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Carcinogenesis. 2018 Oct 8;39(10):1292-1303. doi: 10.1093/carcin/bgy004.

Oroxylin A, a natural compound, mitigates the negative effects of TNFα-treated acute myelogenous leukemia cells.

Li H1, Lu N1, Yu X1, Liu X1, Hu P1, Zhu Y1,2, Shen L1, Xu J3, Li Z1, Guo Q1, Hui H1.

Author information

1
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing, People's Republic of China.
2
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, Jiangsu Province, People's Republic of China.
3
Department of Hematology, The Affiliated DrumTower Hospital of Nanjing University Medical School, Nanjing, People's Republic of China.

Abstract

Tumor necrosis factor alpha (TNFα) is a complicated cytokine which is involved in proliferation and differentiation of acute myelogenous leukemia (AML) cells through a poorly understood mechanism. Mechanistic studies indicate that TNFα induced binding of PI3K subunit p85α to N-terminal truncated nuclear receptor RXRα (tRXRα) proteins, and activated AKT. The activated PI3K/AKT pathway negatively regulated differentiation of AML cells through the upregulation of c-Myc. In addition, TNFα also induced activation of nuclear factor κB (NF-κB), a nuclear transcription factor which was shown to promote cell proliferation. The present study demonstrates that oroxylin A, a natural compound isolated from Scutellariae radix, sensitizes leukemia cells to TNFα and markedly enhances TNFα-induced growth inhibition and differentiation of AML cell including human leukemia cell lines and primary AML cells. Activation of PI3K/AKT pathway could be inhibited by oroxylin A through inhibiting expression of tRXRα in NB4 and HL-60-resistant cells. Furthermore, we found that oroxylin A inhibited the activation of NF-κB and the DNA binding activity by TNFα proved by EMSA in these two AML cell lines. Moreover, in vivo studies showed that treatment with oroxylin A in combination with TNFα decreased AML cell population and prolonged survival in NOD/SCID mice with xenografts of primary AML cells. Overall, our results indicate that oroxylin A is able to inhibit the negative effects of TNFα for AML therapy, suggesting that combination of oroxylin A and TNFα have the potential to delay growth or eliminate the abnormal leukemic cells, thus representing a promising strategy for AML treatment.

PMID:
29346508
DOI:
10.1093/carcin/bgy004
[Indexed for MEDLINE]

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