Abstract
All-trans-retinoic acid (ATRA) has held great promise for differentiation-based therapy but reportedly downregulates retinoic acid receptor-α (RARα) in a proteasome-dependent manner, which leads to decreased acute myeloid leukemia (AML) cell differentiation efficiency. Therefore, research strategies that seek to further sensitize cells to retinoids and extend the range of retinoid-affected myeloid malignancies beyond acute promyelocytic leukemia (APL) are key investigative avenues. Here, we show that bortezomib, the first proteasome inhibitor approved for newly diagnosed and relapsed multiple myeloma, exhibited strong synergism with ATRA to promote HL60 and NB4 AML cell differentiation. We observed that bortezomib sensitized AML cells to ATRA-induced morphologic, biochemical, and functional changes, indicative of myeloid differentiation without cell death. In addition, treatment of human leukemia HL60 xenografts with bortezomib and ATRA together did not increase bortezomib-induced progressive weight loss but resulted in significant tumor growth inhibition in addition to increased differentiation (P < 0.05). These enhanced differentiation effects were accompanied by RARα stabilization and STAT1 activation. Taken together, our study was the first to evaluate bortezomib and ATRA synergy in AML cell differentiation and to assess new opportunities for bortezomib and ATRA combination as a promising approach for future differentiation therapy.
Highlights
A breakthrough in clinical oncology was achieved as all-trans-retinoic acid (ATRA; Fig. 1A) sparked intensive differentiation therapy research [1]
To determine whether there are synergistic effects of bortezomib and ATRA (Fig. 1A) on acute myeloid leukemia (AML) cell proliferation, we set up serial concentrations of 2 drugs based on clinical pharmacokinetic studies and determined that bortezomib showed distinct synergy with ATRA in HL60 and NB4 cell lines, with most combination index (CI) values below 0.8 (Supplementary Fig. S1A and S1B)
In NB4 cells, the same treatment combinations significantly inhibited cell proliferation (Fig. 1B, right panel), but at 7.5 nmol/L bortezomib and ATRA treatment, there was evidence of cell death (Fig. 1C, right). These results revealed that bortezomib and ATRA combination treatment inhibited AML cell proliferation without inducing cell death
Summary
A breakthrough in clinical oncology was achieved as all-trans-retinoic acid (ATRA; Fig. 1A) sparked intensive differentiation therapy research [1].
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