Photochemical Targeting of Mitochondria to Overcome Chemoresistance in Ovarian Cancer

Ovarian cancer is the most lethal gynecologic malignancy with a stubborn mortality rate of ~65%. The persistent failure of multiline chemotherapy, and significant tumor heterogeneity, has made it challenging to improve outcomes. A target of increasing interest is the mitochondrion because of its essential role in critical cellular functions, and the significance of metabolic adaptation in chemoresistance. This review describes mitochondrial processes, including metabolic reprogramming, mitochondrial transfer and mitochondrial dynamics in ovarian cancer progression and chemoresistance. The effect of malignant ascites, or excess peritoneal fluid, on mitochondrial function is discussed. The role of photodynamic therapy (PDT) in overcoming mitochondria‐mediated resistance is presented. PDT, a photochemistry‐based modality, involves the light‐based activation of a photosensitizer leading to the production of short‐lived reactive molecular species and spatiotemporally confined photodamage to nearby organelles and biological targets. The consequential effects range from subcytotoxic priming of target cells for increased sensitivity to subsequent treatments, such as chemotherapy, to direct cell killing. This review discusses how PDT‐based approaches can address key limitations of current treatments. Specifically, an overview of the mechanisms by which PDT alters mitochondrial function, and a summary of preclinical advancements and clinical PDT experience in ovarian cancer are provided. In metastatic ovarian cancer, chemoresistant tumor populations demonstrate increased metabolic flexibility, enhanced capacity for glycolysis and oxidative phosphorylation, increased numbers of mitochondria and of mitochondrial DNA through mitochondrial transfer and altered mitochondrial dynamics (fission/fusion). Photodynamic therapy reverses chemoresistance in ovarian cancer and synergizes with conventional therapies. The role of mechanism‐based combinations using photosensitizers that are, in part, synthesized in mitochondria, or localize to subcellular organelles, including mitochondria, is presented. The effects of photodamage to mitochondria leading to enhanced cell death, as well as priming for increased sensitivity to subsequent treatments, are discussed.