Photochemical Targeting of Mitochondria to Overcome Chemoresistance in Ovarian Cancer^†

Abstract

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 lightbased 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.

Photodynamic and Photothermal Therapies: Synergy Opportunities for Nanomedicine

“… 57 , 58 It is generally accepted that mitochondria- and endoplasmic reticulum-localizing photosensitizers trigger apoptosis via cytochrome C release, 59 , 60 while lysosomal photosensitizers induce protease release. 61 Interestingly, sequential targeting of lysosomes and mitochondria significantly enhances PDT efficacy, which could be explained by the enhanced radical formation in mitochondria as a result of photochemically triggered release of iron from lysosomes. 62 This mechanism has been leveraged in the design of a liposomal photosensitizer formulation that simultaneously targets lysosomes, mitochondria and endoplasmic reticulum.…”

“…Both PDT and PTT can be used to induce cytotoxicity in vitro and in vivo , but the mechanisms of cell killing differ between them. PDT-induced cytotoxicity is mainly driven by the short-lived ROS, so that the photosensitizer chemical structure, subcellular localization and light delivery parameters determine dominant cell death mechanisms. , It is generally accepted that mitochondria- and endoplasmic reticulum-localizing photosensitizers trigger apoptosis via cytochrome C release, , while lysosomal photosensitizers induce protease release . Interestingly, sequential targeting of lysosomes and mitochondria significantly enhances PDT efficacy, which could be explained by the enhanced radical formation in mitochondria as a result of photochemically triggered release of iron from lysosomes .…”

Shedding Light on Chemoresistance: The Perspective of Photodynamic Therapy in Cancer Management

“…All these PSs are porphyrin, chlorin, or phthalocyanine derivatives with strong absorption in the infrared (600-700 nm) or near-infrared (700-1000 nm) region, which allows for deep tissue penetration, improving treatment outcomes. Similarly, PDP can enhance vascular and cellular permeabilization, reduce stromal components (collagen, hyaluronan, and cancer-associated fibroblasts), and activate the immune response, leading to the improvement of chemotherapy or immunotherapy's individual therapeutic effectiveness, as shown in Figure 1 [14][15][16][17].…”

Methods to Evaluate Changes in Mitochondrial Structure and Function in Cancer

“…One treatment approach that has been shown to decrease ∆Ψ m is photodynamic priming (PDP). PDP is a light-based, sub-cytotoxic treatment modality that can enhance tumor cell susceptibility to conventional therapies through the production of reactive molecular species [228]. In a study by Rickard et al [229], PFAS-exposed ovarian cancer cells that had elevated ∆Ψ m and were chemotherapy-resistant demonstrated decreased ∆Ψ m after PDP and were re-sensitized to chemotherapy.…”