The combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) and Genistein is effective in inhibiting pancreatic cancer growth.
OBJECTIVE
Our previous studies have shown that, contrary to many other human pancreatic adenocarcinoma cell lines, AsPC1 cells are resistant to the apoptotic effect of the tumor necrosis factor-related apoptosis-inducing ligand, also called Apo2L (TRAIL/Apo2L). In our in vitro studies, the combination of TRAIL/Apo2L and protein synthesis inhibitor, genistein, but not genistein alone, was, however, effective in inducing apoptosis in AsPC1 cells. In the present study, we examined the effect of TRAIL/Apo2L with genistein on the growth of AsPC1 cells in vitro and in vivo.


METHODS
Mice with orthotopically transplanted AsPC1 cells were treated either with TRAIL/Apo2L, Genistein (Gen) or a combination of both (TRAIL/Apo2L + Gen) for 14 days. After 14 days, the size and weight of the tumors were registered and the apoptosis of the tumor cells were determined by the TUNEL method. In vitro, the effect of combination treatment on cytotoxicity was assessed by MTT assay and apoptosis was assessed by DAPI staining. FADD, caspase 3, and PARP proteins were determined by Western blot.


RESULTS
No toxic side effects were observed in either group. The tumor volume was significantly smaller and the apoptotic ratio was higher in the TRAIL + Gen group than in the other 2 groups. The apoptotic effect was associated with the caspase-3 activation. Z-VAD-FMK partially inhibited apoptosis by TRAIL + Gen.


CONCLUSIONS
These results indicate that the combination of TRAIL/Apo2L with genistein presents a promising therapeutic approach for the treatment of pancreatic cancer. Further detail investigations are needed, however, to verify the mechanisms of this combination therapy.
Nozawa
Fumiaki
F
UNMC Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska 68198-6805, USA.
Itami
Atsushi
A
Saruc
Murat
M
Kim
Min
M
Standop
Jens
J
Picha
Kathleen S
KS
Cowan
Kenneth H
KH
Pour
Parviz M
PM
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor / Q000637:transplantation; D019833:Genistein / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D019833:Genistein