Significance of topical chemotherapy application on human and murine skin

Abstract

<b>Abstract ID 23594</b> <b>Poster Board 249</b> Chemotherapy has remained the mainstay for the treatment of multiple types of cancers. In particular, topical use of chemotherapy has been used for skin cancers. Though effective, topical chemotherapy has been limited due to adverse effects such as local and even systemic toxicities. Our recent studies demonstrated that exposure to pro-oxidative stressors, including therapeutic agents induces the generation of extracellular vesicles known as microvesicle particles (MVP) which are dependent on activation of the Platelet-activating factor-receptor (PAFR), a G-protein coupled receptor present on various cell types, and acid sphingomyelinase (aSMase), an enzyme required for MVP biogenesis. Based upon this premise, we tested the hypothesis that topical application of gemcitabine will induce MVP generation in human and murine skin. Our <i>ex vivo</i> studies using human skin explants demonstrate that gemcitabine treatment results in MVP generation in a dose-dependent manner in a process blocked by PAFR antagonist and aSMase inhibitor. Importantly, gemcitabine-induced MVPs carry PAFR agonists. To confirm the mechanisms, we employed PAFR-expressing and deficient (<i>Ptafr^-/-</i>) mouse models as well as mice deficient in aSMase enzyme (<i>Spmd1^-/-</i>). Using genetic-based approaches, our studies demonstrated that gemcitabine-induced MVP release in WT mice was blunted in <i>Ptafr^-/-</i> and <i>Spmd1^-/-</i> mice. Overall, these findings indicate that pharmacological strategies to target the PAFR/aSMase pathway to block MVP release could be used as a promising approach for improving gemcitabine efficacy.