Inhibition of cell growth and nuclear factor-kappaB activity in pancreatic cancer cell lines by a tylophorine analogue, DCB-3503.
A tylophorine analogue, DCB-3503, has been shown to have potent activity against tumor growth in vitro and in vivo, as well as activity in an autoimmune disease model in vivo. This study focuses on investigating the mechanisms responsible for antitumor activity of DCB-3503. The concentrations for inhibiting 50% growth/colony formation ability are 50/162 and 40/149 nmol/L for PANC-1 and HPAC cells, respectively. The growth inhibition effects are associated with DCB-3503-induced reprogramming of tumor cells. DCB-3503 could interfere with cell cycle progression. Several cell cycle regulatory proteins, including cyclin D(1), are down-regulated by DCB-3503. Using several different transcription elements coupled with a reporter gene, it was found that the nuclear factor-kappaB (NF-kappaB) signaling pathway is the most sensitive pathway mediator affected by DCB-3503. The inhibition of NF-kappaB activity is dependent on the down-regulation of nuclear phosphorylated p65, a component of the active form of the NF-kappaB complex. Such a decrease in nuclear phosphorylated p65 can be reversed by a proteosome inhibitor. Furthermore, the activity and protein expression of nuclear IkappaB kinase alpha, which is responsible for p65 phosphorylation, is suppressed and down-regulated in cells treated with DCB-3503. In summary, DCB-3503 could affect cell cycle regulatory proteins and is a potent modulator of NF-kappaB function. It is a potentially useful compound in the management of cancers in which cyclin D1 overexpression and high NF-kappaB activity play a pivotal role.
Shiah
Her-Shyong
HS
Department of Pharmacology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06510, USA.
Gao
Wenli
W
Baker
David C
DC
Cheng
Yung-Chi
YC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007212:Indolizines / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology*; D010616:Phenanthrenes / Q000494:pharmacology*; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; C509364:DCB 3503; D020672:I-kappa B Proteins; D007212:Indolizines; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010616:Phenanthrenes; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D051550:I-kappa B Kinase