Abstract
BackgroundCD40L 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.MethodsThe 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.ResultsDoxorubicin, 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.ConclusionThese 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.
Highlights
CD40 ligand (CD40L) was found to reduce doxorubicin-induced apoptosis in non Hodgkin's lymphoma cell lines through caspase-3 dependent mechanism
We investigated whether the apoptosis induced by a panel of cytotoxic agents with various modes of action (doxorubicin (Dox), paclitaxel (TAX), vinblastin (VIN), etoposide (ETO), cisplatin (CDDP) was affected by co-culture with CD40L expressing L cells (CD40L L cells)
Co-culture with CD40L L cells reduced the percentage of cells undergoing apoptosis in 4 of the 6 RCC cell lines exposed to DOX (-44% to -70%) and, marginally, in the HCT116 colon carcinoma cell line (-15%) and prostatic carcinoma cell line HTB-81 (-30%)
Summary
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. The acquisition by tumor cells of resistance to the apoptosis induced by cytotoxic drugs involves various biological mechanisms shared by tumors of different histological types [8,9,10,11,3]. These include the amplification of genes encoding for the enzymatic target of the cytotoxic agent, e.g. dihydrofolate reductase (DHFR) for methotrexate (MTX), or the up-regulation of transmembrane molecules capable to transport the drug outside the cell [9,10,11]. There is no consistent correlation between the expression of these proteins and the onset of drug resistance in vivo, suggesting the presence of additional biological mechanisms of drug resistance in vivo in cancer patients [11,12]
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