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)-1H-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 µM ML-7 for 2 h. 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 AraC) against HL-60 cells was assessed. Combination of ML-7 with flavonoids increased the anticancer 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.
Highlights
Carcinogenesis and cancer cell growth are dependent on rapid cell division
The organization and stiffness of the cytoskeleton are determined in large part by the forces generated by actin-myosin 11 interactions (Adelstein, 1983; Mahajan et al, 1989; Oe Lanerolle and Paul, 1991), which are regulated by the phosphorylation of serine 19 of the 20-kOa light chain of myosin 11 (MLC20) that is catalyzed by myosin light chain kinase (MLCK)
Oespite the fact that many reports have demonstrated that MLCK inhibition by ML-7 leads to apoptosis in various cell types, its cytotoxic effect on leukemia cells have not yet been elucidated
Summary
Carcinogenesis and cancer cell growth are dependent on rapid cell division. For rapid cancer cell division, stable cytoskeletal structures are needed and dynamic organization of the actin cytoskeleton has to be supported. Several recent studies were limited in their assessment of ML-7 against invasion and metastasis of solid and epithelial cancer cells through regulation of one of the cytoskeleton's functions - cell motility. To overcome those limitations, first (1) the cytotoxic effects of ML-7 on HL-60 promyelocytic leukemia cell line were investigated. Third (3), and based on those observations, we assessed ML-7 as a potential anti-Ieukemia agent by investigating the combined treatment of ML-7 with anticancer drugs and with flavonoids, to explore possible increased anticancer effects. The results showed that, clinically, ML-7 has potential as an anticancer agent and, if combined with flavonoids rather than conventional anticancer drugs, may reduce the side-effects of combination chemotherapy treatment
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