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  • Title: Arsenic trioxide cooperates with all trans retinoic acid to enhance mitogen-activated protein kinase activation and differentiation in PML-RARalpha negative human myeloblastic leukemia cells.
    Author: Nayak S, Shen M, Bunaciu RP, Bloom SE, Varner JD, Yen A.
    Journal: Leuk Lymphoma; 2010 Sep; 51(9):1734-47. PubMed ID: 20615082.
    Abstract:
    Arsenic trioxide (ATO) synergistically promotes all trans retinoic acid (ATRA)-induced differentiation of PML-RARalpha negative HL-60 myeloblastic leukemia cells. In PML-RARalpha positive myeloid leukemia cells, ATO is known to cause degradation of PML-RARalpha with subsequent induced myeloid differentiation. We found that ATO by itself does not cause differentiation of the PML-RARalpha 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-RARalpha negative leukemias.
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