Posted: Friday, March 11, 2022
Abnormal iron homeostasis is implicated in carcinogenesis and tumor progression, and it may well represent a novel therapeutic approach to high-risk or refractory diffuse large B-cell lymphoma (DLBCL). By establishing a gene expression–based risk score—the Iron Score—Jérôme Moreaux, PhD, of the University of Montpellier, France, and colleagues determined that a lysosomal iron-targeting small molecule, ironomycin, developed by coauthor Raphaël Rodriguez, PhD, of the Institute Curie, France, may inhibit DLBCL proliferation. Ironomycin also seems to induce significant cell growth inhibition, ferroptosis, and autophagy, according to research published in Cancer Research.
“Abnormal iron homeostasis is implicated in carcinogenesis and the progression of many tumors. Ironomycin is a synthetic derivative of salinomycin that presents an antineoplastic effect by accumulating and sequestering iron in lysosomes,” the authors stated. “Altogether, these data demonstrate that a subgroup of high-risk DLBCL patients can be identified with the Iron Score that can potentially benefit from targeting iron homeostasis.”
In this study, researchers identified 11 genes involved in the regulation of iron homeostasis that demonstrated a significant prognostic value; when combined, these genes formed the Iron Score. High expression of three genes—ALAS1, HIF1A, and LRP2—was associated with a good prognosis, whereas high expression of eight other genes was associated with a poor prognosis, including HMOX1, HMOX2, and HFE. The prognostic value of the Iron Score was validated for overall survival in several independent patient cohorts.
Dr. Moreaux and colleagues also analyzed the effect of ironomycin and two clinically approved iron chelators, deferoxamine and deferasirox. Ironomycin exhibited significant toxicity against DLBCL cells at nanomolar concentrations—without major toxicity for non-tumor cells—compared with the other iron chelators. Additionally, significant synergistic effects were observed by combining ironomycin with doxorubicin, BH3 mimetics, Bruton’s tyrosine kinase inhibitors, or Syk tyrosine kinase inhibitors.
Disclosure: The study authors reported no conflicts of interest.