Presence of Cx43 in extracellular vesicles reduces the cardiotoxicity of the anti-tumour therapeutic approach with doxorubicin

References

• Kourembanas S. Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2015; 77: 13–27.
   PubMed Web of Science ®Google Scholar
• Gould SJ, Raposo G. As we wait: coping with an imperfect nomenclature for extracellular vesicles. J Extracell Vesicles. 2013; 2: :20389, doi: http://dx.doi.org/10.3402/jev.v2i0.20389.
   Google Scholar
• György B, Hung ME, Breakefield XO, Leonard JN. Therapeutic applications of extracellular vesicles: clinical promise and open questions. Annu Rev Pharmacol Toxicol. 2015; 55: 439–64.
   PubMed Web of Science ®Google Scholar
• Ohno S, Takanashi M, Sudo K, Ueda S, Ishikawa A, Matsuyama N, etal. Systemically injected exosomes targeted to EGFR deliver antitumor microRNA to breast cancer cells. Mol Ther. 2013; 21: 185–91.
   PubMed Web of Science ®Google Scholar
• Tickner JA, Urquhart AJ, Stephenson S-A, Richard DJ, O'Byrne KJ. Functions and therapeutic roles of exosomes in cancer. Front Oncol. 2014; 4: 127.
   PubMedGoogle Scholar
• Mulcahy LA, Pink RC, Carter DRF. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014; 3: :24641, doi: http://dx.doi.org/10.3402/jev.v3.24641.
   Google Scholar
• Soares AR, Martins-Marques T, Ribeiro-Rodrigues T, Ferreira JV, Catarino S, Pinho MJ, etal. Gap junctional protein Cx43 is involved in the communication between extracellular vesicles and mammalian cells. Sci Rep. 2015; 5: 13243.
   PubMed Web of Science ®Google Scholar
• Zhuang X, Xiang X, Grizzle W, Sun D, Zhang S, Axtell RC, etal. Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain. Mol Ther. 2011; 19: 1769–79.
   PubMed Web of Science ®Google Scholar
• Mizrak A, Bolukbasi MF, Ozdener GB, Brenner GJ, Madlener S, Erkan EP, etal. Genetically engineered microvesicles carrying suicide mRNA/Protein inhibit schwannoma tumor growth. Mol Ther. 2013; 21: 101–8.
   PubMed Web of Science ®Google Scholar
• Tian Y, Li S, Song J, Ji T, Zhu M, Anderson GJ, etal. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. Biomaterials. 2014; 35: 2383–90.
   PubMed Web of Science ®Google Scholar
• Johnsen KB, Gudbergsson JM, Skov MN, Pilgaard L, Moos T, Duroux M. A comprehensive overview of exosomes as drug delivery vehicles – endogenous nanocarriers for targeted cancer therapy. Biochim Biophys Acta. 2014; 1846: 75–87.
   PubMed Web of Science ®Google Scholar
• Ewer MS, Ewer SM. Cardiotoxicity of anticancer treatments. Nat Rev Cardiol. 2015; 12: 547–58.
   PubMed Web of Science ®Google Scholar
• Toffoli G, Hadla M, Corona G, Caligiuri I, Palazzolo S, Semeraro S, etal. Exosomal doxorubicin reduces the cardiac toxicity of doxorubicin. Nanomedicine (Lond). 2015 [cited 2016 May 5]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26420143.
   Google Scholar
• Lener T, Gioma M, Aigner L, Börger V, Buzas E, Camussi G, etal. Applying extracellular vesicles based therapeutics in clinical trials – an ISEV position paper. J Extracell Vesicles. 2015; 4: 30087. doi: http://dx.doi.org/10.3402/jev.v4.30087.
   Google Scholar
• Elzarrad MK, Haroon A, Willecke K, Dobrowolski R, Gillespie MN, Al-Mehdi A-B, etal. Connexin-43 upregulation in micrometastases and tumor vasculature and its role in tumor cell attachment to pulmonary endothelium. BMC Med. 2008; 6: 20.
   PubMed Web of Science ®Google Scholar
• McLachlan E, Shao Q, Laird DW. Connexins and gap junctions in mammary gland development and breast cancer progression. J Membr Biol. 2007; 218: 107–21.
   PubMed Web of Science ®Google Scholar
• Ferreira-Teixeira M, Parada B, Rodrigues-Santos P, Alves V, Ramalho JS, Caramelo F, etal. Functional and molecular characterization of cancer stem-like cells in bladder cancer: a potential signature for muscle-invasive tumors. Oncotarget. 2015; 6: 36185–201.
   PubMedGoogle Scholar
• Martins-Neves SR, Paiva-Oliveira DI, Wijers-Koster PM, Abrunhosa AJ, Fontes-Ribeiro C, Bovée JVMG, etal. Chemotherapy induces stemness in osteosarcoma cells through activation of Wnt/β-catenin signaling. Cancer Lett. 2016; 370: 286–95.
   PubMed Web of Science ®Google Scholar
• Lim E, Modi KD, Kim J. In vivo bioluminescent imaging of mammary tumors using IVIS spectrum. J Vis Exp. 2009. . pii: 1210. [cited 2016 May 4]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19404236.
   Google Scholar
• Théry C, Amigorena S, Raposo G, Clayton A, Théry C, Amigorena S, etal. Isolation and characterization of exosomes from cell culture supernatants and biological fluids. 2006; Hoboken, NJ: Wiley. p. 3.22.1–3.22.29. [cited 4 May 2016]. Available from: http://doi.wiley.com/10.1002/0471143030.cb0322s30 Current protocols in cell biology.
   Google Scholar
• Montecalvo A, Larregina AT, Shufesky WJ, Stolz DB, Sullivan MLG, Karlsson JM, etal. Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. Blood. 2012; 119: 756–66.
   PubMed Web of Science ®Google Scholar
• Johnson S, Nguyen V, Coder D, Johnson S, Nguyen V, Coder D. Assessment of cell viability. 2013; Hoboken, NJ: Wiley. p. 9.2.1–9.2.26. [cited 2016 Jun 6]. Available from: http://doi.wiley.com/10.1002/0471142956.cy0902s64 Current protocols in cytometry.
   Google Scholar
• Strober W. Trypan blue exclusion test of cell viability. In: Current protocols in immunology. 2015; Hoboken, NJ: Wiley. p. A3.B.1–A3.B.3. [cited 2016 Jun 6]. Available from: http://doi.wiley.com/10.1002/0471142735.ima03bs111.
   Google Scholar
• Butler M, Spearman M, Braasch K. Monitoring cell growth, viability, and apoptosis. Methods Mol Biol. 2014; 1104: 169–92.
   Google Scholar
• Pozarowski P, Darzynkiewicz Z. Analysis of cell cycle by flow cytometry. Totowa, NJ: Humana Press.301–12. [cited 2016 May 5]. Available from: http://link.springer.com/10.1385/1-59259-811-0:301 Checkpoint controls and cancer.
   Google Scholar
• Jain P, Worthylake RA, Alahari SK. Quantitative analysis of random migration of cells using time-lapse video microscopy. J Vis Exp. 2012; 63 e3585.
   Google Scholar
• Franken NAP, Rodermond HM, Stap J, Haveman J, van Bree C. Clonogenic assay of cells in vitro . Nat Protoc. 2006; 1: 2315–9.
   PubMed Web of Science ®Google Scholar
• Martins-Marques T, Catarino S, Zuzarte M, Marques C, Matafome P, Pereira P, etal. Ischemia-induced autophagy leads to degradation of gap junction protein connexin43 in cardiomyocytes. Biochem J. 2015; 467: 231–45.
   Web of Science ®Google Scholar
• Martins-Marques T, Catarino S, Marques C, Matafome P, Ribeiro-Rodrigues T, Baptista R, etal. Heart ischemia results in connexin43 ubiquitination localized at the intercalated discs. Biochimie. 2015; 112: 196–201.
   Web of Science ®Google Scholar
• Kawaguchi T, Takemura G, Kanamori H, Takeyama T, Watanabe T, Morishita K, etal. Prior starvation mitigates acute doxorubicin cardiotoxicity through restoration of autophagy in affected cardiomyocytes. Cardiovasc Res. 2012; 96: 456–65.
   Web of Science ®Google Scholar
• Weissgerber TL, Milic NM, Winham SJ, Garovic VD, Cooper R, Schriger D, etal. Beyond bar and line graphs: time for a new data presentation paradigm. PLoS Biol. 2015; 13: e1002128.
   PubMed Web of Science ®Google Scholar
• Lötvall J, Hill AF, Hochberg F, Buzás EI, Vizio D, Di, Gardiner C, etal. Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles. J Extracell Vesicles. 2014; 3: :26913, doi: http://dx.doi.org/10.3402/jev.v3.26913.
   Google Scholar
• Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646–74.
   PubMed Web of Science ®Google Scholar
• Hawat G, Benderdour M, Rousseau G, Baroudi G. Connexin 43 mimetic peptide Gap26 confers protection to intact heart against myocardial ischemia injury. Pflugers Arch. 2010; 460: 583–92.
   Web of Science ®Google Scholar
• Vial E, Sahai E, Marshall CJ. ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell. 2003; 4: 67–79.
   PubMed Web of Science ®Google Scholar
• Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002; 12: 9–18.
   PubMed Web of Science ®Google Scholar
• Chen GG, Lai PBS, Hu X, Lam IKY, Chak ECW, Chun YS, etal. Negative correlation between the ratio of Bax to Bcl-2 and the size of tumor treated by culture supernatants from Kupffer cells. Clin Exp Metastasis. 2002; 19: 457–64.
   Web of Science ®Google Scholar
• Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012; 52: 1213–25.
   PubMed Web of Science ®Google Scholar
• Vedam K, Nishijima Y, Druhan LJ, Khan M, Moldovan NI, Zweier JL, etal. Role of heat shock factor-1 activation in the doxorubicin-induced heart failure in mice. Am J Physiol Heart Circ Physiol. 2010. 298:H1832–41.
   Web of Science ®Google Scholar
• Dowd NP, Scully M, Adderley SR, Cunningham AJ, Fitzgerald DJ. Inhibition of cyclooxygenase-2 aggravates doxorubicin-mediated cardiac injury in vivo . J Clin Invest. 2001; 108: 585–90.
   PubMed Web of Science ®Google Scholar
• Martins-Marques T, Catarino S, Marques C, Pereira P, Girão H. To beat or not to beat: degradation of Cx43 imposes the heart rhythm. Biochem Soc Trans. 2015; 43: 476–81.
   Web of Science ®Google Scholar
• Radić J, Krušlin B, Šamija M, Ulamec M, Milošević M, Jazvić M, etal. Connexin 43 expression in primary colorectal carcinomas in patients with Stage III and IV disease. Anticancer Res. 2016; 36: 2189–96.
   Web of Science ®Google Scholar
• Colombo M, Raposo G, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014; 30: 255–89.
   PubMed Web of Science ®Google Scholar
• Pecoraro M, Sorrentino R, Franceschelli S, Del Pizzo M, Pinto A, Popolo A. Doxorubicin-mediated cardiotoxicity: role of mitochondrial connexin 43. Cardiovasc Toxicol. 15: 366–76.
   Web of Science ®Google Scholar
• Zhang X, Teodoro JG, Nadeau JL. Intratumoral gold-doxorubicin is effective in treating melanoma in mice. Nanomedicine. 2015; 11: 1365–75.
   PubMed Web of Science ®Google Scholar
• Tang K, Zhang Y, Zhang H, Xu P, Liu J, Ma J, etal. Delivery of chemotherapeutic drugs in tumour cell-derived microparticles. Nat Commun. 2012; 3: 1282.
   PubMed Web of Science ®Google Scholar