ХирургСпециалисту
 
17 января 2002 00:00   |   Steffen Frese, MDa, Thomas Brunner, PhDb, Mathias Gugger, MDb, Aima Uduehi, PhDa, Ralph A. Schmid, MDa

Enhancement of Apo2L/TRAIL (tumor necrosis factor–related apoptosis-inducing ligand)–induced apoptosis in non–small cell lung cancer cell lines by chemotherapeutic agents without correlation to the expression level of cellular protease caspase-8 inhibitor

Show('171404'); ?>
Objective: Apo2L/tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a potential anticancer drug that promotes apoptosis specifically in tumor cells. Because not all cancer cells are susceptible to Apo2L/TRAIL, the aim of our study was to determine whether non–small cell lung cancer cells can be sensitized by chemotherapeutic agents for Apo2L/TRAIL−induced apoptosis. In addition, endogenous expression levels of the caspase-inhibiting cellular protease caspase-8 inhibitory protein (C-FLIP) were measured to investigate partial resistance to Apo2L/TRAIL.
Methods: Six human lung cancer cell lines (A549, NCI-H358, Calu1, Calu6, SkMes1, and SkLu1) were incubated with soluble Apo2L/TRAIL and two different concentrations each of cisplatin, paclitaxel, doxorubicin, 5−fluorouracil, and camptothecin. After 24 hours the rate of apoptosis was measured by annexin V/propidium iodide staining followed by FACScan analysis. Expression levels of C-FLIP in cell lines and lung cancer biopsy specimens were determined by Western blotting.
Results: Treatment of lung cancer cells with Apo2L/TRAIL alone resulted in apoptotic cell death in four cell lines (P < .001). Combining Apo2L/TRAIL and chemotherapeutic agents enhanced the rate of apoptosis significantly. Statistical analysis revealed a synergistic effect of Apo2L/TRAIL in combination with 1.8 mmol/L camptothecin and 100 µmol/L cisplatin, each in four of the six cell lines (P < .002). Western blot analysis showed that sensitization to Apo2L/TRAIL did not correlate with the expression of cellular protease caspase-8 inhibitory protein. Furthermore, no increased cellular protease caspase-8 inhibitory protein levels relative to those in normal lung tissue could be found in non–small cell lung cancer specimens from 12 patients.
Conclusion: Apo2L/TRAIL−induced apoptosis in non–small cell lung cancer cell lines is significantly enhanced by chemotherapeutic agents. Resistance and sensitization to Apo2L/TRAIL are not correlated with the endogenous expression level of cellular protease caspase-8 inhibitory protein, implying that in non–small cell lung cancer other mechanisms are responsible for inhibition of the Apo2L/TRAIL pathway. Even though the molecular mechanism remains unclear, the combination of Apo2L/TRAIL with chemotherapy may be a promising treatment modality for non–small cell lung cancer.


Load(21024)->Set('counter', (R('DJEM')->Load(21024)->{'counter'}+1))->Store(); ?>

Просмотров страницы: Load(21024)->{'counter'}+$totalcounter); ?>



Смотри также
Path('1147.$'); $foreach__s->Sort('-_publish_time'); $foreach__s->Type('documents'); $foreach__s->Fields('_id'); $foreach_s__total = $foreach__s->Size(); $foreach_s__count = 0; foreach ($foreach__s as $foreach_s) { ++$foreach_s__count; ?>{'_id'} == R('DJEM')->Load(21024)->{'_id'}) { ?>= 2) { ?> Path('1147.$'); $foreach__x->Where('_id != '.R('DJEM')->Load(21024)->{'_id'}); $foreach__x->Sort('-_publish_time'); $foreach__x->Limit(($var['curr']-2).','.$var['num']); $foreach__x->Type('documents'); $foreach__x->Fields('_name','_publish_time','_url','anons','pic','text'); $foreach_x__total = $foreach__x->Size(); $foreach_x__count = 0; foreach ($foreach__x as $foreach_x) { ++$foreach_x__count; ?>
Time('%d %mrs %yy  |  %h:%mm', $foreach_x->{'_publish_time'}); ?>
{'pic'}) { ?> {'_name'}; ?>
{'anons'}) { ?>{'anons'}; ?>CutSpace(R('DJEMScript')->Notags($foreach_x->{'text'}),200); ?>