Carboplatin-induced cell death in model prostate cancer systems.
BACKGROUND
Many chemotherapeutic agents are believed to kill cancer cells by inflicting cellular damage which triggers the cell to enter apoptosis (programmed cell death). We investigated the means by which carboplatin induces cell death in three model cancer systems: the human prostate carcinoma cell lines PC-3 and LNCaP and the human cervical carcinoma cell line HeLa.


METHODS
Drug cytotoxicity, cell cycle effects, bcl-2 deactivation, and multiple markers for apoptosis were utilized to examine carboplatin activity within these cell lines.


RESULTS
In HeLa cells, carboplatin appears to induce an S-phase block followed by apoptosis. In contrast, PC-3 and LNCaP cells show no cell cycle phase block and die from necrosis rather than apoptosis. The effects of carboplatin contrast sharply with the effects of paclitaxel, which induces an M-phase block and apoptosis in all three cell lines.


CONCLUSIONS
These results show that PC-3 and LNCaP cells are relatively resistant to carboplatin and suggest two causes of resistance: bypassing the cell cycle checkpoints which serve as points of entry into apoptosis, and incomplete execution of the effector mechanisms of apoptosis. Carboplatin resistance in the prostate cancer cell lines fits into the developing scheme of apoptosis-necrosis and raises valuable questions about the root causes of cancer resistance to chemotherapeutic agents.
Yee
C S
CS
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor 48109-0946, USA.
Kamradt
J M
JM
Nielsen
L C
LC
Panvinchian
R
R
Pienta
K J
KJ
D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000633:toxicity*; D002453:Cell Cycle / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D009336:Necrosis; D017239:Paclitaxel / Q000633:toxicity; D011471:Prostatic Neoplasms; D016196:S Phase; D014407:Tumor Cells, Cultured; D002583:Uterine Cervical Neoplasms
D016190:Carboplatin; D017239:Paclitaxel