Figure 1
Figure 1. Therapy-resistant B-NHL cell lines undergo delayed apoptosis when treated with bortezomib. (A) After a 72-hour incubation, bortezomib (25nM) induced the death of an approximately equal (P > .05) percentage of therapy-sensitive (Raji, RL) and therapy-resistant (Raji 2R, Raji 4RH, RL 4RH) cells. Data shown represent the average percent of propidium iodide–positive (PI+) cells ± SD from at least 5 independent experiments. Asterisks (*) indicate a significant increase compared with killing by cisplatinum (CDDP; 100μM). (B) Forty-eight hours following incubation with bortezomib (25nM), increased caspase-3/7 activity was detected in sensitive and resistant cells. Data shown are from 1 representative experiment repeated 3 times. Bars represent the average caspase-3/7 activity from quadruplicate wells ± SD. Asterisks (*) indicate a significant (P < .01) increase in caspase-3/7 activity compared with vehicle-treated cells. Double asterisks (**) indicate a significant increase in caspase-3/7 activity compared with vehicle-treated cells and compared with the same treatment in resistant cells. (C) A kinetic analysis of PARP cleavage indicated that sensitive cells undergo apoptosis more rapidly than resistant cells. PARP cleavage was observed following 24 hours of incubation of sensitive cells (Raji shown here) with 25nM bortezomib but not until 48 hours following incubation of resistant cells (Raji 4RH shown here) with 25nM bortezomib. Western blots shown are from a representative experiment that was repeated twice. (D) Analysis of apoptotic markers by flow cytometry confirmed that bortezomib (25nM) induced apoptosis with delayed kinetics in resistant cells (Raji 2R shown here) compared with sensitive cells (Raji shown here). Data shown represent the average ± SD of at least 3 independent experiments. Asterisks (*) indicate a significant (P < .05) difference between sensitive and resistant cells at a given time point. Other sensitive and resistant cell lines exhibited similar kinetic responses to bortezomib treatment (data not shown).

Therapy-resistant B-NHL cell lines undergo delayed apoptosis when treated with bortezomib. (A) After a 72-hour incubation, bortezomib (25nM) induced the death of an approximately equal (P > .05) percentage of therapy-sensitive (Raji, RL) and therapy-resistant (Raji 2R, Raji 4RH, RL 4RH) cells. Data shown represent the average percent of propidium iodide–positive (PI+) cells ± SD from at least 5 independent experiments. Asterisks (*) indicate a significant increase compared with killing by cisplatinum (CDDP; 100μM). (B) Forty-eight hours following incubation with bortezomib (25nM), increased caspase-3/7 activity was detected in sensitive and resistant cells. Data shown are from 1 representative experiment repeated 3 times. Bars represent the average caspase-3/7 activity from quadruplicate wells ± SD. Asterisks (*) indicate a significant (P < .01) increase in caspase-3/7 activity compared with vehicle-treated cells. Double asterisks (**) indicate a significant increase in caspase-3/7 activity compared with vehicle-treated cells and compared with the same treatment in resistant cells. (C) A kinetic analysis of PARP cleavage indicated that sensitive cells undergo apoptosis more rapidly than resistant cells. PARP cleavage was observed following 24 hours of incubation of sensitive cells (Raji shown here) with 25nM bortezomib but not until 48 hours following incubation of resistant cells (Raji 4RH shown here) with 25nM bortezomib. Western blots shown are from a representative experiment that was repeated twice. (D) Analysis of apoptotic markers by flow cytometry confirmed that bortezomib (25nM) induced apoptosis with delayed kinetics in resistant cells (Raji 2R shown here) compared with sensitive cells (Raji shown here). Data shown represent the average ± SD of at least 3 independent experiments. Asterisks (*) indicate a significant (P < .05) difference between sensitive and resistant cells at a given time point. Other sensitive and resistant cell lines exhibited similar kinetic responses to bortezomib treatment (data not shown).

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