Induction of granulocytic differentiation in acute promyelocytic leukemia cells (HL-60) by water-soluble chitosan oligomer
Introduction
The conventional approach to treatment of acute myeloid leukemia (AML) has been the use of chemotherapy, which is cytotoxic to malignant clones, is also cytodestructive to normal cells. In addition, some leukemic cells develop resistance to chemotherapy and are therefore difficult to eradicate. Differentiation therapy, which is associated with less adverse effects, has been tested as a leukemia treatment modality. Differentiation therapy has been successful as a treatment for acute promyelocytic leukemia [1]. Several compounds including dimethyl sulfoxide, retinoic acid, phorbol ester and 1,25-dihydroxy vitamin D3 induce AML cells to differentiate toward mature cells. Among them, retinoic acid induces AML cells to differentiate toward granulocytes [2], whereas 1,25-dihydroxy vitamin D3 induces AML cells to differentiate toward monocytes [2].
Chitin (Fig. 1(a)), a polymer of N-acetylglucosamine, is cellulose-like biopolymer present in the exoskeleton of crustaceans and in cell walls of fungi, insects and yeast. Chitosan (Fig. 1(b)) is derived from chitin by deacetylation in the presence of alkali. Chitin and chitosan oligomers can be obtained by either chemical or enzymatic hydrolysis of chitin and chitosan [3]. They have lower viscosity, low molecular weights and short chains and are soluble in neutral aqueous solutions. Subsequently, they seem to be readily absorbed in vivo. Chitin and chitosan oligomers are known to have various biological activities including antitumor activities [4], [5], immuno-enhancing effects [6], increased protective effects against infection with some pathogens [7], antifungal activities [8], and antimicrobial activities [8]. To our knowledge, there is no report on the effect of water-soluble chitosan oligomer (WSCO) on leukemia cell proliferation and differentiation. Thus, the aim of the present investigation was to examine the differentiation-inducing effect of WSCO on the human myeloid leukemia HL-60 cells. To our knowledge, this is the first time it has been shown that WSCO is able to inhibit proliferation of HL-60 cells and induce these cells to differentiate.
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Cells and culture
Human myeloid leukemia HL-60 cells were cultured in suspension in RPMI-1640 medium (GIBCO) containing 10% fetal bovine serum (FBS) (Hyclone), 100 U/ml penicillin and 100 μg/ml streptomycin at 37°C in a humidified atmosphere of 5% CO2 in air. Cells were split every 2–3 days to maintain in an exponential growth. Cell number was assessed by the standard procedure of leukocyte counting using a hemocytometer and cell viability was checked by the ability of cells to exclude trypan blue. The
Results
The HL-60 cell line, derived from a patient with acute promyelocytic leukemia, provides a unique in vitro model for studying the cellular and molecular events involved in the differentiation of normal and leukemic cells [11]. Moreover, recent approaches in the treatment of leukemia include the use of differentiating agents such as all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA) [12]. Thus, the strategy of HL-60 cell differentiation has been accepted as a valid model in
Discussion
The study reported herein reveals new biological activities for water-soluble chitosan oligomer (WSCO). Among the activities of WSCO shown here are the inhibition of growth of HL-60 cells and the differentiation of HL-60 cells to granulocytic cells. In addition, the combination of WSCO and all-trans retinoic acid (ATRA) synergically increased the differentiation of HL-60 cells.
Several leukemic diseases are characterized by a break-down in myeloid cell maturation. To restore the normal
Acknowledgements
This work was supported by grants from the 1999 Korean National Cancer Control Program, Ministry of Health & Welfare, R.O.K., and MRRC supported by Chonbuk Principal Government (2000), Intermedpharm, and C-TRI.
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