RESUMEN

Regions of hypoxia occur in most solid tumours and are known to significantly impact therapy response and patient prognosis. Ag5 is a recently reported silver molecular cluster which inhibits both glutathione and thioredoxin signalling therefore limiting cellular antioxidant capacity. Ag5 treatment significantly reduces cell viability in a range of cancer cell lines with little to no impact on non-transformed cells. Characterisation of redox homeostasis in hypoxia demonstrated an increase in reactive oxygen species and glutathione albeit with different kinetics. Significant Ag5-mediated loss of viability was observed in a range of hypoxic conditions which mimic the tumour microenvironment however, this effect was reduced compared to normoxic conditions. Reduced sensitivity to Ag5 in hypoxia was attributed to HIF-1 mediated signalling to reduce PDH via PDK1/3 activity and changes in mitochondrial oxygen availability. Importantly, the addition of Ag5 significantly increased radiation-induced cell death in hypoxic conditions associated with radioresistance. Together, these data demonstrate Ag5 is a potent and cancer specific agent which could be used effectively in combination with radiotherapy.

RESUMEN

Half-sandwich ruthenium(ii) complexes [(η6-p-cymene)Ru(C^N)-(X)]0/+ (X = Cl, py or 4-NMe2-py) containing a cyclometalated 2-ppy or 1-ppz with a non-coordinated CHO group as a handle for further functionalization have been synthesized to achieve selective cytotoxicity to cancer cells, the more potent compounds acting as proteosynthesis inhibitors; this is a new mode of action for half-sandwich metal complexes.

Asunto(s)

Antineoplásicos/farmacología , Proteínas de Neoplasias/antagonistas & inhibidores , Compuestos Organometálicos/farmacología , Rutenio/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Células CHO , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Cricetulus , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Proteínas de Neoplasias/biosíntesis , Compuestos Organometálicos/síntesis química , Compuestos Organometálicos/química , Rutenio/química , Relación Estructura-Actividad

RESUMEN

Nanomaterials with very low atomicity deserve consideration as potential pharmacological agents owing to their very small size and to their properties that can be precisely tuned with minor modifications to their size. Here, it is shown that silver clusters of three atoms (Ag3 -AQCs)-developed by an ad hoc method-augment chromatin accessibility. This effect only occurs during DNA replication. Coadministration of Ag3 -AQCs increases the cytotoxic effect of DNA-acting drugs on human lung carcinoma cells. In mice with orthotopic lung tumors, the coadministration of Ag3 -AQCs increases the amount of cisplatin (CDDP) bound to the tumor DNA by fivefold without modifying CDDP levels in normal tissues. As a result, CDDP coadministered with Ag3 -AQCs more strongly reduces the tumor burden. Evidence of the significance of targeting chromatin compaction to increase the therapeutic index of chemotherapy is now provided.