Publication Date
2023
Document Type
Thesis
Committee Members
Ravi P. Sahu, Ph.D. (Advisor); Jeffrey B. Travers, M.D., Ph.D. (Committee Member); Anita Thyagarajan, Ph.D (Committee Member); Yong-Jie Xu, M.D., Ph.D. (Committee Member); Michael G. Kemp, Ph.D. (Committee Member)
Degree Name
Master of Science (MS)
Abstract
Given that Pancreatic cancer continues to be one of the primary causes of cancer-related death and that existing treatment options have a poor success rate, it is important to investigate the role of potential factor(s) involved in pancreatic cancer growth or diminishing the effectiveness of chemotherapeutic agents. An alternative regimen for pancreatic cancer treatment called FOLFIRINOX has shown to increase the survival rate and improve Eastern Cooperative Oncology Group (ECOG) performance status score among the pancreatic cancer patients. However, FOLFIRINOX therapy is associated with several side effects. Through mechanisms involving the secretion of microvesicle particles (MVP), studies, including ours have demonstrated the crucial roles of a G-protein coupled receptor called Platelet-activating factor-receptor (PAFR) in promoting tumor growth or reducing the effectiveness of chemotherapeutic drugs through the modulation of different signaling pathways in the cancer microenvironment. Following this concept, we investigated the notion that components of FOLFIRINOX regimen via their pro-oxidative stress ability will result in MVP generation in pancreatic cancer cell lines. Our in vitro studies demonstrated that FOLFIRINOX components induce MVP release in a dose dependent pattern from PAFR-expressing, but not from PAFR deficient cell lines. The FOLFIRINOX components-induced MVP release were significantly blocked by the pretreatment with PAFR antagonist and inhibitor of acid sphingomyelinase (aSMase) enzyme. To confirm the PAFR involvement, transfection studies using PAFR specific siRNA confirmed that PAFR expression is necessary for MVP generation by the FOLFIRINOX components. To determine if FOLFIRINOX therapy can exert similar effects on normal organs of epithelial origin, we performed studies where FOLFIRINOX components were topically applied on human and murine skin with or without PAFR antagonist and aSMase inhibitor. We observed similar findings that FOLFIRINOX components stimulate a dose-dependent increased in MVP release in the skin of the wild type mice and human skin, naturally acquired with PAF receptor. To validate the mechanism, we utilized PAFR deficient (Ptafr-/-) and aSMase enzyme deficient (Smpd-/-) mouse models and treated with the topical application of FOLFIRINOX components. Pertaining to the result obtained in wild type mice and human skin, we found that FOLFIRINOX components-induced MVP release was dampened in PAFR deficient (Ptafr-/-) and Smpd-/- mice. The overall findings suggest that PAFR expression is required for FOLFIRINOX components-induced MVP generation in in vitro, in vivo, and ex vivo models. Additionally, our study shows a mechanistic model through which the PAFR-aSMase axis can generate crucial bioactive substances called MVP as a bystander effect, which are believed to limit the efficacy of chemotherapeutic drugs and pose serious risk of adverse drug reaction associated with the chemotherapeutic drugs.
Page Count
61
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
2023
Copyright
Copyright 2023, all rights reserved. My ETD will be available under the "Fair Use" terms of copyright law.
ORCID ID
0000-0002-9253-7133
