Inhibition of nuclear factor-κB and nitric oxide by... : Melanoma Research (original) (raw)

ORIGINAL ARTICLES

Inhibition of nuclear factor-κB and nitric oxide by curcumin induces G2/M cell cycle arrest and apoptosis in human melanoma cells

Zheng, Mingzhong; Ekmekcioglu, Suhendan; Walch, Eugene T.; Tang, Chi-Hui; Grimm, Elizabeth A.

Department of Bioimmunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA

Sponsorship: This work was supported by National Institutes of Health grants CA-R01 090282 and T-32 CA 73954, as well as by a grant from the RGK Foundation of Austin, and the Golfer's Against Cancer, Houston, Texas, USA

Correspondence and requests for reprints to Dr Elizabeth A. Grimm, Department of Bioimmunotherapy, Unit 362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA

Tel: +1 713 792 8990; fax: +1 713 792 2070;

e-mail: [email protected]

Received 8 October 2003 Accepted 27 January 2004

Abstract

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-κB (NFκB) 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 NFκB activation. Curcumin induced melanoma cell apoptosis and cell cycle arrest, which is associated with the downregulation of NFκB activation, iNOS and DNA-dependent protein kinase catalytic subunit expression, and upregulation of p53, p21Cip1, p27Kip1 and checkpoint kinase 2. Curcumin also downregulated constitutive iNOS activity in melanoma cells. Our results demonstrate that curcumin arrested cell growth at the G2/M phase and induced apoptosis in human melanoma cells by inhibiting NFκB activation and thus depletion of endogenous nitric oxide. Therefore, curcumin should be considered further as a potential therapy for patients with melanoma.