An effective in vitro antitumor response against human pancreatic carcinoma with paclitaxel and daunorubicin by induction of both necrosis and apoptosis.
The highly metastatic human pancreatic cell line L3.6 was used to study mechanisms for antitumor activity with various chemotherapeutic drug combinations. The most effective drugs were daunorubicin (IC50 0.4 microM), doxorubicin (IC50 22 microM), paclitaxel (IC50 5.3 microM) and 5-fluorouracil (IC50 5.4 microM). The most effective drug combination was equitoxic concentrations of paclitaxel and daunorubicin. Kinetic analysis demonstrated that both paclitaxel and daunorubicin had to be added simultaneously for maximum cytotoxicity. Daunorubicin treatment alone demonstrated ROS (reactive oxygen species) induction and cellular morphological changes more consistent with chemical damage in a total of 93% of the cells and apoptotic changes in 20% of the cell population. The apoptosis induced by daunorubicin does not appear to be caspase-dependent, as demonstrated by the lack of conversion of the procaspases 8 and 3. Within 24 h of treatment with paclitaxel, Bcl-2 formed a doublet at 26 kilodaltons and the expression was abrogated with daunorubicin and the combination of the two drugs as determined by Western blots. These data suggest that the human pancreatic cell line L3.6 is more effectively killed following treatment with chemotherapeutic agents that cause death through at least two pathways, a caspase-dependent and caspase-independent apoptosis and necrosis.
Gervasoni
James E
JE
Roger Williams Hospital/Boston University, 825 Chalkstone Ave, Providence, Rhode Island 02908, USA. jgervasoni@che-east.org
Hindenburg
Alexander A
AA
Vezeridis
Michael P
MP
Schulze
Scott
S
Wanebo
Harold J
HJ
Mehta
Shashikant
S
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D020128:Inhibitory Concentration 50; D009336:Necrosis; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D000093542:Gemcitabine
D017382:Reactive Oxygen Species; D003841:Deoxycytidine; D004317:Doxorubicin; C505407:CASP3 protein, human; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D017239:Paclitaxel; D002945:Cisplatin; D005472:Fluorouracil; D003630:Daunorubicin; D000093542:Gemcitabine