Overcoming the effects of fluid shear stress in ovarian cancer cell lines: Doxorubicin alone or photodynamic priming to target platinum resistance

Resistance to platinum-based chemotherapies remains a significant challenge in advanced-stage high-grade serous ovarian carcinoma, and patients with malignant ascites face the poorest outcomes. It is, therefore, important to understand the effects of ascites, including the associated fluid shear stress (FSS), on phenotypic changes and therapy response, specifically FSS-induced chemotherapy resistance and the underlying mechanisms in ovarian cancer. This study investigated the effects of FSS on response to cisplatin, a platinum-based chemotherapy, and doxorubicin, an anthracycline, both of which are commonly used to manage advanced-stage ovarian cancer. Consistent with prior research, OVCAR-3 and Caov-3 cells cultivated under FSS demonstrated significant resistance to cisplatin. Examination of the role of mitochondria revealed an increase in mitochondrial DNA copy number and intracellular ATP content in cultures grown under FSS, suggesting that changes in mitochondria number and metabolic activity may contribute to platinum resistance. Interestingly, no resistance to doxorubicin was observed under FSS, the first such observation of a lack of resistance under these conditions. Finally, this study demonstrated the potential of photodynamic priming using benzoporphyrin derivative, a clinically approved photosensitizer that localizes in part to mitochondria and endoplasmic reticula, to enhance the efficacy of cisplatin, but not doxorubicin, thereby overcoming FSS-induced platinum resistance. Resistance to platinum-based chemotherapies poses a major challenge in high-grade serous ovarian carcinoma, especially in patients with malignant ascites. This study examined the effects of fluid shear stress (FSS) on cisplatin, doxorubicin, and benzoporphyrin derivative (BPD)-enabled photodynamic therapy (PDT) in an in vitro perfusion model. Significant resistance to cisplatin and BPD-PDT was observed in OVCAR-3 and Caov-3 cells grown under FSS, while, importantly, no resistance to doxorubicin was noted. Photodynamic priming with BPD enhanced cisplatin efficacy, abrogating FSS-induced platinum resistance. These results elucidate approaches to target FSS-induced platinum resistance in ovarian cancer, particularly roles for photodynamic priming and doxorubicin.image