Iron chelators target both proliferating and quiescent cancer cells

Abstract

Poorly vascularized areas of solid tumors contain quiescent cell populations that are resistant to cell cycle-active cancer drugs. The compound VLX600 was recently identified to target quiescent tumor cells and to inhibit mitochondrial respiration. We here performed gene expression analysis in order to characterize the cellular response to VLX600. The compound-specific signature of VLX600 revealed a striking similarity to signatures generated by compounds known to chelate iron. Validation experiments including addition of ferrous and ferric iron in excess, EXAFS measurements, and structure activity relationship analyses showed that VLX600 chelates iron and supported the hypothesis that the biological effects of this compound is due to iron chelation. Compounds that chelate iron possess anti-cancer activity, an effect largely attributed to inhibition of ribonucleotide reductase in proliferating cells. Here we show that iron chelators decrease mitochondrial energy production, an effect poorly tolerated by metabolically stressed tumor cells. These pleiotropic features make iron chelators an attractive option for the treatment of solid tumors containing heterogeneous populations of proliferating and quiescent cells.

MYC is downregulated by a mitochondrial checkpoint mechanism

“…In our present investigation we identify the existence of a mitochondrial retrograde signaling mechanism whereby perturbation of mitochondrial function leads to a concomitant down-regulation of MYC expression, linking MYC-regulated cell proliferation to mitochondrial integrity. We initially observed this cross talk between mitochondria and MYC via our investigations on VLX600, a novel small molecule mitochondrial inhibitor currently in phase I clinical trials for the treatment of solid tumors [ 31 , 48 ] (NCT02222363, ClinicalTrials.gov ). The existence of mitochondrial retrograde signaling has been extensively delineated in the budding yeast S. cerevisiae where perturbation of mitochondrial function induces the mitochondria-to-nucleus (Rtg) signaling pathway [ 12 ].…”

Altered Iron Metabolism and Impact in Cancer Biology, Metastasis, and Immunology

“…Poor nutrient and oxygen availability within the microenvironment cause cancer cells to secrete factors that inhibit the Akt pathway, resulting in slowly proliferating, quiescent cells and induction of pro-survival autophagy (178). Interestingly, iron chelating agents such ciclopirox olamine (CPX) and VLX600, have been shown to inhibit growth of both proliferating and quiescent cancer cells (179). Through chelation of iron, activity of the iron-dependent enzymes that form part of the electron transport chain become impaired resulting in mitochondrial dysfunction (180).…”

“…A screen for drugs that preferentially target quiescent cells in colon cancer spheroids identified VLX600 as an ideal candidate. Although the precise mechanism of action was unknown at the time, analysis using the Connectivity Map database determined iron chelators CPX and DFO produced similar gene expression profiles, suggesting iron chelation was the mode of action for VLX600 (179). Indeed, compound modeling and subsequent cell culture studies with/without iron supplementation confirmed the cytotoxicity of VLX600 was attributable to iron chelation.…”

Growth Inhibition of a Novel Iron Chelator, DpdtC, against Hepatoma Carcinoma Cell Lines Partly Attributed to Ferritinophagy-Mediated Lysosomal ROS Generation

“…A cancer cell has higher iron demand than normal cell; reduction of iron availability will be a favor to inhibit cancer cell proliferation. One of the mechanisms of iron chelators is a disturbance of iron homeostasis [ 13 – 17 ], in addition, iron chelators can also induce apoptosis, autophagy, and inactivate ribonucleotide reductase. Therefore, iron chelation has been considered as a promising strategy in cancer therapy.…”