Pluto Bioinformatics

GSE95077: Amiloride, an old diuretic drug, is a potential therapeutic agent for multiple myeloma

Bulk RNA sequencing

The introduction of novel therapeutic agents has considerably improved the median survival of patients with multiple myeloma (MM). However, the natural history of the disease is characterized by continuous relapses over time. As a consequence, the development of new drugs is still required to treat MM recurrence. Here, we report for the first time the potent anti-myeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure. Amilorideinduced apoptosis was observed in a broad panel of MM cell lines and in xenograft mouse models. Moreover, amiloride also had a synergistic effect when combined with dexamethasone and melphalan. RNA-seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. Additionally, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, the manageable toxicity profile of amiloride is well known and we did not find a significant systemic toxicity in mice treated with amiloride. Overall, our results provide a mechanistic rationale for the use of amiloride as an alternative treatment option for relapsed MM patients. SOURCE: Norma C. Gutiérrez ( - 12 Centro de Investigación del Cáncer de Salamanca

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