TITLE:
1-Chloromethyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinoline-2-sulfonic acid amide, a derivative of tetrahydroisoquinoline, induces granulocytic differentiation of the human leukemic HL-60 cells via G0/G1 phase arrest
AUTHORS:
Sung-Min Ju, Hyun-Ock Pae, Won-Sin Kim, Chai-Ho Lee, Byung-Hun Jeon
KEYWORDS:
Differentiation; G0/G1 Phase Arrest; HL-60 Cells; Tetrahydroisoquinolines; P27Kip1
JOURNAL NAME:
Health,
Vol.5 No.5A,
May
27,
2013
ABSTRACT: Tetrahydroisoquinolines are known to have various
biological effects, including antitumor activity. This study investigated the
effect of 1-chloromethyl-6, 7-dimethoxy-3, 4-dihydro-1H-isoquinoline-2-sulfonic acid
amide (CDST), a newly synthesized anticancer agent, on cellular differentiation
and proliferation in HL-60 cells. Differentiation and proliferation of HL-60
cells were determined through expression of CD11b and CD14 surface antigens
using flow cytometry and nitroblue tetrazolium (NBT) assay, and through
analysis of cell cycle using propidium iodide staining, western blot analysis
and immunoprecipitation, respectively. CDST induced the differentiation of
HL-60, as shown by increased expression of
differentiation surface antigen CD11b (but no significant change in CD14
expression) and increased NBT-reducing functional activity. DNA flow cytometry analysis indicated that CDST markedly
induced a G0/G1 phase arrest of HL-60 cells. Subsequently, we examined the expre-ssion of G0/G1 phase cell cycle-related proteins, including cyclin-dependent
kinases (CDKs), cyclins and cyclin dependent kinase inhibitors (CKIs), during
the differentiation of HL-60. The levels of
CDK2, CDK6, cyclin E and cyclin A were decreased, whereas steady-state
levels of CDK4 and cyclin D1 were unaffected. The expression of the p27Kip1 was markedly increased by CDST, but not p21WAF1/Cip1. Moreover, CDST
markedly enhanced the binding of p27Kip1 with CDK2 and CDK6, resulting
in the reduced activity of both kinases. Taken together, these results demonstrate
that CDST is capable of inducing cellular differentiation and growth inhibition
through p27Kip1 protein-related G0/G1 phase arrest in HL-60 cells.