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.
Avila
Gina E
GE
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.
Zheng
Xi
X
Cui
Xiao Xing
XX
Ryan
Amanda D
AD
Hansson
Annette
A
Suh
Junghan
J
Rabson
Arnold B
AB
Chang
Richard L
RL
Shih
Weichung Joe
WJ
Lin
Yong
Y
Crowell
Pamela
P
Lu
Yao Ping
YP
Lou
You Rong
YR
Conney
Allan H
AH
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