CD40L induces multidrug resistance to apoptosis in breast carcinoma and lymphoma cells through caspase independent and dependent pathways.
BACKGROUND
CD40L was found to reduce doxorubicin-induced apoptosis in non Hodgkin's lymphoma cell lines through caspase-3 dependent mechanism. Whether this represents a general mechanism for other tumor types is unknown.


METHODS
The resistance induced by CD40L against apoptosis induced by a panel of cytotoxic chemotherapeutic drugs in non Hodgkin's lymphoma and breast carcinoma cell lines was investigated.


RESULTS
Doxorubicin, cisplatyl, etoposide, vinblastin and paclitaxel increased apoptosis in a dose-dependent manner in breast carcinoma as well as in non Hodgkin's lymphoma cell lines. Co-culture with irradiated L cells expressing CD40L significantly reduced the percentage of apoptotic cells in breast carcinoma and non Hodgkin's lymphoma cell lines treated with these drugs. In breast carcinoma cell lines, these 5 drugs induced an inconsistent increase of caspase-3/7 activity, while in non Hodgkin's lymphoma cell lines all 5 drugs increased caspase-3/7 activity up to 28-fold above baseline. Co-culture with CD40L L cells reduced (-39% to -89%) the activation of caspase-3/7 induced by these agents in all 5 non Hodgkin's lymphoma cell lines, but in none of the 2 breast carcinoma cell lines. Co culture with CD40L L cells also blocked the apoptosis induced by exogenous ceramides in breast carcinoma and non Hodgkin's lymphoma cell lines through a caspase-3-like, 8-like and 9-like dependent pathways.


CONCLUSIONS
These results indicate that CD40L expressed on adjacent non tumoral cells induces multidrug resistance to cytotoxic agents and ceramides in both breast carcinoma and non Hodgkin's lymphoma cell lines, albeit through a caspase independent and dependent pathway respectively.
Equipe Cytokines et Cancer, Unité INSERM U590, Centre Léon Bérard, 28 rue Laënnec, 69373 Lyon cedex 08, France. nvr1@netcourrier.com
Nathalie
N
Voorzanger-Rousselot
Laurent
L
Alberti
Jean-Yves
JY
Blay
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000473:pathology*; D023201:CD40 Ligand / Q000096:biosynthesis / Q000502:physiology*; D002277:Carcinoma / Q000473:pathology*; D002292:Carcinoma, Renal Cell / Q000473:pathology; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D002518:Ceramides / Q000494:pharmacology*; D003110:Colonic Neoplasms / Q000473:pathology; D018432:Drug Resistance, Multiple; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000473:pathology*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002518:Ceramides; D023201:CD40 Ligand; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases