Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces G2/M cell cycle arrest and apoptosis in human melanoma cells.
Curcumin (diferuloylmethane) inhibits tumour cell growth by inducing apoptosis in many tumour types, including melanoma, via complex and ill-defined pathways. Recent studies have shown that curcumin is both a nitric oxide scavenger and an inhibitor of inducible nitric oxide synthase (iNOS) expression, low levels of which correlate with antiapoptotic function and poor survival and which may be regulated by inhibition of nuclear factor-kappaB (NFkappaB) activation. To elucidate the mechanisms by which curcumin inhibits melanoma proliferation, we tested the in vitro effects of curcumin on specific cell cycle pathways and melanoma cell survival, including NFkappaB activation. Curcumin induced melanoma cell apoptosis and cell cycle arrest, which is associated with the downregulation of NFkappaB activation, iNOS and DNA-dependent protein kinase catalytic subunit expression, and upregulation of p53, p21(Cip1), p27(Kip1) and checkpoint kinase 2. Curcumin also downregulated constitutive iNOS activity in melanoma cells. Our results demonstrate that curcumin arrested cell growth at the G(2)/M phase and induced apoptosis in human melanoma cells by inhibiting NFkappaB activation and thus depletion of endogenous nitric oxide. Therefore, curcumin should be considered further as a potential therapy for patients with melanoma.
Zheng
Mingzhong
M
Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ekmekcioglu
Suhendan
S
Walch
Eugene T
ET
Tang
Chi-Hui
CH
Grimm
Elizabeth A
EA
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D003474:Curcumin / Q000494:pharmacology*; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008545:Melanoma / Q000378:metabolism* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493956:CDKN1A protein, human; C108573:CdkI-p30 protein, Cricetulus griseus; D018797:Cell Cycle Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003474:Curcumin