Latest news with #ferroptosis
Medscape
a day ago
- Health
- Medscape
Lysosomal Iron Catalyzes Cell Death in Resistant Cancers
A team from French research institutes Centre national de la recherche scientifique (CNRS), Institut Curie, and Institut national de la santé et de la recherche médicale (Inserm) has discovered a new class of molecules capable of inducing the death of cancer cells that are resistant to standard treatments. The study was published in Nature on May 7. Harnessing Iron's Properties in Cancer Cells 'In certain cancers, such as pancreatic cancer or sarcomas, therapeutic options are relatively limited,' Raphaël Rodriguez, research director at CNRS and co-author of the study, told Medscape's French edition . Current cancer treatments mainly target primary tumor cells but often fail to eliminate cells with metastatic potential, which are responsible for 70% of cancer-related deaths. To address this, the team developed a new class of molecules — phospholipid degraders — designed to destroy cancer cell membranes and trigger cell death via ferroptosis. 'We used the properties of iron in cancer cells with metastatic potential. These cells express high levels of the CD44 protein on their surface, which allows them to internalize iron — a resource they need to transform and adapt to standard treatments,' Rodriguez explained. This transformation, however, also makes them more vulnerable to ferroptosis, a form of cell death catalyzed by iron. Within lysosomes — the small organelles that break down cellular debris and foreign material — iron reacts with hydrogen peroxide, generating oxygen radicals. These radicals damage lysosomal membranes and initiate a chain reaction that spreads throughout the cell, leading to the formation of peroxidized lipids in the membranes of other organelles and ultimately causing cell death. 'We were the first to link cancer, adaptability, and vulnerability to ferroptosis. Cancer cells can adapt, but they don't have a thousand identities. They have two: one that proliferates and one that spreads. Today, we target proliferation. We also need to target dissemination,' said Rodriguez. Phospholipid Degraders The researchers developed phospholipid degraders that activate ferroptosis. These molecules contain one segment that targets the cell membrane, enabling penetration and accumulation in lysosomes. A second segment enhances iron reactivity in these compartments of pro-metastatic cancer cells, triggering ferroptosis. The molecules, named fentomycin-1 (Fento-1), were made fluorescent to confirm their lysosomal localization using fluorescence microscopy. 'Ferroptosis results from the cell's inability to repair membrane damage,' Rodriguez summarized. Reduction in Tumor Growth Tested on primary patient-derived cells, tumor organoids, human biopsies, and immunocompetent animal models, these molecules demonstrated greater efficacy than standard treatments. In preclinical models of metastatic breast cancer, Fento-1 led to a significant reduction in tumor growth. It also showed strong cytotoxic effects in biopsies of pancreatic cancers and angiosarcomas. 'The most interesting results come when we combine these molecules with current treatments. The response is even better,' emphasized Rodriguez. 'We're not saying our treatment will replace existing therapies. We need a combination,' he added. The next steps include toxicity studies, followed by clinical trials. 'Industry and investors should be interested in developing this new therapeutic strategy.' This work was supported by the Ligue Contre le Cancer (Les équipes labellisées), the European Union's Horizon 2020 research and innovation programme, Fondation pour la Recherche Médicale, Fondation Charles Defforey - Institut de France, Klaus Grohe Foundation, Institut National du Cancer, Région Île-de-France, the French National Research Agency, Fondation Bettencourt Schueller, CNRS, Institut Curie, and Inserm.
Medscape
26-05-2025
- Health
- Medscape
SCD Impairs T-Cell Function in Cancer
Sickle cell disease (SCD) altered CD8+ T-cell chromatin architecture, triggering ferroptosis and weakening antitumor immunity. Hydrogen sulfide (H2S) treatment restored chromatin interactions and enhanced immune responses, improving immunotherapy effectiveness in renal medullary carcinoma. METHODOLOGY: Researchers analyzed CD8+ T cells from peripheral blood mononuclear cells of healthy donors and patients with SCD, examining chromatin architecture changes through Hi-C technology and DNA fluorescence in situ hybridization (FISH). Analysis included CD34+ hematopoietic stem cell–engrafted humanized mice with high human leukocyte engraftment showing over 75% human CD45+ leukocytes for RMC2C1 cell implantation studies. Treatment protocols involved administration of 10 mg/kg GYY4137 intraperitoneally twice weekly for 3 weeks, followed by anti–programmed cell death 1 (PD-1) antibody treatment at 200 μg per mouse twice weekly. TAKEAWAY: CD8+ T cells from patients with SCD exhibited reduced SLC7A11 expression and increased lipid peroxidation compared with healthy control individuals, with a significantly decreased H2S concentration in serum samples ( P < .0001). < .0001). GYY4137 treatment restored SLC7A11 chromatin interactions and enhanced immune function, with combination therapy showing improved antitumor efficacy ( P < .0001). < .0001). Analysis revealed reduced long-range chromatin interactions in SCD CD8+ T cells, particularly affecting genes involved in H2S biosynthesis including CBS and CTH . and . Treatment with GYY4137 and anti–PD-1 increased tumor-resident CD8+ T-cell infiltration ( P < .0001) and boosted cytotoxic activity through higher percentages of granzyme B+ CD8+ T cells. IN PRACTICE: 'Our study revealed that SCD altered CD8+ T cell 3D genome architecture, triggering ferroptosis and weakening antitumor immunity, thereby promoting tumor growth. Using murine and humanized SCD models, we found that disrupted chromosomal interactions in CD8+ T cells reduced the expression of antiferroptotic genes, including SLC7A11 and hydrogen sulfide (H2S) biogenesis genes, thereby increasing susceptibility to ferroptosis. Therapeutic restoration of H2S concentration in SCD mice rescued SLC7A11 expression, mitigated ferroptosis, and enhanced immune and antitumor responses,' the authors of the study wrote. SOURCE: This study was led by Zilong Zhao, The University of Texas MD Anderson Cancer Center in Houston. It was published online on May 12 in Immunity . LIMITATIONS: According to the authors, while Hi-C and DNA FISH analyses revealed chromatin interaction changes in CD8+ T cells under SCD conditions, altered T-cell subtypes and states may contribute to these findings. The researchers noted that while this study highlights SCD's impact on ferroptosis and chromatin architecture, other tumor microenvironment–related factors remain to be examined. Additionally, the use of peripheral blood mononuclear cell–derived humanized mice may limit insights into early immune development and influence the robustness of tumor growth differences. DISCLOSURES: This study was supported by grants from National Institutes of Health, Cancer Prevention and Research Institute of Texas, and Department of Defense. Pavlos Msaouel received funding from Gateway for Cancer Research, the Kidney Cancer Association, the V Foundation, and the MDACC Physician-Scientist Award. Additional disclosures are noted in the original article.
