PpIX‐enabled fluorescence‐based detection and photodynamic priming of platinum‐resistant ovarian cancer cells under fluid shear stress

Abstract

AbstractOver 75% percent of ovarian cancer patients are diagnosed with advanced‐stage disease characterized by unresectable intraperitoneal dissemination and the presence of ascites, or excessive fluid build‐up within the abdomen. Conventional treatments include cytoreductive surgery followed by multi‐line platinum and taxane chemotherapy regimens. Despite an initial response to treatment, over 75% of patients with advanced‐stage ovarian cancer will relapse and succumb to platinum‐resistant disease. Recent evidence suggests that fluid shear stress (FSS), which results from the movement of fluid such as ascites, induces epithelial‐to‐mesenchymal transition and confers resistance to carboplatin in ovarian cancer cells. This study demonstrates, for the first time, that FSS‐induced platinum resistance correlates with increased cellular protoporphyrin IX (PpIX), the penultimate downstream product of heme biosynthesis, the production of which can be enhanced using the clinically approved pro‐drug aminolevulinic acid (ALA). These data suggest that, with further investigation, PpIX could serve as a fluorescence‐based biomarker of FSS‐induced platinum resistance. Additionally, this study investigates the efficacy of PpIX‐enabled photodynamic therapy (PDT) and the secretion of extracellular vesicles under static and FSS conditions in Caov‐3 and NIH:OVCAR‐3 cells, two representative cell lines for high‐grade serous ovarian carcinoma (HGSOC), the most lethal form of the disease. FSS induces resistance to ALA‐PpIX‐mediated PDT, along with a significant increase in the number of EVs. Finally, the ability of PpIX‐mediated photodynamic priming (PDP) to enhance carboplatin efficacy under FSS conditions is quantified. These preliminary findings in monolayer cultures necessitate additional studies to determine the feasibility of PpIX as a fluorescence‐based indicator, and mediator of PDP, to target chemoresistance in the context of FSS.