Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thiol N-acetylcysteine (NAC) is currently considered one of the most promising cancer chemopreventive agents by virtue of its multiple and coordinated mechanisms affecting the process of chemical carcinogenesis. Recent studies have shown that an unpaired cysteine residue in the propeptide plays a key role in inactivation of latent metastasis-associated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of malignant cells. As assessed by zymographic analysis, NAC completely inhibited the gelatinolytic activity of type-IV collagenases in the cells tested (gelatinases A and B). Moreover, NAC was efficient in inhibiting the chemotactic and invasive activities of tumor cells of human (A2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, which are predictive of the invasive and metastatic properties. Reduced glutathione (GSH) had a similar, although less effective activity. The number of lung metastases decreased sharply when B16-F10 murine melanoma cells, injected i.v. into nude mice, were pre-treated with NAC and resuspended in medium supplemented with 10 mM NAC. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneous inoculation of either B16-F10 cells or of their highly metastatic variant B16-BL6, or intramuscular injection of LLC cells. In all experiments NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneous metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAC. However, this was not observed for Lewis lung tumors. These data indicate that NAC affects the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant activity of this thiol.
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PMID:Inhibition of invasion, gelatinase activity, tumor take and metastasis of malignant cells by N-acetylcysteine. 770 24

Protein kinase C, a family of serine-threonine protein kinases, mediates a variety of intracellular signaling events. Here, the regulatory effect of phorbol 12-myristate 13-acetate(PMA)on the several PKC isozymes in the human lung carcinoma cells A-549 was studied. The expression of PKC-alpha PKC-betaII PKC-gamma PKC-delta and PKC-epsilon in A-549 cells was examined. No detectable PKC-zeta was observed. Short-term treatment of cells with PMA led to the translocation of these PKC isozymes, to different extent, from cytosol to cell membrane. Whereas, prolonged treatment of cells with PMA pronouncedly reduced the levels of PKC-alpha PKC-gamma PKC-delta and PKC-epsilon, but the intracellular level of PKC-betaII was not affected. Furthermore, PMA was observed to have differential effects on the down-regulation of PKC isozymes located in the cytosol and of those located in the membrane. Prolonged PMA treatment caused extensive decrease in the levels of cytosolic PKC-delta and PKC-gamma, and depleted cytosolic PKC-alpha and PKC-betaII. However, the amount levels of membrane PKC-alpha PKC-betaII PKC-gamma PKC-delta isozymes were not decreased. In contrast, PKC-epsilon in both cytosol and membrane fraction was obviously down-regulated by prolonged PMA treatment. This study provided novel evidence on the PMA-mediated activation and down-regulation of different PKC isozymes, which might be helpful in deepening our understanding on the roles of PKC activation and the alterations of their intracellular levels in processes of chemical carcinogenesis.
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PMID:Regulation of Protein Kinase C in A-549 Cells by Phorbol Ester. 1205 80

Arsenic is a known human carcinogen, but development of rodent models of inorganic arsenic carcinogenesis has been problematic. Since gestation is often a period of high sensitivity to chemical carcinogenesis, we performed a transplacental carcinogenicity study in mice using inorganic arsenic. Groups (n = 10) of pregnant C3H mice were given drinking water containing sodium arsenite (NaAsO(2)) at 0 (control), 42.5, and 85 ppm arsenite ad libitum from day 8 to 18 of gestation. These doses were well tolerated and body weights of the dams during gestation and of the offspring subsequent to birth were not reduced. Dams were allowed to give birth, and offspring were weaned at 4 weeks and then put into separate gender-based groups (n = 25) according to maternal exposure level. The offspring received no additional arsenic treatment. The study lasted 74 weeks in males and 90 weeks in females. A complete necropsy was performed on all mice and tissues were examined by light microscopy in a blind fashion. In male offspring, there was a marked increase in hepatocellular carcinoma incidence in a dose- related fashion (control, 12%; 42.5 ppm, 38%; 85 ppm, 61%) and in liver tumor multiplicity (tumors per liver; 5.6-fold over control at 85 ppm). In males, there was also a dose-related increase in adrenal tumor incidence and multiplicity. In female offspring, dose-related increases occurred in ovarian tumor incidence (control, 8%; 42.5 ppm, 26%; 85 ppm, 38%) and lung carcinoma incidence (control, 0%; 42.5 ppm, 4%; 85 ppm, 21%). Arsenic exposure also increased the incidence of proliferative lesions of the uterus and oviduct. These results demonstrate that oral inorganic arsenic exposure, as a single agent, can induce tumor formation in rodents and establishes inorganic arsenic as a complete transplacental carcinogen in mice. The development of this rodent model of inorganic arsenic carcinogenesis has important implications in defining the mechanism of action for this common environmental carcinogen.
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PMID:Transplacental carcinogenicity of inorganic arsenic in the drinking water: induction of hepatic, ovarian, pulmonary, and adrenal tumors in mice. 1258 88

Inorganic arsenic is an important human carcinogen of unknown etiology. Defining carcinogenic mechanisms is critical to assessing the human health hazard of arsenic exposure but requires appropriate model systems. It has proven difficult to induced tumors in animals with inorganic arsenic alone. Several groups have studied the carcinogenic potential of inorganic arsenic in rodents, finding it to act as co-promoter or co-carcinogen, but not as a complete carcinogen. As gestation is a time of high sensitivity to chemical carcinogenesis, we performed two in utero exposure studies with inorganic arsenic. In the first study, pregnant mice received drinking water containing sodium arsenite at 0 (control), 42.5 and 85 ppm arsenic from gestation day 8 to 18, and the offspring were observed for up to 90 weeks. As adults, male offspring developed hepatocellular carcinoma (HCC) and adrenal tumors after in utero arsenite exposure. Although liver tumors were not induced by arsenic in female offspring, they did develop lung carcinoma, ovarian tumors, and uterine and oviduct preneoplasia. In a second study, the same doses of arsenic were used and the skin tumor promoting phorbol ester, TPA, was applied to the skin after birth in an effort to promote skin tumors potentially initiated by arsenic in utero. TPA did not promote dermal tumors after in utero arsenite exposure. Otherwise, results from the second chronic study largely duplicated the first and, irrespective of additional TPA exposure, arsenic exposure in utero induced HCC and adrenal tumors in males and ovarian tumors in females. In addition, combined arsenic and TPA induced a significant increase in hepatocellular tumors in female offspring, although arsenic alone was not effective. Thus, in utero inorganic arsenic exposure can act as a complete carcinogen in mice, with brief exposures consistently inducing tumors at several sites. In addition, it appears gestational arsenic can act as a tumor initiator in the female mouse liver, inducing liver lesions that can be promoted by TPA.
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PMID:Mechanisms underlying arsenic carcinogenesis: hypersensitivity of mice exposed to inorganic arsenic during gestation. 1513 27

Lung cancer is a deadly disease with increasing cases diagnosed worldwide and still a very poor prognosis. While mutations in the retinoblastoma (RB1) tumor suppressor have been reported in lung cancer, mainly in small cell lung carcinoma, the tumor suppressive role of its relatives p107 and p130 is still a matter of debate. To begin to investigate the role of these two Rb family proteins in lung tumorigenesis, we have generated a conditional triple knockout mouse model (TKO) in which the three Rb family members can be inactivated in adult mice. We found that ablation of all three family members in the lung of mice induces tumorlets, benign neuroendocrine tumors that are remarkably similar to their human counterparts. Upon chemical carcinogenesis, DHPN and urethane accelerate tumor development; the TKO model displays increased sensitivity to DHPN, and urethane increases malignancy of tumors. All the tumors developing in TKO mice (spontaneous and chemically induced) have neuroendocrine features but do not progress to fully malignant tumors. Thus, loss of Rb and its family members confers partial tumor susceptibility in neuroendocrine lineages in the lungs of mice. Our data also imply the requirement of other oncogenic signaling pathways to achieve full transformation in neuroendocrine lung lesions mutant for the Rb family.
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PMID:Ablating all three retinoblastoma family members in mouse lung leads to neuroendocrine tumor formation. 2877 59