HDAC inhibitor chidamide overcomes drug resistance in chronic myeloid leukemia with the T315i mutation through the Akt-autophagy pathway

by Selleckchem | Aug 12 2023

Currently, therapy for Chronic Myeloid Leukemia (CML) patients with the T315I mutation is a major challenge in clinical practice due to its high degree of resistance to first- and second-generation Tyrosine Kinase Inhibitors (TKIs). Chidamide, a Histone Deacetylase Inhibitor (HDACi) drug, is currently used to treat peripheral T-cell lymphoma. In this study, we investigated the anti-leukemia effects of chidamide on the CML cell lines Ba/F3 P210 and Ba/F3 T315I and primary tumor cells from CML patients with the T315I mutation. The underlying mechanism was investigated, and we found that chidamide could inhibit Ba/F3 T315I cells at G0/G1 phase. Signaling pathway analysis showed that chidamide induced H3 acetylation, downregulated pAKT expression and upregulated pSTAT5 expression in Ba/F3 T315I cells. Additionally, we found that the antitumor effect of chidamide could be exerted by regulating the crosstalk between apoptosis and autophagy. When chidamide was used in combination with imatinib or nilotinib, the antitumor effects were enhanced compared with chidamide alone in Ba/F3 T315I and Ba/F3 P210 cells. Therefore, we conclude that chidamide may overcome T315I mutation-related drug resistance in CML patients and works efficiently if used in combination with TKIs.

Comments:

The study you described investigated the potential therapeutic effects of chidamide, a Histone Deacetylase Inhibitor (HDACi) drug, on Chronic Myeloid Leukemia (CML) cells carrying the T315I mutation. This mutation is associated with a high degree of resistance to first- and second-generation Tyrosine Kinase Inhibitors (TKIs), which poses a significant challenge in the treatment of CML patients.

The researchers conducted their experiments using CML cell lines (Ba/F3 P210 and Ba/F3 T315I) as well as primary tumor cells obtained from CML patients with the T315I mutation. They found that chidamide exhibited anti-leukemia effects on these cells. Specifically, chidamide was able to inhibit the growth of Ba/F3 T315I cells by inducing cell cycle arrest at the G0/G1 phase.

The study further investigated the underlying molecular mechanisms involved in chidamide's effects. The researchers observed that chidamide induced acetylation of histone H3, a process associated with changes in gene expression. They also found that chidamide downregulated the expression of pAKT (phosphorylated AKT) and upregulated the expression of pSTAT5 (phosphorylated STAT5) in Ba/F3 T315I cells. These findings suggest that chidamide may modulate signaling pathways implicated in CML, potentially contributing to its anti-leukemia effects.

Additionally, the researchers explored the interplay between apoptosis (programmed cell death) and autophagy (a cellular recycling process) in response to chidamide treatment. They found that chidamide regulated this crosstalk, implying that it may influence both of these cellular processes to exert its antitumor effects.

Moreover, the study examined the combination of chidamide with two TKIs, imatinib and nilotinib. The researchers observed that when chidamide was used in conjunction with either of these TKIs, the antitumor effects were enhanced compared to chidamide alone in both Ba/F3 T315I and Ba/F3 P210 cells. This suggests that combining chidamide with TKIs may be an effective strategy to overcome drug resistance associated with the T315I mutation in CML patients.

In conclusion, the study demonstrates that chidamide has potential as a therapeutic option for CML patients with the T315I mutation. It can inhibit the growth of CML cells, induce cell cycle arrest, modulate signaling pathways, and regulate the interplay between apoptosis and autophagy. Furthermore, combining chidamide with TKIs may enhance its antitumor effects. These findings provide valuable insights into overcoming drug resistance in CML and offer a potential treatment approach for patients with the T315I mutation.