title: Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner.
abstract: Accumulation of mechanical stresses during cancer progression can induce blood and lymphatic vessel compression, creating hypo-perfusion, hypoxia and interstitial hypertension which decrease the efficacy of chemo- and nanotherapies. Stress alleviation treatment has been recently proposed to reduce mechanical stresses in order to decompress tumor vessels and improve perfusion and chemotherapy. However, it remains unclear if it improves the efficacy of nanomedicines, which present numerous advantages over traditional chemotherapeutic drugs. Furthermore, we need to identify safe and well-tolerated pharmaceutical agents that reduce stress levels and may be added to cancer patients' treatment regimen. Here, we show mathematically and with a series of in vivo experiments that stress alleviation improves the delivery of drugs in a size-independent manner. Importantly, we propose the repurposing of tranilast, a clinically approved anti-fibrotic drug as stress-alleviating agent. Using two orthotopic mammary tumor models, we demonstrate that tranilast reduces mechanical stresses, decreases interstitial fluid pressure (IFP), improves tumor perfusion and significantly enhances the efficacy of different-sized drugs, doxorubicin, Abraxane and Doxil, by suppressing TGFβ signaling and expression of extracellular matrix components. Our findings strongly suggest that repurposing tranilast could be directly used as a promising strategy to enhance, not only chemotherapy, but also the efficacy of cancer nanomedicine.
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.|Department of Life Sciences, Program in Biological Sciences, European University Cyprus, Nicosia, Cyprus.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papageorgis
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
authors.forename: Christiana
authors.initials: C
authors.lastname: Polydorou
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
authors.forename: Fotios
authors.initials: F
authors.lastname: Mpekris
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
authors.forename: Chrysovalantis
authors.initials: C
authors.lastname: Voutouri
authors.affiliation: Department of Chemistry, University of Cyprus, Nicosia, Cyprus.
authors.forename: Eliana
authors.initials: E
authors.lastname: Agathokleous
authors.affiliation: Department of Chemistry, University of Cyprus, Nicosia, Cyprus.
authors.forename: Constantina P
authors.initials: CP
authors.lastname: Kapnissi-Christodoulou
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Stylianopoulos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D045604:Extracellular Fluid / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D008819:Mice, Nude; D008954:Models, Biological; D050997:Nanomedicine; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010316:Particle Size; D010477:Perfusion; D015398:Signal Transduction / Q000187:drug effects; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000187:drug effects; D062367:ortho-Aminobenzoates / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D004317:Doxorubicin; D006820:Hyaluronic Acid; D003094:Collagen; C012293:tranilast