New therapeutic options for mesothelioma

Goudar, Ranjit K.

doi:10.1007/s11912-005-0048-3

Cited by 13 publications

(7 citation statements)

References 42 publications

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“…3 Generally, radiotherapy and surgical therapy also show limited efficacy against malignant mesothelioma. 4,5 So far, the combination of cisplatin and pemetrexed appears to be the best chemotherapy regimen for mesothelioma, but the median survival of patients with mesothelioma remains under 12 months. Thus, new and more effective approaches to the treatment of malignant mesothelioma are urgently required.…”

Section: Introductionmentioning

confidence: 99%

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Eguchi

Nakano²,

Wakabayashi³

2016

Oncogene

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Malignant mesothelioma is an aggressive tumor arising from the mesothelial cells of serous membranes and is associated with tumor angiogenesis, which is a prerequisite for tumor progression. Vascular endothelial growth factors (VEGFs) including VEGF-A have a crucial role in tumor angiogenesis. However, bevacizumab, a monoclonal antibody to VEGF-A, has recently been reported not to improve the progression-free survival of patients with malignant mesothelioma. Cell culture supernatant contains extracellular components such as serum, which can mask the existence of unknown cell-derived factors in the supernatant and make it difficult to detect the factors by subsequent protein analysis. We tried using serum-free culture for human mesothelioma cell lines, NCI-H28, NCI-H2452 and NCI-H2052, and only NCI-H2052 cells adapted to serum-free culture. We found that serum-free culture supernatant derived from NCI-H2052 cells induces the formation of capillary-like tube structures (tube formation) in three-dimensional culture, in which endothelial cells sandwiched between two layers of collagen or embedded in collagen are incubated with various angiogenic inducers. However, neither neutralization of VEGF-A nor RNA interference of VEGF receptor 2 (VEGFR2) suppressed the supernatant-induced tube formation. Using mass spectrometry, we identified a total of 399 proteins in the supernatant, among which interleukin-8 (IL-8), growth-regulated α-protein, midkine, IL-18, IL-6, hepatoma-derived growth factor, clusterin and granulin (GRN), also known as progranulin (PGRN), were included as a candidate protein inducing angiogenesis. Neutralizing assays and RNA interference showed that PGRN, but not the above seven candidate proteins, caused the supernatant-induced tube formation. We also found that NCI-H28 and NCI-H2452 cells express PGRN. Furthermore, we demonstrate that not only PGRN but also GRN-like protein have an important role in the supernatant-induced tube formation. Thus, mesothelioma-derived GRNs induce VEGF-independent angiogenesis.

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Section: Introductionmentioning

confidence: 99%

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Eguchi

Nakano²,

Wakabayashi³

2016

Oncogene

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“…Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes, including the pleura, peritoneum and pericardium (1)(2)(3). Mesothelioma is highly resistant to most chemotherapeutic drugs and radiation therapy (3), and surgical therapy generally show limited efficacy (3)(4)(5). So far a combination of cisplatin and pemetrexed appears to be the best chemotherapy regimen for mesothelioma, but the median survival of patients with mesothelioma remains at <12 months (5).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Src family kinases overcomes anoikis resistance induced by spheroid formation and facilitates cisplatin-induced apoptosis in human mesothelioma cells

et al. 2015

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Malignant mesothelioma is an aggressive tumor arising from mesothelial cells of serous membranes, and forms spheroid-like cell aggregates in pleural and peritoneal effusions. We examined the levels of anoikis, apoptosis induced by the detachment of cells from the extracellur matrix, in suspension culture in the human mesothelioma cell line NCI-H2052. NCI-H2052 cells were adherent in conventional monolayer cultures, but were found to form spheroids in suspension cultures using dishes with ultra-low cell binding capacity. NCI-H2052 cells proliferated in both cultures, but the proliferation rate was markedly lower in suspension cultures than in monolayer cultures. In addition, NCI-H2052 cells in suspension cultures showed little apoptosis, suggesting that the suspension culture induces anoikis resistance. Western blot analysis revealed that suspension cultures induced activation of Src family kinases (SFK) after spheroid formation. Dasatinib, an inhibitor of multi-tyrosine kinases including SFK, abolished anoikis resistance in suspension cultures, indicating that SFK activated by spheroid formation are responsible for anoikis resistance. Cisplatin induced apoptosis in NCI-H2052 cells, but the apoptotic rate was significantly lower in suspension cultures than in monolayer cultures, suggesting that spheroid formation is involved in cisplatin resistance. Furthermore, a combination of dasatinib and cisplatin induced apoptosis more significantly than either alone in suspension cultures. These results suggest that spheroid formation induces resistance to anoikis and to cisplatin through SFK activation and that dasatinib facilitates cisplatin-induced apoptosis in human mesothelioma cells.

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“…MPM is extremely resistant to most chemotherapy regimens examined and not responsive primarily to radiation therapy in general [3,4]. Pemetrexed (Alimta) and cisplatin combination was shown to be the best chemotherapy regimen for MPM examined so far.…”

Section: Introductionmentioning

confidence: 99%

TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages

et al. 2013

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BackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy closely associated with asbestos exposure and extremely resistant to current treatments. It exhibits a steady increase in incidence, thus necessitating an urgent development of effective new treatments.MethodsProteasome inhibitors (PIs) and TNFα-Related Apoptosis Inducing Ligand (TRAIL), have emerged as promising new anti-MPM agents. To develop effective new treatments, the proapoptotic effects of PIs, MG132 or Bortezomib, and TRAIL were investigated in MPM cell lines NCI-H2052, NCI-H2452 and NCI-H28, which represent three major histological types of human MPM.ResultsTreatment with 0.5-1 μM MG132 alone or 30 ng/mL Bortezomib alone induced a limited apoptosis in MPM cells associated with the elevated Mcl-1 protein level and hyperactive PI3K/Akt signaling. However, whereas 10–20 ng/ml TRAIL alone induced a limited apoptosis as well, TRAIL and PI combination triggered a robust apoptosis in all three MPM cell lines. The robust proapoptotic activity was found to be the consequence of a positive feedback mechanism-governed amplification of caspase activation and cleavage of both Mcl-1 and Akt proteins, and exhibited a relative selectivity in MPM cells than in non-tumorigenic Met-5A mesothelial cells.ConclusionThe combinatorial treatment using TRAIL and PI may represent an effective new treatment for MPMs.

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New therapeutic options for mesothelioma

Cited by 13 publications

References 42 publications

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Progranulin and granulin-like protein as novel VEGF-independent angiogenic factors derived from human mesothelioma cells

Inhibition of Src family kinases overcomes anoikis resistance induced by spheroid formation and facilitates cisplatin-induced apoptosis in human mesothelioma cells

TRAIL and proteasome inhibitors combination induces a robust apoptosis in human malignant pleural mesothelioma cells through Mcl-1 and Akt protein cleavages

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