A preclinical study showed investigational agent AR-42 increased sensitivity of chronic myeloid leukemia (CML) cells to imatinib and appeared to reverse therapeutic resistance to the medication.1 AR-42 is an oral pan-histone deacetylase (HDAC) inhibitor. Evidence suggests that HDAC inhibitors, when combined with chemotherapeutics, can overcome therapeutic resistance in leukemia. The study findings were published in Life Sciences.

“IM [imatinib] represents a significant advance in the first-line treatment of CML,” the study authors wrote. “Yet a large number of CML patients become resistant to IM, which has been challenging thus far.”

To elucidate the effect of AR-42 and imatinib, study researchers performed a variety of assays on human CML cell line K562 and the imatinib-resistant subline K562R. Cells were exposed to imatinib and AR-42 alone and in combination.

Continue Reading

Related Articles

The combination of AR-42 and imatinib showed synergistic activity, together hindering CML cell proliferation, slowing migration and invasion, and inducing cell apoptosis and cell cycle arrest.

HDAC1 expression was also investigated to clarify the mechanism by which AR-42 and imatinib exert synergistic activity. Researchers found that the addition of AR-42 increased the ability of imatinib to inhibit HDAC1 expression in K562 and K562R cells. HDAC1 was expressed at higher levels in K562R cells than K562 cells. HDAC1 overexpression reversed the effects of exposure to imatinib with AR-42 in K562 cells, and HDAC1 knockdown induced cell death and cell-cycle arrest in K562R cells.

“In conclusion, AR-42 may increase the sensitivity of CML cells to IM and reverse IM resistance by regulating HDAC1 expression,” the study authors wrote. “This study provides new insights into the effects of combined therapy using IM and pan-HDAC inhibitor AR-42, paving the way for overcoming IM resistance in clinical practice.”


  1. Wei D, Lu T, Ma D, et al. Synergistic activity of imatinib and AR-42 against chronic myeloid leukemia cells mainly through HDAC1 inhibition. Life Sci. 2018;211:224-237.