Nuclear factor-kappaB and IkappaB kinase are constitutively active in human pancreatic cells, and their down-regulation by curcumin (diferuloylmethane) is associated with the suppression of proliferation and the induction of apoptosis.
BACKGROUND
Pancreatic carcinoma is a lethal malignancy, with the best available therapeutic option-gemcitabine-yielding response rates of < 10%. Because nuclear factor-kappaB (NF-kappaB) has been determined to play a role in cell survival/proliferation in human pancreatic carcinoma, this transcription factor is a potential therapeutic target.


METHODS
The authors investigated the ability of curcumin (diferuloylmethane), an agent that is pharmacologically safe in humans, to modulate NF-kappaB activity.


RESULTS
NF-kappaB and IkappaB kinase (IKK) were constitutively active in all human pancreatic carcinoma cell lines examined, and curcumin consistently suppressed NF-kappaB binding (as assessed using an electrophoretic mobility gel-shift assay) and IKK activity. Curcumin decreased the expression of NF-kappaB-regulated gene products, including cyclooxygenase-2 (as assessed using immunoblot analysis), prostaglandin E2, and interleukin-8 (as assessed using an enzyme-linked immunoassay), all of which have been implicated in the growth and invasiveness of pancreatic carcinoma. These changes were associated with concentration- and time-dependent antiproliferative activity (as assessed using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide [MTT] assay) and proapoptotic effects (as assessed via annexin V/propidium iodide staining [fluorescence-activated cell sorting, as well as with the induction of polyadenosine-5'-diphosphate-ribose polymerase cleavage).


CONCLUSIONS
Curcumin down-regulated NF-kappaB and growth control molecules induced by NF-kappaB in human pancreatic cells. These effects were accompanied by marked growth inhibition and apoptosis. Through these findings, the authors provided a biologic rationale for the treatment of patients with pancreatic carcinoma using this nontoxic phytochemical.
Li
Lan
L
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Aggarwal
Bharat B
BB
Shishodia
Shishir
S
Abbruzzese
James
J
Kurzrock
Razelle
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003474:Curcumin / Q000494:pharmacology*; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051550:I-kappa B Kinase; D015151:Immunoblotting; D016209:Interleukin-8 / Q000378:metabolism; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*
D000970:Antineoplastic Agents; D016209:Interleukin-8; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D003474:Curcumin