Clausse V.,French Institute of Health and Medical Research |
Clausse V.,University of Burgundy |
Goloudina A.R.,French Institute of Health and Medical Research |
Goloudina A.R.,University of Burgundy |
And 17 more authors.
Cell Death and Disease | Year: 2016
Inactivation of p53 found in more than half of human cancers is often associated with increased tumor resistance to anti-cancer therapy. We have previously shown that overexpression of the phosphatase Wip1 in p53-negative tumors sensitizes them to chemotherapeutic agents, while protecting normal tissues from the side effects of anti-cancer treatment. In this study, we decided to search for kinases that prevent Wip1-mediated sensitization of cancer cells, thereby interfering with efficacy of genotoxic anticancer drugs. To this end, we performed a flow cytometry-based screening in order to identify kinases that regulated the levels of γH2AX, which were used as readout. Another criterion of the screen was increased sensitivity of p53-negative tumor cells to cisplatin (CDDP) in a Wip1-dependent manner. We have found that a treatment with a low dose (75 nM) of MK-1775, a recently described specific chemical inhibitor of Wee1, decreases CDDP-induced H2AX phosphorylation in p53-negative cells and enhances the Wip1-sensitization of p53-negative tumors. We were able to reduce CDDP effective concentration by 40% with a combination of Wip1 overexpression and Wee1 kinase inhibition. We have observed that Wee1 inhibition potentiates Wip1- dependent tumor sensitization effect by reducing levels of Hipk2 kinase, a negative regulator of Wip1 pathway. In addition, during CDDP treatment, the combination ofWee1 inhibition and Wip1 overexpression has a mild but significant protective effect in normal cells and tissues. Our results indicate that inhibition of the negative regulators of Wip1 pathway, Wee1 and Hipk2, in p53-negative tumors could potentiate efficiency of chemotherapeutic agents without concomitant increase of cytotoxicity in normal tissues. The development and clinical use of Wee1 and Hipk1 kinase chemical inhibitors might be a promising strategy to improve anti-cancer therapy. © 2016 Macmillan Publishers Limited All rights reserved.
Crehange G.,Anticancer Center Georges Francois Leclerc |
Maingon P.,Anticancer Center Georges Francois Leclerc |
Gauthier M.,Biostatistics and Epidemiological Unit |
Parfait S.,CNRS Laboratory of Electronics Informatics and Images |
And 8 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011
Purpose: To investigate the time course response of prostate metabolism to irradiation using magnetic resonance spectroscopy (MRS) at 3-month intervals and its impact on biochemical control. Methods and Materials: Between January 2008 and April 2010, 24 patients with localized prostate cancer were prospectively enrolled in the Evaluation of the Response to Irradiation with MR Spectroscopy (ERIS) trial. All the patients had been treated with intensity-modulated radiation therapy with or without long-term adjuvant hormonal therapy (LTHT) and underwent 3-T MRS and prostate-specific antigen (PSA) assays at baseline and every 3 months thereafter up to 12 months. Results: After radiation, the mean normalized citrate level (citrate/water) decreased significantly over time, both in the peripheral zone (PZ) (p = 0.0034) and in the entire prostate (p = 0.0008), whereas no significant change was observed in mean normalized choline levels (choline/water) in the PZ (p = 0.84) and in the entire prostate (p = 0.95). At 6 months after radiation, the mean choline level was significantly lower in the PZ for patients with a PSA value of ≤0.5 ng/mL at 12 months (4.9 ± 1.7 vs. 7.1 ± 1.5, p = 0.0378). Similar results were observed at 12 months in the PZ (6.2 ± 2.3 vs. 11.4 ± 4.1, p = 0.0117 for choline level and 3.4 ± 0.7 vs. 16.1 ± 6.1, p = 0.0054 for citrate level) and also in the entire prostate (6.2 ± 1.9 vs. 10.4 ± 3.2, p = 0.014 for choline level and 3.0 ± 0.8 vs. 13.3 ± 4.7, p = 0.0054 for citrate level). For patients receiving LTHT, there was no correlation between choline or citrate levels and PSA value, either at baseline or at follow-up. Conclusions: Low normalized choline in the PZ, 6 months after radiation, predicts which patients attained a PSA ≤0.5 ng/mL at 1 year. Further analyses with longer follow-up times are warranted to determine whether or not these new biomarkers can conclusively predict the early radiation response and the clinical outcome for patients with or without LTHT. © 2011 Elsevier Inc.
Facy O.,University Hospital |
Facy O.,French Institute of Health and Medical Research |
Paquette B.,University Hospital |
Orry D.,Anticancer Center Georges Francois Leclerc |
And 10 more authors.
Annals of Surgery | Year: 2016
Background: Intra-abdominal infections are frequent and life-threatening complications after colorectal surgery. An early detection could diminish their clinical impact and permit safe early discharge. Objective: This study aimed to find the most accurate marker for the detection of postoperative intra-abdominal infection and the appropriate moment to measure it. Methods: A prospective, observational study was conducted in 3 centers. Consecutive patients undergoing elective colorectal surgery with anastomosis were included. C-reactive protein and procalcitonin were measured daily until the fourth postoperative day. Postoperative infections were recorded according to the definitions of the Centres for Diseases Control. The areas under the receiver operating characteristic curve were analyzed and compared to assess the diagnostic accuracy of each marker. Results: Five-hundred and one patients were analyzed. The incidence of intra-abdominal infection was 11.8%, with 24.6% of patients presenting at least one infectious complication. Overall mortality was 1.2%. At the fourth postoperative day, C-reactive protein was more discriminating than procalcitonin for the detection of intra-abdominal infection (areas under the ROC curve: 0.775 vs 0.689, respectively, P=0.03). Procalcitonin levels showed wide dispersion. For the detection of all infectious complications, C-reactive protein was also significantly more accurate than procalcitonin on the fourth postoperative day (areas under the ROC curve: 0.783 vs 0.671, P=0.0002). Conclusions: C-reactive protein is more accurate than procalcitonin for the detection of infectious complications and should be systematically measured at the fourth postoperative day. It is a useful tool to ensure a safe early discharge after elective colorectal surgery. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Dewas C.V.,Anticancer center Georges Francois Leclerc |
Maingon P.,Anticancer center Georges Francois Leclerc |
Dalban C.,Anticancer center Georges Francois Leclerc |
Petitfils A.,Anticancer center Georges Francois Leclerc |
And 6 more authors.
Radiation Oncology | Year: 2012
Background: Chemoradiation is the standard treatment for anal cancer. 3D conformal radiotherapy (3D-CRT) is usually split in 2 sequences with a therapeutic break (gap) in between. Intensity-modulated radiation therapy (IMRT) makes it possible to reduce treatment time by abandoning this gap. The purpose of this study was to compare outcomes and toxicities in patients treated with either IMRT or 3D-CRT.Methods: Between 2004 and 2011, the data of 51 patients treated with exclusive radiotherapy with or without concomitant chemotherapy for non-metastatic anal carcinoma were retrospectively analyzed. Twenty-seven patients were treated with 3D-CRT and 24 patients with IMRT, with a median dose delivered to the tumor of 59.4Gy [30.6-66.6], whatever the radiotherapy technique (p= 0.99). The median follow-up was 40 months [26.4-51.6].Results: There was no difference between the two groups for response to treatment (p= 0.46). Two-year overall survival, locoregional relapse-free survival and colostomy-free survival rates were 88.5%, 63% and 60.3%, respectively for the IMRT group and 81%, 76.5% and 81.1% for the 3D-CRT group (all NS). Ten patients (37%) in 3D-CRT and 11 patients (45.8%) in IMRT (p= 0.524) had grade 3 acute toxicity. No grade 4 toxicity occurred.Conclusions: Our study suggests that further investigations concerning the use of IMRT to treat cancer of the anus are warranted. IMRT makes it possible to remove the gap, but with no impact on the prognosis. Nonetheless, a longer follow-up is essential to determine whether or not IMRT has an impact on late toxicity, local control and survival compared with conventional 3D-CRT. © 2012 Dewas et al.; licensee BioMed Central Ltd.