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Clinical responses to second generation androgen signaling inhibitors (e.g., enzalutamide) in metastatic castration-resistant prostate cancer (mCRPC) are variable and transient, and are associated with dose limiting toxicities, including rare but severe CNS effects. We hypothesized that changes to iron metabolism coincident with more advanced disease might be leveraged for tumor-selective delivery of antiandrogen therapy. Using the recently described chemical probes SiRhoNox and 18F-TRX in mCRPC models, we found elevated Fe2+ to be a common feature of mCRPC in vitro and in vivo. We next synthesized ferrous-iron activatable drug conjugates of second and third-generation antiandrogens and found these conjugates possessed comparable or enhanced antiproliferative activity across mCRPC cell line models. Mouse pharmacokinetic studies showed that these prototype antiandrogen conjugates are stable in vivo and limited exposure to conjugate or free antiandrogen in the brain. Our results reveal elevated Fe2+ to be a feature of mCRPC that might be leveraged to improve the tolerability and efficacy of antiandrogen therapy.
Asunto(s)
Antagonistas de Andrógenos , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Animales , Ratones , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Hierro , Nitrilos/farmacología , Resultado del TratamientoRESUMEN
Senescent cells can spread the senescent phenotype to other cells by secreting senescence-associated secretory phenotype factors. The resulting paracrine senescent cells make a significant contribution to the burden of senescent cell accumulation with age. Previous efforts made to characterize paracrine senescence are unreliable due to analyses being based on mixed populations of senescent and non-senescent cells. Here, we use dipeptidyl peptidase-4 (DPP4) as a surface maker to isolate senescent cells from mixed populations. Using this technique, we enrich the percentage of paracrine senescence from 40% to 85%. We then use this enriched culture to characterize DPP4+ primary and paracrine senescent cells. We observe ferroptosis dysregulation and ferrous iron accumulation as a common phenomenon in both primary and paracrine senescent cells. Finally, we identify ferroptosis induction and ferrous iron-activatable prodrug as a broad-spectrum senolytic approach to ablate multiple types of primary and paracrine senescent cells.
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Senescencia Celular , Hierro , Senescencia Celular/genética , Dipeptidil Peptidasa 4/metabolismo , FenotipoRESUMEN
Dysregulated iron homeostasis underlies diverse pathologies, from ischemia-reperfusion injury to epithelial-mesenchymal transition and drug-tolerant "persister" cancer cell states. Here, we introduce ferrous iron-activatable luciferin-1 (FeAL-1), a small-molecule probe for bioluminescent imaging of the labile iron pool (LIP) in luciferase-expressing cells and animals. We find that FeAL-1 detects LIP fluctuations in cells after iron supplementation, depletion, or treatment with hepcidin, the master regulator of systemic iron in mammalian physiology. Utilizing FeAL-1 and a dual-luciferase reporter system, we quantify LIP in mouse liver and three different orthotopic pancreatic ductal adenocarcinoma tumors. We observed up to a 10-fold increase in FeAL-1 bioluminescent signal in xenograft tumors as compared to healthy liver, the major organ of iron storage in mammals. Treating mice with hepcidin further elevated hepatic LIP, as predicted. These studies reveal a therapeutic index between tumoral and hepatic LIP and suggest an approach to sensitize tumors toward LIP-activated therapeutics.
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Hierro , Neoplasias , Humanos , Ratones , Animales , Hepcidinas , Luciferinas , Xenoinjertos , Hígado , Luciferasas , MamíferosRESUMEN
KRAS mutations drive a quarter of cancer mortality, and most are undruggable. Several inhibitors of the MAPK pathway are FDA approved but poorly tolerated at the doses needed to adequately extinguish RAS/RAF/MAPK signaling in the tumor cell. We found that oncogenic KRAS signaling induced ferrous iron (Fe2+) accumulation early in and throughout mutant KRAS-mediated transformation. We converted an FDA-approved MEK inhibitor into a ferrous iron-activatable drug conjugate (FeADC) and achieved potent MAPK blockade in tumor cells while sparing normal tissues. This innovation allowed sustainable, effective treatment of tumor-bearing animals, with tumor-selective drug activation, producing superior systemic tolerability. Ferrous iron accumulation is an exploitable feature of KRAS transformation, and FeADCs hold promise for improving the treatment of KRAS-driven solid tumors.
Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Animales , Línea Celular Tumoral , Hierro/farmacología , Mutación/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas p21(ras)/genética , Transducción de SeñalRESUMEN
Sterically shielded 1,2,4-trioxolanes prepared by Griesbaum co-ozonolysis have been utilized as chemical sensors of ferrous iron in several recently described chemical probes of labile iron. Here we report optimized conditions for co-ozonolysis that proceed efficiently and with high diastereoselectivity across an expanded range of substrates, and should enable a new generation of labile iron probes with altered reaction kinetics and physicochemical properties.
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[This corrects the article DOI: 10.1039/D1RA05932G.].
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Chemical tools capable of detecting ferrous iron with oxidation-state specificity have only recently become available. Coincident with this development in chemical biology has been increased study and appreciation for the importance of ferrous iron during infection and more generally in host-pathogen interaction. Some of the recent findings are surprising and challenge long-standing assumptions about bacterial iron homeostasis and the innate immune response to infection. Here, we review these recent developments and their implications for antibacterial therapy.
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Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Interacciones Huésped-Patógeno , Hierro/farmacología , HumanosRESUMEN
The recent emergence of oxidation state selective probes of cellular iron has produced a more nuanced understanding of how cells utilize this crucial nutrient to empower enzyme function, and also how labile ferrous iron contributes to iron-dependent cell death (ferroptosis) and other disease pathologies including cancer, bacterial infections, and neurodegeneration. These findings, viewed in light of the Fenton chemistry promoted by ferrous iron, suggest a new category of therapeutics exhibiting ferrous iron-dependent pharmacology. While still in its infancy, this nascent field draws inspiration from the remarkable activity and tremendous clinical impact of the antimalarial artemisinin. Here, we review recent insights into the role of labile ferrous iron in biology and disease, and describe new therapeutic approaches designed to exploit this divalent transition metal.
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Ferroptosis , Hierro , Muerte Celular , Oxidación-ReducciónRESUMEN
The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogues with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogues bearing a trans-3â³ carbamate side chain and find these to be superior, both in vitro and in vivo, to the previously reported amides. We identified multiple analogues that surpass the oral efficacy of arterolane in the Plasmodium berghei model while exhibiting drug-like properties (logD, solubility, metabolic stability) similar or superior to next-generation clinical candidates like E209 and OZ609. While the preclinical assessment of new analogues is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class.