Synergistic suppression of ovarian cancer by combining NRF2 and GPX4 inhibitors: in vitro and in vivo evidence.

Ovarian cancer is a significant challenge in women's health due to the lack of effective screening and diagnostic methods, often leading to late detection and the highest mortality rate among all gynecologic tumors worldwide. Recent research has shown that ovarian cancer has an "iron addiction" phenotype which makes it vulnerable to ferroptosis inducers. We tested the combination of NRF2-targeted inhibitors with GPX4-targeted inhibitors in ovarian cancer through in vitro and in vivo experiment. The data showed that combination treatment effectively suppressed adherent cell growth, inhibited suspended cell spheroid formation, and restrained the ability of spheroid formation in 3D-culture. Mechanistically, the combination induced accumulation of ROS, 4-HNE, as well as activation of caspase-3 which indicates that this combination simultaneously increases cell ferroptosis and apoptosis. Notably, inhibition of GPX4 or NRF2 can suppress ovarian cancer spreading and growth in the peritoneal cavity of mice, while the combination of NRF2 inhibitor ML385 with GPX4 inhibitors showed a significant synergistic effect compared to individual drug treatment in a syngeneic mouse ovarian cancer model. Overall, these findings suggest that combining NRF2 inhibitors with GPX4 inhibitors results in a synergy suppression of ovarian cancer in vitro and in vivo, and maybe a promising therapeutic strategy for the treatment of ovarian cancer.

Antimicrobial peptides CS-piscidin-induced cell death involves activation of RIPK1/PARP, and modification with myristic acid enhances its stability and tumor-targeting capability.

Ovarian cancer (OC) is a highly lethal gynecological malignancy, often diagnosed at advanced stages with limited treatment options. Here, we demonstrate that the antimicrobial peptide CS-piscidin significantly inhibits OC cell proliferation, colony formation, and induces cell death. Mechanistically, CS-piscidin causes cell necrosis by compromising the cell membrane. Furthermore, CS-piscidin can activate Receptor-interacting protein kinase 1 (RIPK1) and induce cell apoptosis by cleavage of PARP. To improve tumor targeting ability, we modified CS-piscidin by adding a short cyclic peptide, cyclo-RGDfk, to the C-terminus (CS-RGD) and a myristate to the N-terminus (Myr-CS-RGD). Our results show that while CS-RGD exhibits stronger anti-cancer activity than CS-piscidin, it also causes increased cytotoxicity. In contrast, Myr-CS-RGD significantly improves drug specificity by reducing CS-RGD toxicity in normal cells while retaining comparable antitumor activity by increasing peptide stability. In a syngeneic mouse tumor model, Myr-CS-RGD demonstrated superior anti-tumor activity compared to CS-piscidin and CS-RGD. Our findings suggest that CS-piscidin can suppress ovarian cancer via multiple cell death forms and that myristoylation modification is a promising strategy to enhance anti-cancer peptide performance.

ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability.

Reprogramming of lipid metabolism, which modulates energy utilization and cell signaling, maintains cell survival and promotes cancer metastasis in cancer cells. Ferroptosis is a type of cell necrosis caused by an overload of lipid oxidation, which has been demonstrated to be involved in cancer cell metastasis. However, the mechanism by which fatty acid metabolism regulates the anti-ferroptosis signaling pathways is not fully understood. The formation of ovarian cancer spheroids helps to counteract the hostile microenvironment of the peritoneal cavity with low oxygen, shortage of nutrients, and subjected to platinum therapy. Previously, we demonstrated that Acyl-CoA synthetase long-chain family member 1 (ACSL1) promotes cell survival and peritoneal metastases in ovarian cancer, but the mechanism is still not well elucidated. In this study, we demonstrate that the formation of spheroids and under exposure to platinum chemotherapy increased the levels of anti-ferroptosis proteins as well as ACSL1. Inhibition of ferroptosis can enhance spheroid formation and vice versa. Genetic manipulation of ACSL1 expression showed that ACSL1 reduced the level of lipid oxidation and increased the resistance to cell ferroptosis. Mechanistically, ACSL1 increased the N-myristoylation of ferroptosis suppressor 1 (FSP1), resulting in the inhibition of its degradation and translocation to the cell membrane. The increase in myristoylated FSP1 functionally counteracted oxidative stress-induced cell ferroptosis. Clinical data also suggested that ACSL1 protein was positively correlated with FSP1 and negatively correlated with the ferroptosis markers 4-HNE and PTGS2. In conclusion, this study demonstrated that ACSL1 enhances antioxidant capacity and increases ferroptosis resistance by modulating the myristoylation of FSP1.

miR-93-5p suppresses ovarian cancer malignancy and negatively regulate CCND2 by binding to its 3'UTR region.

Ovarian cancer is the most fatal gynecological cancer worldwide, yet the fundamental mechanism of malignancy acquisition in ovarian cancer remains unknown. miRNA has been implicated to a variety of diseases, including cancer initiation and progression. Cyclin-D2 (CCND2) is ubiquitously implicated in cancer uncontrol cell proliferation. Bioinformatic research revealed that CCND2 is a candidate gene for miR-93-5p with a binding site in its 3'UTR region in the current study. Using our ovarian cancer sample, we verified that miR-93-5p is negatively correlated with CCND2 mRNA and protein levels. Luciferase report assay revealed miR-93-5p inhibits CCND2 production through binding to the 3'UTR region. The expression of miR-93-5p in ovarian cancer patient samples was then determined, and a survival analysis was performed. Our findings showed that miR-93-5p is downregulated in ovarian cancer and is a favorable predictive factor in ovarian cancer patient. CCK8 assay, wound healing assay and flow cytometry-based cell cycle and apoptotic cell analyses were employed here. We found that miR-93-5p suppresses ovarian cancer cell proliferation and migration while enhances cell death. Our research certified that miR-93-5p reduces ovarian cancer malignancy by targeting CCND2.

Focal adhesion kinase inhibitors, a heavy punch to cancer.

Kinases are the ideal druggable targets for diseases and especially were highlighted on cancer therapy. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and its aberrant signaling extensively implicates in the progression of most cancer types, involving in cancer cell growth, adhesion, migration, and tumor microenvironment (TME) remodeling. FAK is commonly overexpressed and activated in a variety of cancers and plays as a targetable kinase in cancer therapy. FAK inhibitors already exhibited promising performance in preclinical and early-stage clinical trials. Moreover, substantial evidence has implied that targeting FAK is more effective in combination strategy, thereby reversing the failure of chemotherapies or targeted therapies in solid tumors. In the current review, we summarized the drug development progress, chemotherapy strategy, and perspective view for FAK inhibitors.