Anti-Leukaemic Activity of Rilpivirine Is Mediated by Aurora A Kinase Inhibition

SIMPLE SUMMARY: Rilpivirine is an anti-viral drug used for treating human immunodeficiency virus (HIV) patients. In a recent study, we demonstrated that rilpivirine inhibited Aurora A, a protein kinase that mainly regulates the mitotic events of the cell-division cycle. Importantly, Aurora A kinase is aberrantly expressed in multiple cancer types, including acute myeloid leukaemia (AML). In the current report, we have shown that rilpivirine suppressed the growth of all AML cells investigated, consistent with its Aurora A kinase inhibition. These findings open the way for exploring this anti-viral drug as a candidate for an anti-cancer drug against AML in further pre-clinical studies. ABSTRACT: Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell-division cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes. In a previous study, we demonstrated that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In the current study, we have further explored the selectivity of rilpivirine for Aurora A kinase inhibition by testing this drug against a panel of 429 kinases. Concurrently, we demonstrated that rilpivirine significantly inhibited the proliferation of AML cells in a time- and concentration-dependent manner that was preceded by G(2)/M cell-cycle arrest leading to the induction of apoptosis. Consistent with its kinase inhibitory role, rilpivirine modulated the expression of critical proteins in the Aurora A kinase-signalling pathway. Importantly, orally administered rilpivirine significantly inhibited tumour growth in an HL-60 xenograft model without showing body weight changes or other clinical signs of toxicity. Furthermore, rilpivirine enhanced the anti-proliferative efficacy of the conventional anti-leukaemic chemotherapeutic agent cytarabine. Collectively, these findings provide the stimulus to explore further the anti-leukaemic activity of the anti-viral drug rilpivirine.