Title : Mechanisms of chemotherapy drug-induced microvesicle particles release
Abstract:
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 of whether topical application of gemcitabine will induce MVP generation in human and murine skin. Our ex vivo 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 (Ptafr-/-) mouse models as well as mice deficient in aSMase enzyme (Spmd1-/-). Similar to the findings using human skin explants, our studies demonstrate that gemcitabine-induced MVP release in WT mice was blunted in Ptafr-/- and Spmd1-/- mice. These findings demonstrate a possible mechanism by which local chemotherapy can generate bioactive components as a bystander effect in a process that is dependent upon the PAFR-aSMase pathway.
Audience Take Away Notes:
- Despite the fact that chemotherapeutic agents are mostly used systemically, a few of them, including gemcitabine have also been used topically for skin conditions such as skin cancer, actinic keratosis, etc. However, topical chemotherapeutic agents are often associated with side effects such as skin rash, skin necrosis, etc. In this research, we determined the impact of topical gemcitabine-induced effect, in particular, secretion of microvesicle particles (MVP), which carry bioactive components such as PAF lipids. Overall, the audience will learn possible strategies to mitigate topical gemcitabine-induced effects.
- The knowledge gained via these studies can prepare the audience if they are applying for related research jobs in the pharmaceutical industry.
- Faculties often get novel ideas from research studies of other participants.
- Cancer researchers and medical oncologists are exploring novel strategies to overcome the ongoing challenges associated with FDA-approved therapeutic agents. Our studies provide one of the possible approaches that could be used to explore these strategies.
