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Givinostat, a type II histone deacetylase inhibitor, induces potent caspase-dependent apoptosis in human lymphoblastic leukemia.
Genes & Cancer 2016 September
Unlike chronic myeloid leukemia, patients with acute lymphoblastic leukemia (ALL) with Philadelphia chromosome (Ph+) do not respond well to Imatinib or tyrosine kinase inhibitors (TKI). In addition, TKI might induce resistant mutations in kinase domain (KD) of ABL in patients with relapsed diseases. Of the histone deacetylase (HDAC) inhibitors, suberoylanilide hydroxamic acid (SAHA) has shown to induce potent cytotoxicity on acute myeloid leukemia cell lines but Givinostat effect on acute lymphoblastic leukemia (ALL) has not been reported. We investigated if Givinostat could exert similar inhibitory effect on SUP-B15, an established B-cell ALL with Philadelphia chromosome (Ph+). Two Ph+ leukemia cell lines, SUP-B15 and an AML cell line K562 were studied in parallel for their responses to Givinostat. Mutation status of TP53 genes was also examined to correlate cellular proliferation and apoptosis. Givinostat significantly inhibited cell proliferation of SUP-B15 (IC50:0.18±0.03μM) and simultaneously inhibited BCR-ABL signal pathway. A remarkable apoptosis was induced by 0.25μM Givinostat in SUP-B15 along with the activation of caspase cascades and increased expression of p21. These inhibitory and proapoptotic effects were not observed in K562 simultaneously treated with Givinostat. Finally our studies showed that TP53 mutation status might determine responder or non-responder to Givinostat in these two Ph+ leukemia cell lines.
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