Interferon receptors and the caspase cascade regulate the antitumor effects of interferons on human pancreatic cancer cell lines.
BACKGROUND
Interferons (IFNs) have antiproliferative effects on tumor cells. The apoptotic effects and sensitization to chemotherapy conferred by IFN therapy, however, are not clearly understood. The aims of the present study were to explore the apoptotic effects of IFNs in human pancreatic cancer cell lines and to attempt to define their ability to synergistically enhance sensitivity to 5-fluorouracil (5-FU) and gemcitabine, a mechanism that depends on the expression of IFN receptors.


METHODS
Human pancreatic cancer cells were cultured alone or in combination with the chemotherapeutic agents 5-FU and gemcitabine. Differential dosages of IFN-alpha, -beta, and -gamma were also added to the cell lines concomitantly during a period of 24 to 96 hours. The cell line viability and effects of treatment were examined using the methylthiazol tetrazolium assay and single-stranded DNA apoptosis assay. The expression of IFN receptors was determined using immunohistochemistry. Caspase-8 inhibitor was used to block the caspase cascade.


RESULTS
The antiproliferative and apoptotic effects of IFNs were most profoundly demonstrated on those cells that expressed the respective IFN receptor. The apoptotic effects provided by the interferons, however, were blocked by caspase-8 inhibition. The addition of IFNs significantly enhanced the cytotoxic effects of 5-FU and gemcitabine in those cell lines that expressed the corresponding IFN-alpha, -beta, or -gamma receptors.


CONCLUSIONS
This study on pancreatic cancer cell lines has demonstrated that IFNs mediate apoptosis through IFN receptors and the caspase cascade. Enhanced cytotoxicity occurred when IFNs were combined with 5-FU and gemcitabine.
Department of Surgery, Providence Hospital and Medical Centers, 22250 Providence Drive, Suite 700, Southfield, MI 48075, USA.
Reza F
RF
Saidi
Frances
F
Williams
Jennica
J
Ng
Grace
G
Danquah
Vijay K
VK
Mittal
Stephen G
SG
ReMine
Michael J
MJ
Jacobs
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D061945:Caspase Inhibitors; D020169:Caspases / Q000187:drug effects*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007372:Interferons / Q000008:administration & dosage / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D017471:Receptors, Interferon / Q000187:drug effects*; D000093542:Gemcitabine
D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D017471:Receptors, Interferon; D003841:Deoxycytidine; D007372:Interferons; D020169:Caspases; D005472:Fluorouracil; D000093542:Gemcitabine