Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dichloromethane is widely used in industrial processes, food preparation, and agriculture. In industry, dichloromethane is used as a solvent in paint removers, degreasing agents, aerosol propellants, and triacetate solutions; as a blowing agent in flexible urethane foams; and as a process solvent in the manufacture of steroids, antibiotics, vitamins, and tablet coatings. The use of dichloromethane as an extraction solvent for spice oleoresins, hops, and caffeine from coffee has been approved by the U.S. Food and Drug Administration. Dichloromethane has been used as an inhalation anesthetic and as a fumigant for grain and strawberries. Toxicology and carcinogenesis studies of dichloromethane (99% pure) were conducted by inhalation exposure of groups of 50 male and 50 female F344/N rats and B6C3F1 mice 6 hours per day, 5 days per week, for 102 weeks. The exposure concentrations used (0, 1,000, 2,000, or 4,000 ppm for rats and 0, 2,000, or 4,000 ppm for mice) were selected on the basis of results from 13-week inhalation studies in which groups of 10 rats and 10 mice of each sex were exposed to dichloromethane at concentrations of 525-8,400 ppm 6 hours per day, 5 days per week. During the 2-year studies in rats, body weight gains for exposed males and females were comparable to those of the chamber controls. The survival of exposed male rats was comparable to that of the chamber controls; however, the survival of all groups of males at the termination of the study was low (control, 16/50; low dose, 16/50; mid dose, 17/50; high dose, 9/50). Most of the early deaths among male rats occurred during the final weeks of the study; the survival of male rats through week 86 of the study was 36/50, 39/50, 37/50, and 33/50. This decreased survival is believed to be related to the high incidence of leukemia (34/50; 26/50; 32/50; 35/50). Survival of female rats exposed at 4,000 ppm was reduced relative to that of the chamber controls (30/50; 22/50; 22/50; 15/50); leukemia occurred frequently in all female rat groups. Final mean body weights of high dose male mice and low and high dose female mice were 10%-17% lower than those of the chamber controls; these reductions occurred during the last 16 weeks of the study. The survival of dosed male mice and high dose female mice was reduced relative to that of the chamber controls (male: control, 39/50; low dose, 24/50; high dose, 11/50; female: 25/50; 25/50; 8/50). This reduced survival may have been due to the chemically induced development of liver and lung neoplasia in male and female mice. Increased incidences of benign mammary gland lesions (adenomas and fibroadenomas) occurred in male and female rats exposed to dichloromethane (male: 0/50; 0/50; 2/50; 5/50; female: 5/50; 11/50; 13/50; 23/50). The incidence of malignant mammary gland neoplasms was not increased in female rats (2/50; 2/50; 2/50; 0/50); none was observed in male rats. In addition, integumentary system tumors in the area of the mammary chain occurred with a positive trend in male rats (subcutaneous tissue fibroma or sarcoma: 1/50; 1/50; 2/50; 5/50); the combined incidence of all tumors in the mammary area in male rats was 1/50, 1/50, 4/50, and 9/50. Exposure to dichloromethane was associated with increased incidences of hepatic hemosiderosis, cytomegaly, cytoplasmic vacuolization, necrosis, granulomatous inflammation, and bile duct fibrosis in both male and female rats. There was a positive but marginal trend in the incidence of hepatocellular neoplastic nodules or hepatocellular carcinomas (combined) in female rats (2/50; 1/50; 4/50; 5/50). The incidence of squamous metaplasia of the nasal cavity was increased in female rats exposed at 4,000 ppm (1/50; 2/50; 3/50; 9/50) but not in males (4/50; 5/50; 3/50; 3/50). No nasal cavity tumors were observed in rats. The increased incidences of mononuclear cell leukemia in mid dose and high dose female rats (17/50; 17/50; 23/50; 23/50) were statistically significant by age-adjusted analyses. In male rats, mesotheliomas (arising primarily from the tunica vaginalis) occurred at increas) occurred at increased incidences (0/50; 2/50; 5/50; 4/50). Lung tumors occurred at increased incidences in male and female mice exposed to dichloromethane (alveolar/bronchiolar adenomas: male - 3/50; 19/50; 24/50; female - 2/50; 23/48; 28/48; alveolar/bronchiolar carcinomas: male - 2/50; 10/50; 28/50; female - 1/50; 13/48; 29/48). Cytologic degeneration of the liver was observed at increased incidences in high dose male and dosed female mice (male: 0/50; 0/49; 22/49; female: 0/50; 23/48; 21/48). Incidences of hepatocellular adenomas or hepatocellular carcinomas (combined) were increased in high dose male and dosed female mice (male: 22/50; 24/49; 33/49; female: 3/50; 16/48; 40/48). There were also dose-related increases in the numbers of mice bearing multiple lung or liver neoplasms. Dose-related increases were observed in the incidences of testicular atrophy in male mice and uterine and ovarian atrophy in female mice; these effects are considered to be secondary responses to neoplasia. An audit of the experimental data was conducted for the 2-year studies of dichloromethane. No data discrepancies were found that influenced the final interpretations. Under the conditions of these inhalation studies, there was some evidence of carcinogenicity of dichloromethane for male F344/N rats as shown by an increased incidence of benign neoplasms of the mammary gland. There was clear evidence of carcinogenicity of dichloromethane for female F344/N rats as shown by increased incidences of benign neoplasms of the mammary gland. There was clear evidence of carcinogenicity of dichloromethane for male and female B6C3F1 mice, as shown by increased incidences of alveolar/bronchiolar neoplasms and of hepatocellular neoplasms. Synonyms: DCM; methylene chloride
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PMID:NTP Toxicology and Carcinogenesis Studies of Dichloromethane (Methylene Chloride) (CAS No. 75-09-2) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1274 23

Trichloroethylene (TCE) is an industrial solvent used for vapor degreasing and cold cleaning of fabricated metal parts. TCE has also been used as a carrier solvent for the active ingredients of insecticides and fungicides, as a solvent for waxes, fats, resins, and oils, as an anesthetic for medical and dental use, and as an extractant for spice oleoresins and for caffeine from coffee. Trichloroethylene may be found in printing inks, varnishes, adhesives, paints, lacquers, spot removers, rug cleaners, disinfectants, and cosmetic cleansing fluids. TCE may also be used as a chain terminator in polyvinyl chloride production and as an intermediate in the production of pentachloroethane. Trichloroethylene is no longer used with food, drugs, or cosmetics. NTP Carcinogenesis studies of epichlorohydrin-free trichloroethylene were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Dosage levels were 500 and 1,000 mg/kg for rats and 1,000 mg/kg for mice. Trichloroethylene was administered five times per week for 103 weeks, and surviving animals were killed between weeks 103 and 107. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Groups of 50 male and 50 female rats were used as untreated controls. The dosage levels selected for the 2-year study were based on the results of the 13-week studies. Groups of 10 male and 10 female rats received TCE by gavage at doses of 125 to 2,000 mg/kg (males) and 62.5 to 1,000 mg/kg (females) for 13 weeks. Groups of 10 male and 10 female mice received gavage doses of 375 to 6,000 mg/kg of TCE for 13 weeks. Survival, body weight gains, and previous experience with TCE were used to select doses for the 2-year study. All rats survived the 13-week study, but males receiving 2,000 mg/kg exhibited a 24% difference in final body weight. At the 1,000 mg/kg dose, final body weights for males (-3%) and for females (-2%) were similar to those of controls. The doses selected for the 2-year study in rats were 500 and 1,000 mg/kg for both sexes. The initial doses used in the earlier bioassay in Osborne-Mendel rats were 549 and 1,097 mg/kg for both sexes. A total of 8/10 male mice and 10/10 female mice receiving doses of TCE as high as 1,500 mg/kg survived the 13-week experimental period. The single dosage level selected for the 2-year study in mice was 1,000 mg/kg for both sexes. This dose was less than the high dose used in the earlier bioassay in B6C3F1 mice (2,339 mg/kg for males and 1,739 for females) and was similar to the previous low doses (1,169 mg/kg for males and 869 for females). In the 2-year study, the survival of both low and high dose male rats and dosed male mice was less (P</=0.005) than that of the vehicle controls. Mean body weights of dosed rats of each sex were lower than those of the vehicle controls, and after week 65, the decrements in body weight gains were dose related. The mean body weight of dosed male mice was lower than that of the vehicle controls throughout the study, while those of the dosed and vehicle control female mice were comparable. Cytomegaly (toxic nephrosis) of the kidney was observed in 96/98 male and in 97/97 female rats given TCE, with none being found in male or female vehicle control rats. This lesion was more severe in males, particularly in the high dose group. Cytomegaly was observed in 45/50 male mice and in 48/49 female mice administered TCE, and in none of the vehicle controls. Renal tubular cell adenocarcinomas were found in the three high dose male rats; these neoplasms were observed in those male rats killed at the end of the study (0/33, 0/20, and 3/16, 19%). The incidence in the high dose male rats at the end of the study was greater (P<0.05) than that in the controls. Renal tubular cell adenocarcinomas are considered uncommon occurrences in F344/N rats, with 3/748 (0.4%) being observed in historical vehicle gavage controls. Additional renal tumors in dosed male rats included one transitional cell carcats included one transitional cell carcinoma of the renal pelvis and two tubular cell adenomas in low dose animals and one carcinoma of the renal pelvis in a high dose animal. No renal neoplasms were found in vehicle control rats; one untreated control male rat had a transitional cell papilloma of the renal pelvis. In female rats, one tubular cell adenocarcinoma was found in the high dose group. An increased incidence (P&lt;0.05, life table) of peritoneal mesotheliomas was detected in low dose male rats (control, 1/50; low dose, 5/50; high dose, 1/49). Mesotheliomas have been diagnosed in 16/752 (2.1&percnt;) historical vehicle control male F344/N rats, and the increased incidence in the present study may have been related to the administration of TCE. The results in male F344/N rats were considered equivocal for detecting a carcinogenic response because both groups receiving TCE showed significantly reduced survival compared to vehicle controls (35/50, 70&percnt;, 20/50, 40&percnt;; 16/50, 32&percnt;) and because 20&percnt; of the animals in the high dose group were killed accidently by gavage error. Negative trends were observed for chromophobe adenomas of the pituitary gland and for endometrial stomal polyps in female rats. These decreases were not considered to be related to the administration of TCE. The administration of TCE to mice caused increased incidences of hepatocellular carcinoma in males (control, 8/48; dosed, 31/50; P&lt;0.001) and in females (control, 2/48; dosed, 13/49; P&lt;0.005). Hepatocellular carcinomas metastasized to the lungs in five dosed male mice and one control male mouse, and none were observed in females. The incidence of hepatocellular adenomas was increased in male mice (control, 7/48; dosed 14/50) and in female mice (control, 4/48; dosed, 16/49; P&lt;0.05). Under the conditions of these studies, epichlorohydrin-free trichloroethylene caused renal tubular-cell neoplasms in male F344/N rats, produced toxic nephrosis in both sexes, and shortened the survival time of males. This experiment in male F344/N rats was considered to be inadequate to evaluate the presence or absence of a carcinogenic response to trichloroethylene. For female F344/N rats receiving trichloroethylene, containing no epichlorohydrin, there was no evidence of carcinogenicity. Trichloroethylene (without epichlorohydrin) was carcinogenic for B6C3F1 mice, causing increased incidences of hepatocellular carcinomas in males and females and of hepatocellular adenomas in females. Levels of Evidence of Carcinogenicity: Male Rats: Inadequate Study Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonym: TCE
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PMID:NTP Carcinogenesis Studies of Trichloroethylene (Without Epichlorohydrin) (CAS No. 79-01-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1275 Jul 50

Clinical and epidemiological studies on cancer etiology seldom treat coffee drinking as a potential effect modifier. Yet caffeine exerts significant effects upon a large variety of physiologic, cellular and molecular systems. Caffeine, 'the world's most popular drug', is also a fundamental research tool, widely used in clinical studies on drug metabolism, and in experimental studies on cell cycle checkpoints, DNA repair, and apoptosis, among many other. Caffeine can profoundly alter cell cycle checkpoint function and several mechanisms of DNA repair, as well as carcinogen metabolism. The impact of caffeine on cell cycle checkpoint function occurs in spite of it being nonmutagenic in traditional mutagenesis assays. A complex body of biologic evidence suggests that caffeine-containing beverages can both enhance and antagonise potentially carcinogenic exposures. However, most pathways leading to the ultimate effects in human beings remain unknown. It is unclear whether any of the hundreds of compounds contained in coffee and tea exert a direct and significant carcinogenic effect per se in any human tissue at usual conditions of use. Reasons exist to consider that coffee may sometimes be an indirect, positive confounder. The study of interactions between caffeine-containing beverages and environmental agents in well defined groups of healthy and diseased people could yield new insights into checkpoint signal transduction and other mechanisms of carcinogenesis. Information on the use of caffeine-containing beverages should more often be integrated in studies on the role of gene-environment interactions in the pathogenesis of cancer.
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PMID:Coffee drinking: the rationale for treating it as a potential effect modifier of carcinogenic exposures. 1280 68

The p53 tumour suppressor gene is a transcription factor that can induce cell cycle arrest and apoptosis. In response to various stress-inducing signals, p53 level increases and this is accompanied with increased activities of p53. Interestingly, the methylxanthine caffeine can abrogate the p53 accumulation induced by certain DNA-damaging agents by an unknown mechanism. In an effort to understand how different signals induce p53, human tumour cell lines were treated with combinations of various stress-inducing agents and caffeine. Caffeine inhibited the accumulation of p53 induced by leptomycin B (LMB), an inhibitor of CRM1, but not N-acetyl-leu-leu-norleucinal, a proteasome inhibitor. Furthermore, caffeine also inhibited the accumulation of p53 by a variety of stress-inducing agents in vivo, such as 5-fluorouracil, doxorubicin, mitomycin C, camptothecin and roscovitine. However, caffeine failed to affect the accumulation of p53 in hypoxia (HYP)-treated cells. These results suggested that HYP must use a distinct pathway from most DNA-damaging and stress-inducing agents to induce p53.
Carcinogenesis 2003 Jul
PMID:Hypoxia induces p53 through a pathway distinct from most DNA-damaging and stress-inducing agents. 1280 44

The combined effects of caffeine (1,3,7-trimethylxanthine) with iodine deficiency (ID) were examined in a rat two-stage thyroid carcinogenesis model using N-bis(2-hydroxypropyl)nitrosamine (DHPN). Male F344 rats were divided into 6 groups each consisting of 10 animals, and received a single s.c. injection of 2800 mg/kg DHPN. From 1 week after the DHPN initiation, the rats were respectively fed a basal diet in which the protein was exchanged for 20% gluten, containing 1500 ppm caffeine + ID, 300 ppm caffeine + ID, 60 ppm caffeine + ID, 1500 ppm caffeine or ID or a basal diet alone for 12 weeks. Relative thyroid weights were significantly (P < 0.05) increased due to the development of proliferative lesions induced by the ID diet as compared to the DHPN-alone group value, which was enhanced by caffeine, albeit without statistical significance. Relative pituitary weights were significantly (P < 0.05) increased with 300 or 1500 ppm caffeine + ID as compared to the DHPN-alone group value. Serum thyroid stimulating hormone (TSH) levels were slightly increased by ID, an effect which was further enhanced by 300 or 1500 ppm caffeine. Serum thyroxine (T(4)) levels were slightly increased by caffeine or ID alone, but decreased by caffeine with ID. Histopathologically, thyroid follicular carcinomas were found only in the 1500 ppm caffeine + ID group, although thyroid follicular adenomas were detected in all the ID-treated groups. The multiplicity of focal thyroid follicular hyperplasias was significantly (P < 0.05) increased by 1500 ppm caffeine. These results indicate that caffeine may synergistically promote thyroid carcinogenesis with ID partially through a pituitary-dependent pathway in rats, implying the possible implication of routine caffeine intake in the promotion of thyroid carcinogenesis.
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PMID:Synergistic interaction between excess caffeine and deficient iodine on the promotion of thyroid carcinogenesis in rats pretreated with N-bis(2-hydroxypropyl)nitrosamine. 1282

Administration of green tea or caffeine was shown previously to inhibit ultraviolet B light-induced carcinogenesis in SKH-1 mice, and this effect was associated with a reduction in dermal fat. In the present study, oral administration of 0.6% green tea (6 mg tea solids/ml) or 0.04% caffeine (0.4 mg/ml; equivalent to the amount of caffeine in 0.6% green tea) as the sole source of drinking fluid to SKH-1 mice for 15 weeks increased total 24 hr locomotor activity by 47 and 24%, respectively (p<0.0001). Oral administration of 0.6% decaffeinated green tea (6 mg tea solids/ml) for 15 weeks increased locomotor activity by 9% (p<0.05). The small increase in locomotor activity observed in mice treated with decaffeinated green tea may have resulted from the small amounts of caffeine still remaining in decaffeinated green tea solutions (0.047 mg/ml). The stimulatory effects of orally administered green tea and caffeine on locomotor activity were paralleled by a 38 and 23% increase, respectively, in the dermal muscle layer thickness. In addition, treatment of the mice with 0.6% green tea or 0.04% caffeine for 15 weeks decreased the weight of the parametrial fat pad by 29 and 43%, respectively, and the thickness of the dermal fat layer was decreased by 51 and 47%, respectively. These results indicate that oral administration of green tea or caffeine to SKH-1 mice increases locomotor activity and muscle mass and decreases fat stores. The stimulatory effect of green tea and caffeine administration on locomotor activity described here may contribute to the effects of green tea and caffeine to decrease fat stores and to inhibit carcinogenesis induced by UVB in SKH-1 mice.
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PMID:Stimulatory effect of oral administration of green tea and caffeine on locomotor activity in SKH-1 mice. 1285 Apr 99

Research on cancer chemoprevention is an important approach for decreasing both the incidence and number of deaths from cancer. The use of tamoxifen to prevent breast cancer, finasteride to prevent prostate cancer, and aspirin to prevent colon cancer are recent examples of cancer chemoprevention. This article describes research from my laboratory and related research from other laboratories on the effects of enzyme induction on chemical carcinogenesis as an approach to cancer chemoprevention, as well as studies on the inhibitory effects of curcumin, caffeine, (-)-epigallocatechin gallate (EGCG), and tea in animal models of carcinogenesis. The later substances appear to work, at least in part, by enhancing apoptosis in DNA-damaged cells or in tumors. The results of our studies and those of others provide a rationale for clinical trials on the potential chemopreventive effects of curcumin, caffeine, EGCG, and tea on the formation of cancer of the skin, mouth, esophagus, stomach, and colon in people with precancerous lesions and a high risk of developing these cancers. It was pointed out that several compounds that are effective cancer chemopreventive agents in one experimental setting can enhance carcinogenesis in another experimental setting. These results suggest that it may be necessary to tailor the cancer chemopreventive regimen to individual subjects with known carcinogen exposures or to high cancer risk individuals with mechanistically understood pathways of carcinogenesis so that chemopreventive agents with known mechanisms of action can be better customized to the individual and selected on a more rational basis.
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PMID:Enzyme induction and dietary chemicals as approaches to cancer chemoprevention: the Seventh DeWitt S. Goodman Lecture. 1461 89

The incidence rate of testicular cancer has increased during the last 50 years. An interplay between changing environmental factors and individual susceptibility, e.g. in foreign compound metabolizing enzymes, may have important influences on the risk of testicular cancer. The cytochrome P4501A2 (CYP1A2) enzyme and the bimodally expressed enzyme N-acetyltransferase2 (NAT2) metabolize many procarcinogens/carcinogens. The aim of this population-based case-control study was to investigate if CYP1A2 or NAT2 activity measured as a ratio of urinary metabolites of dietary caffeine is a risk factor in testicular cancer. 378 men participated (80 seminomas, 104 non-seminomas and 194 controls). The CYP1A2 activity was lower in the cases than in the controls [median and 30-70% percentiles: 4.7 (3.9-5.7) and 5.2 (4.4-6.4), respectively]. The subjects were classified in tertiles with low, medium or high CYP1A2 activity. A low CYP1A2 activity was associated with the highest risk of testicular cancer. Including all participants except men using drugs suspected to influence CYP1A2 activity (n = 15), medium and low activity conferred odds ratios (ORs) of 1.54 [confidence intervals of 95% (CI(95%)) 0.93-2.55] and 2.11; CI(95%) (1.23-3.62), respectively, of having testicular cancer. Excluding smokers (n = 157) the ORs of medium and low activity were 3.63; CI(95%) (1.53-8.60) and 4.70; CI(95%) (2.03-10.89), respectively. After further exclusion of cases that had received chemotherapy or radiation (n = 47), similar significant results were achieved. In the groups with the lowest CYP1A2 activity the ORs for seminoma and non-seminoma were 2.12; CI(95%) (0.93-4.81) and 2.10; CI(95%) (1.02-4.32). The phenotype of NAT2 was not associated with testicular cancer. In conclusion, we found no association of NAT2 phenotype to testicular cancer, whereas significant associations between CYP1A2 activity and testicular cancer were shown.
Carcinogenesis 2004 Jun
PMID:Low CYP1A2 activity associated with testicular cancer. 1497 27

Consumption of red meat is associated with an increased risk of colorectal cancer, whereas cruciferous vegetable consumption reduces cancer risk. While the mechanisms remain to be determined, cruciferous vegetables may act by altering the metabolism of carcinogens present in cooked food, such as the heterocyclic amine 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). The aim of this study was to evaluate the effect of cruciferous vegetable consumption on the metabolism of PhIP in 20 non-smoking Caucasian male subjects. The study consisted of three 12-day phases, namely two periods of avoidance of cruciferous vegetables (phases 1 and 3) and a high cruciferous vegetable diet period (phase 2), when subjects ingested 250 g each of Brussels sprouts and broccoli per day. At the end of each study phase, the subjects consumed a cooked meat meal containing 4.90 microg PhIP and urine samples were collected for up to 48 h. Cruciferous vegetable consumption significantly increased hepatic CYP1A2, as demonstrated by changes in saliva caffeine kinetics. Samples of N(2)-hydroxy-PhIP-N(2)-glucuronide (the major urinary metabolite of PhIP in humans), N(2)-hydroxy-PhIP-N(3)-glucuronide and their trideuterated derivatives (to serve as internal standards) were synthesized and a liquid chromatography-mass spectrometry-mass spectrometry method developed for their analysis. In phases 1 and 3, the excretion of N(2)-hydroxy-N(2)-PhIP-glucuronide in 0-48 h urine samples was six times that of N(2)-hydroxy-PhIP-N(3)-glucuronide. Cruciferous vegetable consumption significantly increased the urinary excretion of N(2)-hydroxy-PhIP-N(2)-glucuronide in 0-48 h urine samples to 127 and 136% of levels observed in phases 1 and 3, respectively. In contrast, the urinary excretion of N(2)-hydroxy-PhIP-N(3)-glucuronide was unchanged. While the urinary excretion of both PhIP metabolites accounted for approximately 39% of the PhIP dose in phases 1 and 3, they accounted for approximately 49% of the dose in phase 2. This study demonstrates that cruciferous vegetable consumption can induce both the phase I and II metabolism of PhIP in humans.
Carcinogenesis 2004 Sep
PMID:Cruciferous vegetable consumption alters the metabolism of the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in humans. 1507 45

Caffeine is a major biologically active constituent in coffee and tea. Because caffeine has been reported to inhibit carcinogenesis in UVB-exposed mice, the cancer-preventing effect of caffeine has attracted considerable attention. In the present study, the effect of caffeine in quiescent (G0 phase) cells was investigated. Pretreatment with caffeine suppressed cell proliferation in a dose-dependent manner 36 h after addition of fetal bovine serum as a cell growth stimulator. Analysis by flow cytometry showed that caffeine suppressed cell cycle progression at the G0/G1 phase, i.e., 18 h after addition of fetal bovine serum, the percentages of cells in G0/G1 phase in 1 mM caffeine-treated cells and in caffeine-untreated cells were 61.7 and 29.0, respectively. The percentage of cells in G0/G1 phase at 0 h was 75.5. Caffeine inhibited phosphorylation of retinoblastoma protein at Ser780 and Ser807/Ser811, the sites where retinoblastoma protein has been reported to be phosphorylated by cyclin-dependent kinase 4 (cdk4). Furthermore, caffeine inhibited the activation of the cyclin D1-cdk4 complex in a dose-dependent manner. However this compound did not directly inhibit the activity of this complex. In addition, caffeine did not affect p16INK4 or p27Kip1 protein levels, but inhibited the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3beta. Our results showed that caffeine suppressed the progression of quiescent cells into the cell cycle. The inhibitory mechanism may be due to the inhibition of cell growth signal-induced activation of cdk4, which may be involved in the inhibition of carcinogenesis in vivo.
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PMID:Caffeine inhibits cell proliferation by G0/G1 phase arrest in JB6 cells. 1512 79


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