Interferon-alpha modulates the chemosensitivity of CD133-expressing pancreatic cancer cells to gemcitabine.
Pancreatic cancer is a lethal disease as current chemotherapies with gemcitabine (GEM) are still insufficient. Accumulating evidence suggests that cancer stem cells (CSC) are responsible for chemoresistance and that CD133 is one of the CSC markers in pancreatic cancer. Interferon-alpha (IFN-α), a cytokine with pleiotropic effects, has direct cytotoxic and cytostatic effects on tumor cells. The aim of the present study was to investigate whether IFN-α can modulate the chemosensitivity of a human pancreatic cancer cell line, Capan-1, to GEM. Cell cycles were evaluated for response to GEM with and without IFN-α by BrdU assay. GEM inhibited Capan-1 cell growth in a dose-dependent manner. GEM (IC(50); 100 ng/mL) treatment reduced the number of both CD133(+) and CD133(-) cells in the S phase, induced apoptosis of CD133(-) cells more than that of CD133(+) cells and increased accumulation of CD133(+) cells into the G0/G1 phase. These results infer that CD133(+) cells take shelter into the G0/G1 phase from GEM treatment. IFN-α modulated CD133(+) cells from the G0/G1 phase to the S phase. Consequently, apoptosis was accelerated in both CD133(+) and CD133(-) cells after IFN-α combined with GEM treatment. Furthermore, GEM combined with IFN-α treatment showed a significant tumor suppressive effect in the in vivo study. Importantly, CD133(+) cells showed CSC-like properties, such as generation of spheres, highly invasive ability and high tumorigenesis. These results suggest that IFN-α, as a modulator, could contribute to the treatment of CD133(+) cancer cells and be effective in combined chemotherapies with GEM for pancreatic cancer stem-like cells.
Cancer and Regenerative Medicine, Frontier Science Research Center, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
Tomomi
T
Hayashi
Qiang
Q
Ding
Taisaku
T
Kuwahata
Koki
K
Maeda
Yumi
Y
Miyazaki
Shuichiro
S
Matsubara
Toru
T
Obara
Shoji
S
Natsugoe
Sonshin
S
Takao
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism*; D000093542:Gemcitabine
D000071916:AC133 Antigen; D015703:Antigens, CD; D000964:Antimetabolites, Antineoplastic; D006023:Glycoproteins; D016898:Interferon-alpha; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D003841:Deoxycytidine; D000093542:Gemcitabine