Cytotoxic naphthoquinones from Alkanna cappadocica ( perpendicular).
Journal of Natural Products (impact factor: 3.13). 01/2010;
Article: Intracellular Nanoparticle Aggregation as a Mechanism for Inducing Apoptosis in Breast Cancer Cells[show abstract] [hide abstract]
ABSTRACT: The current paradigm of drug delivery using nanotechnology has been focused on coupling chemotherapeutic molecules to nanoparticulate delivery systems. In this work, we propose that pH-triggered aggregation alone of nanoparticles (that are non-toxic when not aggregated) can induce death in breast cancer cells. We hypothesize that non-toxic, protein nanoparticles, when internalized by endocytosis and triggered to aggregate inside breast cancer cells, will be cytotoxic to them. We will examine (a) the extent to which pH-induced intracellular aggregation is cytotoxic, and (b) whether coupling a chemotherapeutic drug to a pH-responsive protein nanoparticle yields synergistic effects on the toxicity. Although this was a Concept Award which only funded one year of proposed research, a one-year, no-cost extension has been granted to complete the remaining tasks. This current report reflects the one-year update report.08/2010;
Article: ALCAPs induce mitochondrial apoptosis and activate DNA damage response by generating ROS and inhibiting topoisomerase I enzyme activity in K562 leukemia cell line.[show abstract] [hide abstract]
ABSTRACT: Endemic Alkanna cappadocica was used to isolate novel antitumor molecules from Turkish landscapes in our previous studies. In this study, deoxyalkannin (ALCAP1), β,β-dimethylacrylalkannin (ALCAP2), acetylalkannin (ALCAP3), and alkannin (ALCAP4) as well as the novel isolated compounds 5-methoxydeoxyalkannin (ALCAP5), 8-methoxydeoxyalkannin (ALCAP6), 5-methoxyacetylalkannin (ALCAP7), 5-methoxy-β,β-dimethylacrylalkannin (ALCAP8) were characterized. The topoisomerase I (topo I) inhibitory activity of ALCAPs was investigated using in vitro plasmid relaxation assay and found that ALCAP2, 3, 4 and 7 were potent inhibitors at 2-6μM concentrations. Further, DNA damage response to ALCAP treatments was also studied by measuring the H2AX((S139)) and ATM((S1981)) phosphorylations. ALCAP2, 7 and 8 induced the DNA damage and apoptosis, consistently resulted in PARP cleavage at nanomolar concentrations in K562 leukemia cells. Moreover, when the free radical (ROS) generating capacity of the compounds was studied by 2',7'-dichlorofluorescein-diacetate assay using flow cytometry, we found that a known antioxidant N-acetyl-cysteine almost completely abrogated the H2AX((S139)) phosphorylations and the caspase 3 cleavage and activation. Thus, γH2AX((S139)) foci formation remained higher than the control, and an increase in CHK2((T68)) phosphorylation was observed by ALCAP2 and 7 treatments suggested that, these compounds can be potential therapeutics against tumor cell growth because of their unique DNA damaging abilities additional to enzyme inhibition similar to those of doxorubicin.Biochemical and Biophysical Research Communications 06/2011; 409(4):738-44. · 2.48 Impact Factor
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