Fucoidan enhances the therapeutic potential of arsenic trioxide and all-trans retinoic acid in acute promyelocytic leukemia, in vitro and in vivo
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Farzaneh Atashrazm1, Ray M. Lowenthal1, Joanne L. Dickinson1, Adele F. Holloway2, Gregory M. Woods1,2
1Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia
2School of Medicine, University of Tasmania, Hobart, Tasmania 7000, Australia
Gregory M. Woods, email: G.M.Woods@utas.edu.au
Keywords: APL, fucoidan, synergy, ATRA, arsenic trioxide
Received: March 17, 2016 Accepted: May 23, 2016 Published: June 14, 2016
The morbidity and mortality associated with current therapies for acute promyelocytic leukemia (APL) remain a significant clinical concern, despite improvements in patient survival. Consequently, the development of adjuvant therapies that increase efficacy while reducing morbidities is important. Reducing the concentration of the toxic drugs in adjuvant therapy has the potential to reduce unwanted side effects. Therefore, this study aimed to determine the synergistic effects of fucoidan, an anti-tumor agent, with current APL therapies.
When the human APL cell line, NB4, was treated in vitro with fucoidan plus ATO and ATRA at therapeutic and sub-therapeutic doses, there was an increase in sub-G0/G1 cells, annexin V/PI-positive-apoptotic cells and DNA fragmentation. This reduction in proliferation and increase in apoptosis was accompanied by enhanced myeloid differentiation as indicated by an increased expression of CD11b. This was not observed with the AML cell line Kasumi-1, suggesting specificity for APL.
In vivo treatment of APL-bearing mice with fucoidan+ATRA or fucoidan+ATO delayed tumor growth, induced differentiation and increased tumor volume doubling time. The differentiated APL cells derived from the excised tumor mass exhibited decreased CD44 expression in fucoidan+ATRA treated mice. This could translate to decreased cell migration in APL patients.
Our findings provide evidence supporting the use of fucoidan as an adjuvant therapeutic agent in the treatment of APL.
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