Cancer letters
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Cisplatin (diamminedichloroplatinum, DDP) is widely used as the first-line treatment for patients with unresectable or no metastatic cancer. However, the appearance of DDP resistance frequently occurred in the treatment of cancers, including esophageal carcinoma (EC). The purposes of this study are to determine the antitumor effects of miR-let-7g/i (let-7g/i) on EC cells and to investigate whether let-7g and let-7i have a relationship with the drug resistance gene ABCC10 on EC cells. qRT-PCR and western blot analysis demonstrated that Bcl2-associated athanogene 3 (BAG3) and miR-let-7g/i have the opposite expression levels in primary esophageal squamous cell carcinoma tissues and EC cell lines. ⋯ Finally, ABCC10, a drug resistance gene, was identified as a functional and direct target gene of miR-let-7g/i. Luciferase reporter assay confirmed that let-7g and let-7i combined directly with 3'UTR of ABCC10, in consequence, inhibiting ABCC10 expression and enhancing cellular sensitivity to drugs. This study provides the first demonstration that miR-let-7g/i target ABCC10 and modulate DDP resistance in EC cell lines.
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Glioblastoma multiforme (GBM) is the most frequent and most aggressive brain tumor in adults. The introduction of temozolomide (TMZ) has advanced chemotherapy for malignant gliomas. However, a considerable number of GBM cases are refractory to TMZ, the need for more effective therapeutic options is overwhelming. ⋯ Inhibition of mTOR (p70S6K) signaling with the combination of TMZ and NVP-BEZ235 can be augmented beyond that achieved using each agent individually. In vivo xenograft models in mice, the combinatorial treatment with TMZ and NVP-BEZ235 significantly reduced tumor growth rates and prolonged median survival of tumor-bearing mice. These findings exhibit that TMZ in combination with NVP-BEZ235 act synergistically to inhibit proliferation of glioma cells by down-regulating of the PI3K-AKT-mTOR pathway, suggesting TMZ and NVP-BEZ235 combination therapy may be an option for GBM treatment.
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Intermittent hypoxia (IH)-induces alterations in tumor-associated macrophages (TAMs) that are associated with adverse cancer outcomes, as reported in patients suffering from sleep apnea. Adipose tissues (AT) and bone-marrow (BM)-derived cells are the inferred sources of macrophages infiltrating malignant tumors. Here, the sources of TAMs and the phenotypic changes induced by IH in the ipsilateral and contralateral AT were investigated by using a syngeneic murine solid tumor model (TC1). ⋯ However, differential responses in the tumor ipsilateral and contralateral AT emerged: IH increased infiltration of preferentially M1 macrophages in contralateral AT, while reductions in macrophages emerged in ipsilateral AT and primarily consisted of the M2 phenotype. These changes were accompanied by reciprocal increases in resident and BM-derived TAMs in the tumor. IH-induced phenotypic alterations in AT macrophages surrounding the tumor and their increased infiltration within the tumor may contribute to the accelerated tumor progression associated with IH.
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Neuroblastoma (NB) is the most common and deadly solid tumor in children. The majority of NB patients have advanced stage disease with poor prognosis, so more effective, less toxic therapy is needed. We developed a novel nanocarrier-based strategy for tumor-targeted delivery of a prodrug of SN38, the active metabolite of irinotecan. ⋯ Comparison of SN38-TS NPs (8, 8, and 16 doses, respectively) to irinotecan (40 doses) showed that all SN38-TS NP regimens were far superior to irinotecan, and "cures" were obtained in all NP arms. SN38-TS NP delivery resulted in 200× the amount of SN38 in NB tumors at 4 hr post-treatment, compared to SN38 detected for the irinotecan arm; no toxicity was seen with NPs. We conclude that this SN38-TS NP formulation improved delivery, retention, and efficacy, without causing systemic toxicity.
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Gastric cancer (GC) is a major cause of global cancer mortality. Previous genomic studies have reported that several RTK-RAS pathway components are amplified in GC, with individual tumours often amplifying one component and not others ("mutual exclusivity"). Here, we sought to validate these findings for three RTK/RAS components (FGFR2, HER2, KRAS) using fluorescence in situ hybridisation (FISH) on a series of gastric tumours, cell lines and patient-derived xenografts. ⋯ Our data confirm that RTK/RAS components are mutually exclusively amplified in GC, and demonstrate the feasibility of identifying multiple aneuploidies using a single FISH assay. Application of this assay to GC samples, particularly diagnostic biopsies, may facilitate enrollment of GC patients into clinical trials evaluating RTK/RAS directed therapies. However, the presence of intra-tumour heterogeneity may require multiple biopsy samples to be obtained per patient before a definitive diagnosis can be attained.