A novel mechanism by which N-(4-hydroxyphenyl)retinamide inhibits breast cancer cell growth: the production of nitric oxide.
N-(4-Hydroxyphenyl)retinamide (4-HPR) induces apoptosis in breast cancer cells; however, the molecular basis by which 4-HPR induces apoptosis is not well understood. In breast cancer cells, nitric oxide (NO) is predominantly an apoptotic inducer. Apoptotic agents, such as phorbol ester, tumor necrosis factor-alpha, and peptide hormones, have been shown to increase NO production in breast cancer cells. Therefore, we hypothesized that the production of No is vital for 4-HPR to induce apoptosis in breast cancer cells. We found that 4-HPR induced NO production in a dose-dependent manner in all of the breast cancer cell lines tested. The degree of growth inhibition and apoptotic induction by 4-HPR was directly correlated with the amount of NO produced. To prove that NO is essential for 4-HPR to induce apoptosis, breast cancer cells were coincubated with a competitive NO synthase (NOS) inhibitor, NG-monomethyl-L-arginine (L-NMMA), and 4-HPR, L-NMMA prevented 4-HPR from inducing inhibitory effects, indicating that NO is crucial for 4-HPR to induce its apoptotic effects in breast cancer cells. IFNs and tamoxifen (TAM) have been shown to potentiate 4-HPR effects in breast cancer cells. Both IFN-gamma and TAM enhanced the ability of 4-HPR to induce NO production in breast cancer cells, which was correlated with increased apoptosis. Alone, 4-HPR increased expression of both inducible NOS (NOSII) and endothelial NOS (NOSIII). When combined with 4-HPR, IFN-gamma and TAM enhanced NOSII expression. Thus, we have identified a novel mechanism by which 4-HPR induces apoptosis in breast cancer cells, i.e., by increasing NOS expression to induce NO production.
Simeone
Ann-Marie
AM
Department of Bioimmunotherapy, Sections of Immunobiology and Drug Carriers, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Ekmekcioglu
Suhendan
S
Broemeling
Lyle D
LD
Grimm
Elizabeth A
EA
Tari
Ana M
AM
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017313:Fenretinide / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D007371:Interferon-gamma / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D013629:Tamoxifen; D017313:Fenretinide; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase