کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
2580909 1130165 2011 12 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
A novel parthenin analog exhibits anti-cancer activity: Activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells
موضوعات مرتبط
علوم زیستی و بیوفناوری علوم محیط زیست بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
A novel parthenin analog exhibits anti-cancer activity: Activation of apoptotic signaling events through robust NO formation in human leukemia HL-60 cells
چکیده انگلیسی

This study describes the anti-cancer activity of P19, an analog of parthenin. P19 induced apoptosis in HL-60 cells and inhibited cell proliferation with 48 h IC50 of 3.5 μM. At 10 mg/kg dose, it doubled the median survival time of L1210 leukemic mice and at 25 mg/kg it inhibited Ehrlich ascites tumor growth by 60%. Investigation of the mechanism of P19 induced apoptosis in HL-60 cells revealed that N-acetyl-l-cysteine (NAC) and s-methylisothiourea (sMIT) could reverse several molecular events that lead to cell death by inhibiting nitric oxide (NO) formation. It selectively produced massive NO in cells while quenching the basal ROS levels with concurrent elevation of GSH. P19 disrupted mitochondrial integrity leading to cytochrome c release and caspase-9 activation. P19 also caused caspase-8 activation by selectively elevating the expression of DR4 and DR5. All these events lead to the activation of caspase-3 leading to PARP-1 cleavage and DNA fragmentation. However, knocking down of AIF by siRNA also suppressed the apoptosis substantially thus indicating caspase independent apoptosis, too. Further, contrary to enhanced iNOS expression, its transcription factor, NF-κB (p65) was cleaved with a simultaneous increase in cytosolic IκB-alpha. In addition, P19 potently inhibited pro-survival proteins pSTAT3 and survivin. The multi-modal pro-apoptotic activity of P19 raises its potential usefulness as a promising anti-cancer therapeutic.

Schematic presentation of the mechanism of apoptosis induced by parthenin analog P19 in HL-60 cells.Figure optionsDownload as PowerPoint slideHighlights
► The parthenin analog P19 shows promising in vitro and in vivo anticancer activity.
► P19 kills human leukemia HL-60 cells by apoptosis.
► Nitric oxide synthase (iNOS) plays key role in P19 induced apoptosis.
► P19 requires both caspases and AIF (apoptosis inducing factor) for execution of apoptosis.
► P19 induced apoptosis is associated with down-regulation of NF-κB and STAT3.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Chemico-Biological Interactions - Volume 193, Issue 3, 30 September 2011, Pages 204–215
نویسندگان
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