0 9 Apoptosis Apoptosis NNP 10 13 and and CC 14 20 growth growth NN 21 31 inhibition inhibition NN 32 34 in in IN 35 44 malignant malignant JJ 45 56 lymphocytes lymphocyte NNS 57 62 after after IN 63 72 treatment treatment NN 73 77 with with IN 78 85 arsenic arsenic JJ 86 94 trioxide trioxide NN 95 97 at at IN 98 108 clinically clinically RB 109 119 achievable achievable JJ 120 134 concentrations concentration NNS 135 136 [ [ ( 136 139 see see VB 140 148 comments comment NNS 148 149 ] ] ) 151 161 BACKGROUND BACKGROUND NNP 161 162 : : : 163 170 Arsenic arsenic JJ 171 179 trioxide trioxide NN 180 181 ( ( ( 181 186 As2O3 as2o3 NN 186 187 ) ) ) 188 191 can can MD 192 198 induce induce VB 199 207 clinical clinical JJ 208 217 remission remission NN 218 220 in in IN 221 229 patients patient NNS 230 234 with with IN 235 240 acute acute JJ 241 254 promyelocytic promyelocytic JJ 255 263 leukemia leukemia NN 264 267 via via IN 268 277 induction induction NN 278 280 of of IN 281 296 differentiation differentiation NN 297 300 and and CC 301 311 programmed program VBN 312 316 cell cell NN 317 322 death death NN 323 324 ( ( ( 324 333 apoptosis apoptosis NN 333 334 ) ) ) 334 335 . . . 336 338 We we PRP 339 351 investigated investigate VBD 352 355 the the DT 356 363 effects effect NNS 364 366 of of IN 367 372 As2O3 as2o3 NN 373 375 on on IN 376 377 a a DT 378 383 panel panel NN 384 386 of of IN 387 396 malignant malignant JJ 397 408 lymphocytes lymphocyte NNS 409 411 to to TO 412 421 determine determine VB 422 429 whether whether IN 430 447 growth-inhibitory growth-inhibitory JJ 448 451 and and CC 452 461 apoptotic apoptotic JJ 462 469 effects effect NNS 470 472 of of IN 473 478 As2O3 As2O3 NNP 479 482 can can MD 483 485 be be VB 486 494 observed observe VBN 495 497 in in IN 498 503 these these DT 504 509 cells cell NNS 510 512 at at IN 513 523 clinically clinically RB 524 534 achievable achievable JJ 535 549 concentrations concentration NNS 549 550 . . . 551 558 METHODS methods NNS 558 559 : : : 560 565 Eight eight CD 566 575 malignant malignant JJ 576 587 lymphocytic lymphocytic JJ 588 592 cell cell NN 593 598 lines line NNS 599 602 and and CC 603 610 primary primary JJ 611 619 cultures culture NNS 620 622 of of IN 623 634 lymphocytic lymphocytic JJ 635 643 leukemia leukemia NN 644 647 and and CC 648 656 lymphoma lymphoma NN 657 662 cells cell NNS 663 667 were be VBD 668 675 treated treat VBN 676 680 with with IN 681 686 As2O3 As2O3 NNP 686 687 , , , 688 692 with with IN 693 695 or or CC 696 703 without without IN 704 718 dithiothreitol dithiothreitol NN 719 720 ( ( ( 720 723 DTT DTT NNP 723 724 ) ) ) 725 727 or or CC 728 738 buthionine buthionine NN 739 750 sulfoximine sulfoximine NN 751 752 ( ( ( 752 755 BSO BSO NNP 755 756 ) ) ) 757 758 ( ( ( 758 760 an an DT 761 770 inhibitor inhibitor NN 771 773 of of IN 774 785 glutathione glutathione NN 786 795 synthesis synthesis NN 795 796 ) ) ) 796 797 . . . 798 807 Apoptosis Apoptosis NNP 808 811 was be VBD 812 820 assessed assess VBN 821 823 by by IN 824 828 cell cell NN 829 839 morphology morphology NN 839 840 , , , 841 845 flow flow NN 846 855 cytometry cytometry NN 855 856 , , , 857 864 annexin annexin NN 865 866 V V NNP 867 874 protein protein NN 875 880 level level NN 880 881 , , , 882 885 and and CC 886 894 terminal terminal JJ 895 911 deoxynucleotidyl deoxynucleotidyl NN 912 923 transferase transferase NN 924 932 labeling labeling NN 933 935 of of IN 936 939 DNA dna NN 940 949 fragments fragment NNS 949 950 . . . 951 959 Cellular cellular JJ 960 973 proliferation proliferation NN 974 977 was be VBD 978 988 determined determine VBN 989 991 by by IN 992 1015 5-bromo-2’-deoxyuridine 5-bromo-2'-deoxyuridine NN 1016 1029 incorporation incorporation NN 1030 1034 into into IN 1035 1038 DNA dna NN 1039 1042 and and CC 1043 1047 flow flow NN 1048 1057 cytometry cytometry NN 1058 1061 and and CC 1062 1064 by by IN 1065 1068 use use NN 1069 1071 of of IN 1072 1073 a a DT 1074 1081 mitotic mitotic JJ 1082 1088 arrest arrest NN 1089 1094 assay assay NN 1094 1095 . . . 1096 1109 Mitochondrial mitochondrial JJ 1110 1123 transmembrane transmembrane JJ 1124 1133 potential potential NN 1134 1135 ( ( ( 1135 1140 delta delta SYM 1141 1148 psi(m)) psi(m)) NN 1149 1152 was be VBD 1153 1161 measured measure VBN 1162 1164 by by IN 1165 1170 means mean NNS 1171 1173 of of IN 1174 1183 rhodamine rhodamine NN 1184 1187 123 123 CD 1188 1196 staining staining NN 1197 1200 and and CC 1201 1205 flow flow NN 1206 1215 cytometry cytometry NN 1215 1216 . . . 1217 1224 Protein protein NN 1225 1235 expression expression NN 1236 1239 was be VBD 1240 1248 assessed assess VBN 1249 1251 by by IN 1252 1259 western western JJ 1260 1264 blot blot NN 1265 1273 analysis analysis NN 1274 1276 or or CC 1277 1295 immunofluorescence immunofluorescence NN 1295 1296 . . . 1297 1304 RESULTS results NNS 1304 1305 : : : 1306 1317 Therapeutic therapeutic JJ 1318 1332 concentrations concentration NNS 1333 1335 of of IN 1336 1341 As2O3 As2O3 NNP 1342 1343 ( ( ( 1343 1346 1-2 1-2 CD 1347 1353 microM microM NNP 1353 1354 ) ) ) 1355 1358 had have VBD 1359 1363 dual dual JJ 1364 1371 effects effect NNS 1372 1374 on on IN 1375 1384 malignant malignant JJ 1385 1396 lymphocytes lymphocyte NNS 1396 1397 : : : 1398 1399 1 1 LS 1399 1400 ) ) ) 1401 1411 inhibition inhibition NN 1412 1414 of of IN 1415 1421 growth growth NN 1422 1429 through through IN 1430 1439 adenosine adenosine NN 1440 1452 triphosphate triphosphate NN 1453 1454 ( ( ( 1454 1457 ATP ATP NNP 1457 1458 ) ) ) 1459 1468 depletion depletion NN 1469 1472 and and CC 1473 1485 prolongation prolongation NN 1486 1488 of of IN 1489 1493 cell cell NN 1494 1499 cycle cycle NN 1500 1504 time time NN 1505 1508 and and CC 1509 1510 2 2 LS 1510 1511 ) ) ) 1512 1521 induction induction NN 1522 1524 of of IN 1525 1534 apoptosis apoptosis NN 1534 1535 . . . 1536 1549 As2O3-induced as2o3-induced JJ 1550 1559 apoptosis apoptosis NN 1560 1563 was be VBD 1564 1572 preceded precede VBN 1573 1575 by by IN 1576 1581 delta delta NN 1582 1588 psi(m) psi(m) NN 1589 1597 collapse collapse NN 1597 1598 . . . 1599 1602 DTT DTT NNP 1603 1614 antagonized antagonize VBD 1615 1618 and and CC 1619 1622 BSO bso NN 1623 1631 enhanced enhance VBD 1632 1645 As2O3-induced as2o3-induced JJ 1646 1649 ATP ATP NNP 1650 1659 depletion depletion NN 1659 1660 , , , 1661 1666 delta delta NN 1667 1673 psi(m) psi(m) NN 1674 1682 collapse collapse NN 1682 1683 , , , 1684 1687 and and CC 1688 1697 apoptosis apoptosis NN 1697 1698 . . . 1699 1708 Caspase-3 caspase-3 NN 1709 1719 activation activation NN 1719 1720 , , , 1721 1728 usually usually RB 1729 1738 resulting result VBG 1739 1743 from from IN 1744 1749 delta delta NN 1750 1756 psi(m) psi(m) NN 1757 1765 collapse collapse NN 1765 1766 , , , 1767 1770 was be VBD 1771 1774 not not RB 1775 1781 always always RB 1782 1792 associated associate VBN 1793 1797 with with IN 1798 1811 As2O3-induced as2o3-induced JJ 1812 1821 apoptosis apoptosis NN 1821 1822 . . . 1823 1828 As2O3 As2O3 NNP 1829 1836 induced induce VBD 1837 1840 PML PML NNP 1841 1842 ( ( ( 1842 1855 promyelocytic promyelocytic JJ 1856 1864 leukemia leukemia NN 1864 1865 ) ) ) 1866 1873 protein protein NN 1874 1885 degradation degradation NN 1886 1889 but but CC 1890 1893 did do VBD 1894 1897 not not RB 1898 1906 modulate modulate VB 1907 1917 expression expression NN 1918 1920 of of IN 1921 1925 cell cell NN 1926 1939 cycle-related cycle-related JJ 1940 1948 proteins protein NNS 1948 1949 , , , 1950 1959 including include VBG 1960 1965 c-myc c-myc NN 1965 1966 , , , 1967 1981 retinoblastoma retinoblastoma NN 1982 1989 protein protein NN 1989 1990 , , , 1991 2007 cyclin-dependent cyclin-dependent JJ 2008 2014 kinase kinase NNP 2015 2016 4 4 CD 2016 2017 , , , 2018 2024 cyclin cyclin NN 2025 2027 D1 d1 NN 2027 2028 , , , 2029 2032 and and CC 2033 2036 p53 p53 NN 2036 2037 , , , 2038 2040 or or CC 2041 2051 expression expression NN 2052 2054 of of IN 2055 2078 differentiation-related differentiation-related JJ 2079 2087 antigens antigen NNS 2087 2088 . . . 2089 2100 CONCLUSIONS conclusions NNS 2100 2101 : : : 2102 2113 Substantial substantial JJ 2114 2120 growth growth NN 2121 2131 inhibition inhibition NN 2132 2135 and and CC 2136 2145 apoptosis apoptosis NN 2146 2153 without without IN 2154 2162 evidence evidence NN 2163 2165 of of IN 2166 2181 differentiation differentiation NN 2182 2186 were be VBD 2187 2194 induced induce VBN 2195 2197 in in IN 2198 2202 most most JJS 2203 2212 malignant malignant JJ 2213 2224 lymphocytic lymphocytic JJ 2225 2230 cells cell NNS 2231 2238 treated treat VBN 2239 2243 with with IN 2244 2247 1-2 1-2 CD 2248 2254 microM microm NN 2255 2260 As2O3 as2o3 NN 2260 2261 . . . 2262 2267 As2O3 As2O3 NNP 2268 2271 may may MD 2272 2277 prove prove VB 2278 2284 useful useful JJ 2285 2287 in in IN 2288 2291 the the DT 2292 2301 treatment treatment NN 2302 2304 of of IN 2305 2314 malignant malignant JJ 2315 2334 lymphoproliferative lymphoproliferative JJ 2335 2344 disorders disorder NNS 2344 2345 . . .