EFECTOS CITOTÓXICOS DE LAS COMBINACIONES DE LA AURANOFINA CON DOS INHIBIDORES DE LA PROTEÍNA QUINASA CK2 EN UNA LÍNEA CELULAR DE LINFOCITOS T.

Auranofin (AF) is an antiarthritic drug with potential anticancer activity. By inhibiting thioredoxin reductase (TrxR) activity and increasing intracellular reactive oxygen species levels, AF can induce a lethal oxidative stress response in malignant cells. However, AF can activate the antioxidant transcription factor Nrf2 which may limit its efficacy. Because phosphorylation by kinases such as CK2 is essential for the full activation of Nrf2, the combinations of AF with the CK2 inhibitors emodin (EM) and TBB, were evaluated in Jurkat T cells by using a fixed dose ratio according to the Chou-Talalay method. The TrxR activity was potently inhibited by low nanomolar concentrations of AF. Moreover, by treatment with AF 1 µM, the observed decrease of cell viability was partly reversed by pretreatment with catalase. At the same concentration, AF increased the total thiols whereas inhibition of GSH synthesis with buthionine sulfoximine, followed by incubation with AF, resulted in stronger inhibition of viability. These results suggested that AF stimulates an adaptive response to oxidative stress in Jurkat cells. Essentially, the combinations of AF with EM (molar ratio AF/EM = 1/12) or TBB (molar ratio AF/TBB = 1/50) synergistically inhibited cell proliferation and induced cell death. [ABSTRACT FROM AUTHOR]