J Cancer 2020; 11(15):4373-4383. doi:10.7150/jca.39996

Research Paper

Trisenox Disrupts MDM2-DAXX-HAUSP Complex and Induces Apoptosis in a Mouse Model of Acute Leukemia

Sanjay Kumar, Paul B. Tchounwou

Cellomics and Toxicogenomics Research Laboratory, NIH/NIMHD-RCMI Center for Environmental Health, College of Science, Engineering and Technology, Jackson State University, 1400 Lynch Street, Box18750, Jackson, Mississippi, MS 39217, USA.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Citation:
Kumar S, Tchounwou PB. Trisenox Disrupts MDM2-DAXX-HAUSP Complex and Induces Apoptosis in a Mouse Model of Acute Leukemia. J Cancer 2020; 11(15):4373-4383. doi:10.7150/jca.39996. Available from http://www.jcancer.org/v11p4373.htm

File import instruction

Abstract

Trisenox (TX) is successfully used for both de novo and relapsed acute promyelocytic leukemia (APL) treatment. Although TX toxicity to APL cells is mediated by oxidative stress, DNA damage, cell cycle arrest, and apoptosis, its mode of action in the transgenic mice model of APL is poorly understood. We hypothesized that TX regulates cell cycle and apoptosis in APL mice by p53 activation, DNA damage, and reduced expression of MDM2-DAXX-HAUSP complex. To test hypothesis, we treated APL mice with different doses (0, 1.25.2.5.5.0 & 7.5 mg/kg body wt) of TX and collected the liver and bone marrow cells. We applied several techniques to check the expression of PML-RARα, complex molecules, and DNA damage in APL mice bone marrow cells and liver. Our findings indicate that TX reduced the expression of PML-RARα and complex molecules, induced DNA damage and activated p53 leading to cell cycle arrest and apoptosis in APL mice liver. We found that TX promoted more promyelocytes formation with dense granules in bone marrow cells. It also transmitted the DNA damage signal through protein kinase (ATM & ATR) leading to disruption of complex and activation of p53 in APL mice liver. TX induced cell cycle arrest through activation of p53, p21, and reduced expression of cyclin D1 and cyclin dependent kinases (CDK 2, 4 & 6) in mice liver. It also caused apoptosis through upregulation of caspase 3 and Bax expression, and down-regulation of Bcl2 expression. Taken together, these molecular targets provide new insights into TX mode of action in APL mice.

Keywords: Trisenox, p53, DAXX, HAUSP, MDM2.