PSK-mediated NF-kappaB inhibition augments docetaxel-induced apoptosis in human pancreatic cancer cells NOR-P1.
Docetaxel, a member of the taxane family, has been shown to induce apoptosis in a variety of cancer cells. However, toxicity at therapeutic doses has precluded the use of docetaxel alone for the management of cancer patients. PSK, a protein-bound polysaccharide, is widely used in Japan as an immunopotentiating biological response modifier for cancer patients. Our previous study showed that PSK induced downregulation of several invasion-related factors, suggesting an interaction of PSK with transcriptional factors. In this study, we showed that PSK dose dependently enhanced apoptosis induced by 1 nM of docetaxel in a human pancreatic cancer cell line NOR-P1. Furthermore, PSK inhibited docetaxel-induced nuclear factor kappa B (NF-kappaB) activation. Moreover, the expression of cellular inhibitor of apoptosis protein (cIAP-1), which is transcriptionally regulated by NF-kappaB and functions as an antiapoptotic molecule through interrupting the caspase pathway, was also inhibited by treatment with PSK plus docetaxel. As a result, PSK enhanced the docetaxel-induced caspase-3 activation. In addition, treatment by transfection of NF-kappaB decoy oligodeoxynucleotides (ODNs), but not scramble ones, inhibited the expression of cIAP-1 in NOR-P1 cells and induced a significant increase in docetaxel-induced apoptosis. Our data indicate that PSK suppresses the docetaxel-induced NF-kappaB activation pathway. Combination of PSK with a low dose of docetaxel may be a new therapeutic strategy to treat patients with pancreatic cancer.
Zhang
Hao
H
Department of Hospital Clinical Laboratory, Saga Medical School, Nabeshima, Saga, Japan.
Morisaki
Takashi
T
Nakahara
Chihiro
C
Matsunaga
Hisashi
H
Sato
Noshiro
N
Nagumo
Fumio
F
Tadano
Jutaro
J
Katano
Mitsuo
M
D017209:Apoptosis; D002455:Cell Division / Q000187:drug effects; D000077143:Docetaxel; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D011509:Proteoglycans / Q000494:pharmacology*; D043823:Taxoids; D014407:Tumor Cells, Cultured
D016328:NF-kappa B; D011509:Proteoglycans; D043823:Taxoids; D000077143:Docetaxel; C010770:polysaccharide-K; D017239:Paclitaxel