Involvement of ferroptosis in eribulin-induced cytotoxicity in ovarian clear cell carcinoma.

Ovarian clear cell carcinoma (OCCC) is a unique clinicopathological subtype of epithelial ovarian cancer that is resistant to standard chemotherapy. Eribulin, a microtubule dynamics inhibitor of halichondrin class, has unique effects in the cancer microenvironment such as induction of epithelization and reduction in metastatic potential in breast cancer cells; however, nothing is known about the effect of eribulin and the detailed mechanisms in OCCC. This study aimed to investigate the involvement of ferroptosis and its mechanism in the antitumor activity of eribulin in OCCC cells and a mouse xenograft model. We found that eribulin-induced cell death was reduced by ferroptosis inhibitors; deferoxamine, an iron chelator and ferrostatin-1, a lipid peroxidation inhibitor. Eribulin increased the levels of intracellular iron, reactive oxygen species (ROS), and lipid peroxides, and increased the mitochondrial membrane potential. Eribulin downregulated the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), and superoxide dismutase (SOD) activity. The combination of eribulin and ML210, a glutathione peroxidase 4-inhibiting ferroptosis inducer, had a synergistic effect on ferroptosis. Taken together, our findings show firstly that eribulin triggers ferroptosis in OCCC and this effect occurs via the suppression of the Nrf2-HO-1 signaling pathway, SOD activity and the promotion of lipid peroxidation. These findings suggest that eribulin-induced ferroptosis is associated with its anti-tumor effect and also could be a potential therapeutic target in OCCC.

Effect of photodynamic therapy (PDT), posterior subtenon injection of triamcinolone acetonide with PDT, and intravitreal injection of ranibizumab with PDT for retinal angiomatous proliferation.

BACKGROUND: The purpose of this work was to compare the efficacy of photodynamic therapy (PDT) with or without posterior subtenon injections of triamcinolone acetonide (STA) or intravitreal injections of ranibizumab (IVR) for retinal angiomatous proliferation (RAP). METHODS: Thirty-seven eyes from 33 consecutive patients with RAP were treated by PDT monotherapy (Group 1), PDT combined with STA (Group 2), or PDT combined with IVR (Group 3). The best-corrected visual acuity, greatest linear dimension, central retinal thickness, and number of treatments were compared among the three groups. RESULTS: The change in mean best-corrected visual acuity (logMAR) at month 3, 6, and 12 after the initial treatment was better in Group 2 (-0.13, -0.23, and -0.21, respectively) and Group 3 (-0.018, 0.0028, and -0.0067, respectively) than in Group 1 (0.13, 0.19, and 0.23, respectively); Group 1 versus Group 2 was statistically significant (P = 0.018). The mean central retinal thickness was reduced from baseline in all groups, but the reduction amplitude was significantly greater in Group 2 than in Group 1 and Group 3. The mean number of treatments was significantly lower in Group 2 (1.1 ± 0.4) and Group 3 (1.5 ± 0.5) than in Group 1 (2.9 ± 0.9) in the 12 months after the initial treatment. CONCLUSION: Treatment with STA + PDT may be an effective therapy for RAP lesions over 12 months of follow-up.