Arsenic trioxide cooperates with all-trans retinoic acid to enhance mitogen-activated protein kinase activation and differentiation in PML-RAR alpha negative human myeloblastic leukemia cells

作者：Nayak Satyaprakash; Shen Miaoqing; Bunaciu Rodica P; Bloom Stephen E; Varner Jeffrey D; Yen Andrew^*

来源：Leukemia and Lymphoma, 2010, 51(9): 1734-1747.

DOI：10.3109/10428194.2010.501535

• HL-60
• all-trans retinoic acid
• arsenic trioxide
• MAPK
• differentiation

Arsenic trioxide (ATO) synergistically promotes all-trans retinoic acid (ATRA)-induced differentiation of PML-RAR alpha negative HL-60 myeloblastic leukemia cells. In PML-RARa positive myeloid leukemia cells, ATO is known to cause degradation of PML-RAR alpha with subsequent induced myeloid differentiation. We found that ATO by itself does not cause differentiation of the PML-RAR alpha negative HL-60 cells, but enhances ATRA's capability to cause differentiation. ATO augmented ATRA-induced RAF/MEK/ERK axis signaling, expression of CD11b and p47(PHOX), and inducible oxidative metabolism. ATO enhanced ATRA-induced population growth retardation without evidence of apoptosis or enhanced G1/ G0 growth arrest. Compared to ATRA-treated cells, the ATRA plus ATO-treated cells progressed more slowly through the cell cycle as detected by a slower rate of accumulation in G2/M following nocodazole treatment. Hoechst/PI staining showed that low-dose ATO did not induce apoptosis. In summary, our results indicate that ATO in conjunction with ATRA is of potential chemotherapeutic use in PML-RAR alpha negative leukemias.

• 出版日期2010-9