Targeting Mitochondrial Iron Metabolism Suppresses Tumor Growth and Metastasis by Inducing Mitochondrial Dysfunction and Mitophagy

Abstract

Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (i) impairment of iron-sulfur [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (ii) inhibition of mitochondrial respiration leading to mitochondrial reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anticancer drug via mitochondrial targeting. Significance: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death.

Acquired Evolution of Mitochondrial Metabolism Regulated by HNF1B in Ovarian Clear Cell Carcinoma

“…Mitochondria play a crucial role in ferroptosis [64][65][66]; therefore, we believe that resistance to chemotherapies and ferroptosis could be overcome by activating mitochondrial function as a novel attractive therapeutic target in ovarian CCC. Targeting mitochondria itself using iron chelator results in the inhibition of the proliferation and induction of cell death via interfering with the iron metabolism and destabilizing the mitochondria in cancer cells [67]. pression of SMAD6 expression, which is repressed by CDKN2A as an HNF1B-interacting protein [60].…”

An Analysis of the Multifaceted Roles of Heme in the Pathogenesis of Cancer and Related Diseases

“…For example, Hx scavenges labile heme and normalizes heme-induced dysfunction in SCD [255] and acute and chronic lung injury [251,253]. Mitochondrially targeted deferoxamine (mitoDFO) that chelates mitochondrial [Fe-S] clusters/heme iron suppresses proliferation and migration and induces cell death in varied cancer types, including breast, ovarian, and pancreatic cancers [24]. Inhibition of heme uptake and heme synthesis by heme-sequestering peptides (HSPs) and cyclopamine tartrate (CycT), respectively, represses lung tumor growth [21,26,28].…”

“…Hence, the characterization of heme-associated pathogenesis and regulators will advance the study of potential therapeutic approaches targeting heme for the treatment of cancer and other diseases. [24]. Inhibition of heme uptake and heme synthesis by heme-sequestering peptides (HSPs) and cyclopamine tartrate (CycT), respectively, represses lung tumor growth [21,26,28].…”

“…Growing evidence indicates that various cancers, including lung cancer, primarily rely on mitochondria to produce ATP, which fuels tumor proliferation, making mitochondrial respiration an attractive target in cancer therapy [22][23][24]. Lung cancer accounts for almost one-quarter of all cancer mortality in the United States, and NSCLC is the most common form of lung cancer, comprising about 80% of lung cancer cases [25].…”

Iron–Sulfur Cluster Biogenesis as a Critical Target in Cancer

“…MitoDFO can enhance cancer cell killing by impairing Fe–S biogenesis to disrupt mitochondrial function and generate ROS. Despite the interest in DFO and its pre-clinical promise as a cancer therapy, clinical trials in neuroblastoma and prostate cancer patients yielded limited benefit for DFO utilization [ 140 , 141 , 142 ]. The poor clinical trial results in combination with poor bioavailability (t 1/2, plasma ≈ 10 min) and subcutaneous administration of DFO have led to a search for more promising iron chelators [ 142 ].…”