Apoptosis is a form of programmed cell death characterized by nuclear chromatin condensation, cell shrinkage, membrane blebbing, and DNA fragmentation. [1][2][3] The relationship between intracellular acidification and apoptosis has been studied. [4][5][6][7][8][9] In recent studies, the intracellular acidification may lead to activation of endonucleases and induce apoptosis in tumor cells. 6,8,9 In addition, the role of intracellular pH (pHi) in apoptosis and cell proliferation has been investigated. 10,11 The pHi of cancer cells has been reported to be more alkaline than that of normal cells, and the maintenance of a neutral or slightly alkaline pHi is required for cell growth, transformation, and metabolism. 10,11 Therefore, increasing the intracellular acidity by inhibiting the pHi regulatory mechanisms is cytotoxic and suggests that the pHi regulatory mechanisms may serve as targets for tumor therapy. 6,8,9 Prodigiosins (prodigiosin, metacycloprodigiosin, and prodigiosin 25-C) are red pigments produced as chromophores by various bacteria including Serratia marcescens, Pseuodomonas magnesiorubera, and others. 12 Among the prodigiosin family, prodigiosin 25-C inhibited H ϩ translocation by vacuolar-type H ϩ -ATPase (V-ATPase) without any effect on its ATP hydrolytic activity and suppressed the growth of neoplastic Chinese hamster ovary cells. 13 We previously reported that cycloprodigiosin hydrochloride (cPrG-HCl), which is a member of the prodigiosin family and is more pure and stable than the others, inhibited H ϩ translocation by V-ATPase in the same manner as other prodigiosins. 14 Recently, it was found that prodigiosins promote H ϩ /Cl Ϫ symport across vesicular membranes, resulting in an uncoupling of V-ATPase. 13,15,16 Therefore, these reports suggested that prodigiosins are useful pH regulators and may be promising anticancer drugs.To date, the nature of the interaction between the alteration of pHi and apoptosis induced by cPrG-HCl has not been investigated. Therefore, in this study, we have shown that cPrG-HCl suppressed the cellular proliferation and induced apoptosis as a result of a decrease of pHi on liver cancer cell lines. MATERIALS AND METHODSCell Culture. Six liver cancer cell lines (Huh-7, HCC-M, and HCC-T, human hepatocellular carcinoma; HepG2, human hepatoAbbreviations: pHi, intracellular pH; V-ATPase, vacuolar-type H ϩ -ATPase; cPrG-HCl, cycloprodigiosin hydrochloride; DMEM, Dulbecco' s modified Eagle minimum essential medium; FBS, fetal bovine serum; DMSO, dimethylsulfoxide; PBS, phosphate-buffered saline; MTT, 3-(4,5-dimethylthiazol-2-2-yl), 5 diphenyltetrazolium bromide; IC 50 , 50% inhibitory concentration; BCECF-AM, 2Ј,7Ј-bis-(Carboxyethyl)-5(6Ј)-carboxyfluorescein acetoxymethyl ester; TUNEL, terminal deoxynucleotidyl transferase mediated dUTP biotin nick end labeling.From the
The depressant effect of interferon-alpha on drug metabolizing activity in the liver has been investigated in 12 patients with chronic active hepatitis B. 7-methoxy-coumarin (7-MC) O-demethylase and 7-ethoxycoumarin (7-EC) O-deethylase, in specimens obtained by liver biopsy, were measured before and after interferon treatment. 7-MC and 7-EC O-dealkylase activity were significantly reduced after interferon treatment, from 13.4 to 9.24 nmol.g-1 liver.min-1, and from 3.22 to 2.16 nmol.g-1 liver.min-1, respectively. The magnitude of the fall varied widely between individual patients. The study provides the first direct evidence that interferon-alpha can impair the activity of drug metabolizing enzymes in the human liver.
The depressant effect of interferon beta on drug-metabolizing activity in the human liver was investigated. Seven patients with chronic hepatitis C were treated with interferon beta at doses of 3 x 10(6) to 9 x 10(6) IU/day for 8 wk. The activities of 7-methoxycoumarin O-demethylase and 7-ethoxycoumarin O-deethylase in specimens obtained by liver biopsy were examined before and after interferon treatment. Theophylline pharmacokinetics were also examined before and after interferon treatment. Interferon beta treatment reduced the activities of both O-dealkylases from 6.0 (100%) to 3.2 (53%) nmol/gm liver per minute and from 1.9 (100%) to 1.1 (58%) nmol/gm liver per minute, respectively (p < 0.05). The total body clearance of theophylline was also decreased (from 0.76 to 0.56 ml/kg/min; p < 0.05), and its elimination half-life was increased (from 8.4 to 11.7 hr; p < 0.05); however, the volume of distribution was not significantly affected. The magnitude of the decreases in enzyme activities and in theophylline clearance varied widely in individual patients and did not correlate with the dose of interferon administered. This study provides the first direct evidence that interferon beta can depress the activity of drug-metabolizing enzymes in the human liver.
Background. The incidence of hepatocellular carcinoma (HCC) in southern China, including Guangxi Province, is among the highest in the world. Investigations of the etiology of HCC in this area have focused on hepatitis B virus (HBV) and aflatoxin. However, hepatitis C virus (HCV) has been shown to be a possible pathogenic agent for HCC in a number of countries. Methods. Antibodies to HCV (anti‐HCV), determined by second‐generation enzyme immunoassay, and hepatitis B surface antigen (HBsAg) were assayed in the sera of 186 patients with HCC and 48 healthy control subjects from Guangxi Province in southern China. Results. HBsAg was detected in 131 (70.4%) of 186 patients with HCC, whereas only 10 (5.4%) patients were found to be positive for anti‐HCV. The prevalence of anti‐HCV in patients with HBsAg‐positive HCC was 6.9% (9 of 131) and that in patients with HBsAg‐negative HCC was 1.8% (1 of 55); there was no significant difference between these two groups. Anti‐HCV was not detected in any of the healthy control subjects, in whom the prevalence of HBsAg was 10.4% (5 of 48). Conclusions.These findings indicate that HCV does not seem to play an important role in the development of HCC in Guangxi Province; however, HBV infection appears to be a major pathogenic factor for HCC in this area.
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