Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer (NSCLC). Nicotine, an active component of cigarettes, has been found to induce proliferation of lung cancer cell lines. In addition, nicotine can induce angiogenesis and confer resistance to apoptosis. All these events are mediated through the nicotinic acetylcholine receptors (nAChRs) on lung cancer cells. In this study, we demonstrate that nicotine can promote anchorage-independent growth in NSCLCs. In addition, nicotine also induces morphological changes characteristic of a migratory, invasive phenotype in NSCLCs on collagen gel. These morphological changes were similar to those induced by the promigratory growth factor VEGF. The proinvasive effects of nicotine were mediated by a7-nAChRs on NSCLCs. RT-PCR analysis showed that the a7-nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines. Nicotine was found to promote proliferation and invasion in human breast cancer. The proinvasive effects of nicotine were mediated via a nAChR, Src and calcium-dependent signaling pathway in breast cancer cells. In a similar fashion, nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells. Most importantly, nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition (EMT), characterized by reduction of epithelial markers like E-cadherin expression, ZO-1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells. Therefore, it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers. ' 2008 Wiley-Liss, Inc.Key words: lung cancer; nicotine; epithelial-mesenchymal transition; tumor progression; metastasis Cigarette smoke is the strongest documented risk factor for the development of lung cancer, accounting for about 157,000 deaths every year in the US. 1 A significant proportion of nonsmall cell lung cancer (NSCLC) cases are detected only in the advanced stage after the onset of metastasis, leading to a remarkably low 5-year survival rate (about 15%) in patients. 1 Tobacco-derived carcinogens like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N 0 -nitrosonornicotine (NNN) are known to form DNA adducts, mutating vital growth regulatory genes like p53 and Ras, initiating oncogenesis. [2][3][4] In addition, several lines of evidence indicate that cigarette smoking correlates with increased metastasis of lung, pancreatic, breast and bladder cancers. [5][6][7] Although cigarette smoke is a complex mixture of over 4,000 compounds, nicotine has been shown the major addictive component of cigarettes. 8-10 Nicotine, while not carcinogenic by itself, has been shown to induce proliferation and angiogenesis in several experimental models 11-14 ; these effects occurred at concentrations normally found in the blood stream of smokers (10 28 -10 27 M). 12 These levels can vary greatly in smokers, and uri...

Non-small cell lung cancer (NSCLC) demonstrates a strong etiologic association with smoking. Although nicotine is not carcinogenic, it can induce cell proliferation and angiogenesis and suppress apoptosis induced by certain agents. Here we show that nicotine inhibits apoptosis induced by the drugs gemcitabine, cisplatin, and taxol, which are used to treat NSCLCs. This protection correlated with the induction of XIAP and survivin by nicotine in a panel of human NSCLC cell lines, and depletion of XIAP and survivin ablated the protective effects of nicotine. The antiapoptotic effects of nicotine were mediated by dihydro ␤-erythroidine-sensitive ␣3-containing nicotinic acetylcholine receptors and required the Akt pathway. Chromatin immunoprecipitation assays demonstrated that nicotine stimulation caused an increased recruitment of E2F1 and concomitant dissociation of retinoblastoma tumor suppressor protein (Rb) from survivin promoter in A549 cells. Moreover, ablation of E2F1 levels caused abrogation of the protective effects of nicotine against cisplatin-induced apoptosis in A549 cells whereas ablation of signal transducer and activator of transcription 3 levels had no effect. These studies suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that survivin and XIAP play a key role in the antiapoptotic activity of nicotine.E2F ͉ retinoblastoma ͉ Stat 3 ͉ IAP ͉ lung cancer C igarette smoking is a major risk factor in the development of non-small cell lung cancer (NSCLC), which accounts for 80% of all lung cancers (1-3). Previous studies have implied that nicotine may be genotoxic, forming adducts with DNA, histone H1͞H3, or H1b, thereby causing mutations in vital genes leading to neoplastic transformation (4, 5). However, recent evidence has shown that nicotine can also lead to sustained activation of mitogenic pathways, promote angiogenesis, and accelerate tumor growth and atherosclerosis (6-13). Nicotine and its related carcinogens, like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, have been found to activate Raf-1-, EGFR-, c-Src-, Akt-, and 5-lipooxygenase-mediated growth stimulatory pathways (14-19). In addition, nicotine has been also found to inhibit apoptosis induced by opioids, etoposide, cisplatin, and UV irradiation in lung cancer cells (7,10,14). The inhibitory effect of nicotine on apoptosis has been attributed to its ability to activate and phosphorylate antiapoptotic proteins like Bcl-2, induction of NF-B complexes, activation of the Akt pathway, as well as inactivation of proapoptotic proteins like Bax and Bad through phosphorylation in lung cancer cells (7,(20)(21)(22)(23)(24).NSCLC is characterized by its poor prognosis and resistance to the apoptotic activity of antineoplastic drugs both in vivo and in vitro (25,26). Although many signaling cascades have been implicated in the acquisition of chemoresistance in NSCLC (3, 26, 27), we conjectured that it is probable that the antiapoptotic effects of nicotine contribute to the process. Here we...

Although it is well established that cyclin-dependent kinases phosphorylate and inactivate Rb, the Raf-1 kinase physically interacts with Rb and initiates the phosphorylation cascade early in the cell cycle. We have identified an orally active small molecule, Rb/Raf-1 disruptor 251 (RRD-251), that potently and selectively disrupts the Rb/Raf-1 but not Rb/E2F, Rb/prohibitin, Rb/cyclin E, and Rb/HDAC binding. The selective inhibition of Rb/Raf-1 binding suppressed the ability of Rb to recruit Raf-1 to proliferative promoters and inhibited E2F1-dependent transcriptional activity. RRD-251 inhibited anchorage-dependent and anchorage-independent growth of human cancer cells and knockdown of Rb with short hairpin RNA or forced expression of E2F1 rescued cells from RRD-251-mediated growth arrest. P.o. treatment of mice resulted in significant tumor growth suppression only in tumors with functional Rb, and this was accompanied by inhibition of angiogenesis, inhibition of proliferation, decreased phosphorylated Rb levels, and inhibition of Rb/Raf-1 but not Rb/E2F1 binding in vivo. Thus, selective targeting of Rb/Raf-1 interaction seems to be a promising approach for developing novel chemotherapeutic agents. [Cancer Res 2008;68(10):3810-8]

] on the synthesis of R-amino phosphonates catalyzed by Mg(ClO 4 ) 2 or molecular iodine appeared which describes the reaction of diethyl phosphite with aldehydes amines.