Synergistic effects of acyclic retinoid and gemcitabine on growth inhibition in pancreatic cancer cells.
Pancreatic cancer is a serious healthcare problem worldwide because of its high mortality. Gemcitabine, a DNA synthesis inhibitor, is the standard first-line treatment for advanced pancreatic cancer and is also expected as a key drug for the combination therapy of this malignancy. Retinoids, which are derivatives of vitamin A, exert anti-tumor effects in various types of human malignancies, including pancreatic cancer. This study examined whether combination therapy with gemcitabine and acyclic retinoid (ACR), a new synthetic retinoid, had enhanced anti-tumor efficacy in pancreatic cancer. ACR, 9-cis-retinoic acid and gemcitabine preferentially inhibited the growth of human pancreatic cancer cells (Panc-1 and KP-2) in comparison to PE normal human pancreatic epithelial cells. The combination of ACR plus gemcitabine synergistically inhibited the growth of Panc-1 cells. The combined treatment with these two agents also acted synergistically to induce apoptosis and to inhibit Ras activation in these cancer cells. In vivo, the combination therapy augmented tumor growth inhibition through the induction of apoptosis and inhibition of cell proliferation in tumor tissue. These results suggest that the combination of ACR plus gemcitabine may therefore be an effective regimen for the chemotherapy of pancreatic cancer.
Nakagawa
Takayuki
T
Department of Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Shimizu
Masahito
M
Shirakami
Yohei
Y
Tatebe
Hideharu
H
Yasuda
Ichiro
I
Tsurumi
Hisashi
H
Moriwaki
Hisataka
H
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D012176:Retinoids / Q000008:administration & dosage*; D000093542:Gemcitabine
D012176:Retinoids; D003841:Deoxycytidine; D015689:Oncogene Protein p21(ras); D000093542:Gemcitabine