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http://dx.doi.org/10.5487/TR.2009.25.4.181

Cytotoxic Effects on HL-60 Cells of Myosin Light Chain Kinase Inhibitor ML-7 Alone and in Combination with Flavonoids  

Lee, Joong-Won (School of Public Health and Institute of Health and Environment, Seoul National University)
Kim, Yang-Jee (School of Public Health and Institute of Health and Environment, Seoul National University)
Choi, Young-Joo (School of Public Health and Institute of Health and Environment, Seoul National University)
Woo, Hae-Dong (School of Public Health and Institute of Health and Environment, Seoul National University)
Kim, Gye-Eun (School of Public Health and Institute of Health and Environment, Seoul National University)
Ha, Tae-Kyung (School of Public Health and Institute of Health and Environment, Seoul National University)
Lee, Young-Hyun (School of Public Health and Institute of Health and Environment, Seoul National University)
Chung, Hai-Won (School of Public Health and Institute of Health and Environment, Seoul National University)
Publication Information
Toxicological Research / v.25, no.4, 2009 , pp. 181-188 More about this Journal
Abstract
Uncontrolled cell growth and increased cell proliferation are major features of cancer that are dependent on the stable structure and dynamics of the cytoskeleton. Since stable cytoskeleton structure and dynamics are partly regulated by myosin light chain kinase (MLCK), many current studies focused on MLCK inhibition as a chemotherapeutic target. As a potent and selective MLCK inhibitor, ML-7 [1-(5-iodonaphthalene-1-sulfonyl)-1 H-hexahydro-1,4-diazapine hydrochloride] is a promising candidate for an anticancer agent, which would induce apoptosis as well as prevents invasion and metastasis in certain types of cancer cells. This study assessed cytotoxic effects of ML-7 against HL-60 cells and therapeutic efficacy of ML-7 as a potential antileukemia agent. Trypan-blue exclusion assays showed dose- and time- dependent decreases in ML-7 treated HL-60 cells (p<0.05). Comet assays revealed a significant increase in DNA damage in HL-60 cells after treatment with $40{\mu}M$ ML-7 for 2h. Sub-G1 fractions, analyzed by flow cytometry increased in a dose-dependent manner, suggesting that ML-7 can induce apoptotic cell death in HL-60 cells. ML-7 was selectively cytotoxic towards HL-60 cells; not affecting normal human lymphocytes. That selective effect makes it a promising potential anti-leukemia agent. In addition, anticancer efficacy of ML-7 in combination with flavonoids (genistein or quercetin) or anticancer drugs (cisplatin or Ara-C) against HL-60 cells was assessed. Combination of ML-7 with flavonoids increased the anti-cancer effect of ML-7 to a greater extent than combination with the anticancer drugs. This implies that ML-7 in combination with flavonoids could increase the efficacy of anticancer treatment, while avoiding side effects cansed by conventional anticancer drug-containing combination chemotherapy.
Keywords
Myosin light chain kinase inhibitor; 1-(5-iodonaphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazapine hydrochloride (ML-7); Apoptosis; DNA damage; Flavonoids; HL-60 cells;
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