Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma.
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ABSTRACT:
SUBMITTER: Salaroglio IC
PROVIDER: S-EPMC4359222 | biostudies-literature | 2015 Jan
REPOSITORIES: biostudies-literature
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Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma.
Salaroglio Iris Chiara IC Campia Ivana I Kopecka Joanna J Gazzano Elena E Orecchia Sara S Ghigo Dario D Riganti Chiara C
Oncotarget 20150101 2
The human malignant mesothelioma (HMM) is characterized by a chemoresistant and immunosuppressive phenotype. An effective strategy to restore chemosensitivity and immune reactivity against HMM is lacking. We investigated whether the use of zoledronic acid is an effective chemo-immunosensitizing strategy. We compared primary HMM samples with non-transformed mesothelial cells. HMM cells had higher rate of cholesterol and isoprenoid synthesis, constitutive activation of Ras/extracellular signal-reg ...[more]
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Project description:Background: There is no standard chemotherapy for refractory or relapsing malignant pleural mesothelioma (MPM). Our previous reports nevertheless indicated that a combination of an anthracycline (doxorubicin) and a lysine deacetylase inhibitor (valproic acid, VPA) synergize to induce the apoptosis of MPM cells and reduce tumor growth in mouse models. A Phase I/II clinical trial indicated that this regimen is a promising therapeutic option for a proportion of MPM patients. Methods: The transcriptomes of mesothelioma cells were compared after Illumina HiSeq 4000 sequencing. The expression of differentially expressed genes was inhibited by RNA interference. Apoptosis was determined by cell cycle analysis and Annexin V/7-AAD labeling. Protein expression was assessed by immunoblotting. Preclinical efficacy was evaluated in BALB/c and NOD-SCID mice. Results: To understand the mechanisms involved in chemoresistance, the transcriptomes of two MPM cell lines displaying different responses to VPA-doxorubicin were compared. Among the differentially expressed genes, transforming growth factor alpha (TGFα) was associated with resistance to this regimen. The silencing of TGFα by RNA interference correlated with a significant increase in apoptosis, whereas the overexpression of TGFα desensitized MPM cells to the apoptosis induced by VPA and doxorubicin. The multi-targeted inhibition of histone deacetylase (HDAC), HER2 and TGFα receptor (epidermal growth factor receptor/EGFR) improved treatment efficacy in vitro and reduced tumor growth in two MPM mouse models. Finally, TGFα expression but not EGFR correlated with patient survival. Conclusions: Our data show that TGFα but not its receptor EGFR is a key factor in resistance to MPM chemotherapy. This observation may contribute to casting light on the promising but still controversial role of EGFR signaling in MPM therapy.
| S-EPMC7352199 | biostudies-literature
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| S-EPMC3905399 | biostudies-other
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Project description:Metastatic and primary bone tumors are malignant tumors affecting the skeleton. Although the prognosis of patients with these tumors has improved with the development of effective chemotherapy, the challenges of local recurrence, subsequent osteolysis, degradation of bone strength and unresectable tumors persist. Local control of these tumors is therefore a key strategy to address these limitations. The third-generation bisphosphonate (BP), zoledronic acid (ZOL), has been demonstrated to reduce osteoclasts and exhibited potent antitumor effects in a number of malignancies. Hydroxyapatite (HA) and polymethyl methacrylate (PMMA) bone cement are used in orthopedic surgery as bone graft substitutes, for implant arthroplasty and bone strengthening, and as a sustained-release system for drugs such as antibiotics. At present, the antitumor effects of ZOL-loaded HA in vitro or in vivo or of ZOL-loaded bone cement in vivo have not been described. Therefore, the present study assessed the effects of ZOL-loaded HA and bone cement in malignant tumor cells. The two materials exerted strong antitumor effects against osteosarcoma, fibrosarcoma, synovial sarcoma, renal cancer, prostate cancer and lung cancer cells upon releasing ZOL. The antitumor effects of ZOL-loaded HA were less potent compared with those of ZOL-loaded bone cement, possibly as BPs exhibit higher affinity to HA. ZOL-loaded bone cement also exerted antitumor effects against pulmonary metastases and primary lesions, without exhibiting systemic toxicity in vivo. These results demonstrate that these materials may be beneficial for the treatment of malignant bone tumors, including metastatic bone tumors. In addition, as these materials are already in clinical use, such applications may be easily implemented.
| S-EPMC5529883 | biostudies-other
Project description:Malignant pleural mesothelioma (MPM) is a highly lethal, poorly understood neoplasm that is typically associated with asbestos exposure. We performed transcriptional profiling using high-density oligonucleotide microarrays containing approximately 22,000 genes to elucidate potential molecular and pathobiological pathways in MPM using discarded human MPM tumor specimens (n=40), normal lung specimens (n=4), normal pleura specimens (n=5), and MPM and SV40-immortalized mesothelial cell lines (n=5). In global expression analysis using unsupervised clustering techniques, we found two potential subclasses of mesothelioma which correlate loosely with tumor histology. We also identified sets of genes with expression levels that distinguish between multiple tumor subclasses, normal and tumor tissues, and tumors with different morphologies. Microarray gene expression data were confirmed using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and protein analysis for three novel candidate oncogenes (NME2, CRI1, and PDGFC) and one candidate tumor suppressor (GSN). Finally, we used bioinformatics tools (i.e. software) to create and explore complex physiological pathways that may be relevant in mesothelioma tumorigenesis, pathobiology, or both. Tissues and cell lines profiled using microarrays. Discarded MPM surgical specimens (n=40), normal pleura specimens (n=5), and normal lung specimens (n=4) were freshly collected (and snap frozen) from patients who underwent surgery at Boston's Brigham and Women's Hospital (BWH) between October 1998 and August 2000. All of these patients underwent extrapleural pneumonectomy with heated intra-pleural cisplatin chemotherapy delivered after the specimens were removed. All normal specimens were obtained from patients who were never diagnosed with MPM. Two human MPM cell lines (MS589 and MS428) were kindly provided by Jonathan A. Fletcher, M.D., Department of Pathology, BWH. The JMN1B MPM cell line19,20 has been described previously. The SV40-immortalized, non-tumorigenic mesothelial cell line (Met-5A)21 and the MPM cell line MSTO-211H22 were purchased from the American Type Culture Collection. Normal tissues were obtained from additional consented patients undergoing treatment for diseases other than MPM. All MPM samples used in these studies contained relatively pure tumor (greater than 50% tumor cells per high power field examined in a section adjacent to the tissue used). The microscopic slides from the patients' resection specimens were reviewed by one of the authors (J.G.), and the diagnosis and histologic subclassification of MPM confirmed in all cases. Linked clinical and pathological data were obtained for all patients who contributed tumor specimens. Specimens and data were rendered anonymous to protect patient confidentiality. Studies utilizing human tissues were approved by and conducted in accordance with the policies of the Institutional Review Board at BWH.
2005-06-01 | GSE2549 | GEO