Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells.

Enzastaurin enhances ATRA-induced differentiation of acute myeloid leukemia cells. Am J Transl Res. 2020;12(12):7836-7854 Authors: Li ZY, Liang C, Ding M, Weng XQ, Sheng Y, Wu J, Lu H, Cai X Abstract All-trans retinoic acid (ATRA) is considered to be the sole clinically-useful differentiating agent in the treatment of acute myeloid leukemia (AML). However, ATRA has been effective only in acute promyelocytic leukemia (APL) but not other subtypes of AML. Therefore, discovering strategies to sensitize cells to ATRA may lead to the development of ATRA-based treatments in non-APL AML patients. In the present study, a clinically-achievable concentration of enzastaurin enhanced ATRA-induced differentiation in AML cell lines, HL-60 and U937 as well as non-APL AML primary cells. Furthermore, it also restored ATRA sensitivity in ATRA-resistant cell line, HL-60Res. Mechanistically, in all these cell lines, enzastaurin-ATRA (enz-ATRA) co-treatment enhanced the protein levels of PU.1, CCAAT/enhancer-binding protein β (C/EBPβ) and C/EBPε. The activity of protein kinase C β (PKCβ) was suppressed by enz-ATRA treatment in HL-60 and HL-60Res cells. However, another PKCβ-selective inhibitor mimicked the cellular and molecular effects of enzastaurin only in HL-60 cells. Furthermore, in U937 cells, enz-ATRA activated MEK and ERK, and a MEK-specific inhibitor suppressed enz-ATRA-triggered differentiation and reduced the protein levels of PU.1, C/EBP...
Source: American Journal of Translational Research - Category: Research Tags: Am J Transl Res Source Type: research