Inhibitory effects of 12-O-tetradecanoylphorbol-13-acetate alone or in combination with all-trans retinoic acid on the growth of cultured human pancreas cancer cells and pancreas tumor xenografts in immunodeficient mice.
Treatment of cultured PANC-1, MIA PaCa-2, and BxPC-3 human pancreatic adenocarcinoma cells with 0.1 to 1.6 nM 12-O-tetradecanoylphorbol-13-acetate (TPA) for 96 h inhibited the proliferation of these cells in a dose-dependent manner, and PANC-1 and MIA PaCa-2 cells were more sensitive to TPA than BxPC-3 cells. Inhibition of proliferation by TPA in PANC-1 cells was associated with an increase in the level of p21, but this was not observed in MIA PaCa-2 or BxPC-3 cells. The TPA-induced increase of p21 in PANC-1 cells was blocked by bisindolylmaleimide or rottlerin (inhibitors of protein kinase C). Studies in NCr-immunodeficient mice with well established PANC-1 tumor xenografts indicated that daily i.p. injections of TPA strongly inhibited tumor growth, increased the percentage of caspase-3-positive cells, and decreased the ratio of mitotic cells to caspase-3-positive cells in the tumors. Studies with BxPC-3 tumors in NCr mice receiving daily i.p. injections of vehicle, TPA, all-trans retinoic acid (ATRA), or a TPA/ATRA combination showed that TPA had an inhibitory effect on tumor growth, but treatment of the animals with the TPA/ATRA combination had a greater inhibitory effect on tumor growth than TPA alone. Treatment with the TPA/ATRA combination resulted in a substantially decreased ratio of the percentage of mitotic cells to the percentage of caspase-3-positive cells in the tumors compared with tumors from the vehicle-treated control animals. The inhibitory effects of TPA on tumor growth occurred at clinically achievable blood levels.
Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Gina E
GE
Avila
Xi
X
Zheng
Xiao Xing
XX
Cui
Amanda D
AD
Ryan
Annette
A
Hansson
Junghan
J
Suh
Arnold B
AB
Rabson
Richard L
RL
Chang
Weichung Joe
WJ
Shih
Yong
Y
Lin
Pamela
P
Crowell
Yao Ping
YP
Lu
You Rong
YR
Lou
Allan H
AH
Conney
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D010766:Phosphorylation; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011493:Protein Kinase C / Q000032:analysis; D016160:Retinoblastoma Protein / Q000378:metabolism; D013467:Sulindac / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000097:blood / Q000494:pharmacology*; D014183:Transplantation, Heterologous; D014212:Tretinoin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D016160:Retinoblastoma Protein; D013467:Sulindac; D014212:Tretinoin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D017239:Paclitaxel