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Background:Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM).Methods:The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed.Results:Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression.Conclusion:Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.

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In recent years, much effort has been focused on an appropriate combination of chemotherapeutic drugs and nucleic acids to exploit additive or synergistic therapeutic effects and overcome many obstacles such as the reduction of side effects and drug resistance. Short hairpin RNA (shRNA) has designed to allow the production of small interfering RNA (siRNA) within the cells and offer long-lasting silencing of target genes. In this study, alkyl-modified polyethylenimine (PEI 10 kD) was used for co-delivery of doxorubicin (DOX) encapsulated into poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) and Bcl-xL shRNA (one class of molecules that block apoptosis of tumor cells) into breast cancer cells. Our results demonstrated that modification of PEI with alkyl chain could enhance the induction of apoptosis in tumor cells by suppression of Bcl-xL gene using Bcl-xL shRNA more than PEI alone. On the other hand, DOX encapsulated into PLGA had more synergistic effect with shRNA in comparison with DOX alone. In conclusion, combination of PLGA-DOX NPs and alkyl-PEI/shRNA complexes may have promising applications in breast cancer therapy.

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Nanoscale vesicles have provided a versatile platform for the transportation of various types of anticancer and diagnostic agents. Vesicular carriers comprised of liposomes, polymersomes, and peptide-based vesicles have exhibited potential characteristics for nanomedicine developments. However, the represented systems and current therapeutic approaches to cancers are confronted with serious limitations that hinder their clinical translation. The aforementioned limitations could be minimized by implementing combinatorial hybrid systems. With this method, hybrid vesicular systems can integrate the advantages of several carriers into one structure thereby resulting in an increased therapeutic index and better clinical outcome. The current study has reviewed recently introduced types of hybrid vesicles made of polymer-lipids, polymer-peptides, and lipid-peptides, and its main focus is on multiple metallic-based nanoparticles incorporated into vesicular carriers to provide theranostic platforms and to boost the efficient cytotoxic effects of the delivered agents.