Dietary fish oil associated with increased apoptosis and modulated expression of Bax and Bcl-2 during 7,12-dimethylbenz(alpha)anthracene-induced mammary carcinogenesis in rats.

The present study investigated the chemopreventive effect of dietary fish oil (Maxepa), rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on induction of apoptosis in mammary carcinogenesis model. Mammary carcinogenesis was initiated by a single, tail vein injection of 7,12-dimethylbenz(alpha)anthracene (DMBA) (0.5mg/0.2ml corn oil/100g body weight) at 7 weeks of animal age. Ninety female Sprague-Dawley rats were divided into two parts: part one was used for histology and immunohistochemical study and part two for morphological analysis. Each part consists of three experimental groups having 15 animals, i.e., Group A (DMBA control), Group B (DMBA+fish oil) and Group C (DMBA+corn oil). Rats were fed either fish oil or corn oil (0.5ml/day/rat) by oral gavage, 2 weeks prior to DMBA injection. Treatment was continued 25 weeks, studying histopathology, expression of Bax and Bcl-2 proteins by immunohistochemistry and apoptosis by TUNEL assay and morphological study at 36 weeks. Results showed that the fish oil-treated group exhibited a substantial increase in Bax (p<0.05) immunolabelling and a reduction of Bcl-2 immunopositivity (p<0.05), and increased TUNEL-positive apoptotic cells (p<0.05); however, corn oil treatment did not show these beneficial effects toward mammary preneoplasia. We conclude that fish oil has the potential to play a significant role in limiting mammary tumourigenesis in vivo.

Acanthus ilicifolius plant extract prevents DNA alterations in a transplantable Ehrlich ascites carcinoma-bearing murine model.

AIM: To investigate the chemopreventive efficacy of the Indian medicinal plant Acanthus ilicifolius L Acanthaceae in a transplantable Ehrlich ascites carcinoma (EAC)-bearing murine model. METHODS: Male Swiss albino mice were divided into four groups: Group A was the untreated normal control; Group B was the EAC control mice group that received serial, intraperitoneal (ip) inoculations of rapidly proliferating 2 x 10(5) viable EAC cells in 0.2 mL of sterile phosphate buffered saline; Group C was the plant extract-treated group that received the aqueous leaf extract (ALE) of the plant at a dose of 2.5 mg/kg body weight by single ip injections, once daily for 10, 20 and 30 consecutive days following tumour inoculation (ALE control); and Group D was the EAC + ALE-treatment group. The chemopreventive potential of the ALE was evaluated in a murine model by studying various biological parameters and genotoxic markers, such as tumour cell count, mean survival of the animals, haematological indices, hepatocellular histology, immunohistochemical expression of liver metallothionein (MT) protein, sister-chromatid exchanges (SCEs), and DNA alterations. RESULTS: Treatment of the EAC-bearing mice with the ALE significantly (P < 0.001) reduced viable tumour cell count by 68.34% (228.7 x 10(6) +/- 0.53) when compared to EAC control mice (72.4 x 10(6) +/- 0.49), and restored body and organ weights almost to the normal values. ALE administration also increased (P < 0.001) mean survival of the hosts from 35 +/- 3.46 d in EAC control mice to 83 +/- 2.69 d in EAC + ALE-treated mice. Haematological indices also showed marked improvement with administration of ALE in EAC-bearing animals. There was a significant increase in RBC count (P < 0.001), hemoglobin percent (P < 0.001), and haematocrit value (P < 0.001) from 4.3 +/- 0.12, 6.4 +/- 0.93, and 17.63 +/- 0.72 respectively in EAC control mice to 7.1 +/- 0.13, 12.1 +/- 0.77, and 30.23 +/- 0.57 respectively in EAC + ALE-treated group, along with concurrent decrement (P < 0.001) in WBC count from 18.8 +/- 0.54 in EAC control to 8.4 +/- 0.71 in EAC + ALE. Furthermore, treatment with ALE substantially improved hepatocellular architecture and no noticeable neoplastic lesions or foci of cellular alteration were observed. Daily administration of the ALE was found to limit liver MT expression, an important marker of cell proliferation with concomitant reduction in MT immunoreactivity (62.25 +/- 2.58 vs 86.24 +/- 5.69, P < 0.01). ALE was also potentially effective in reducing (P < 0.001) the frequency of SCEs from 14.94 +/- 2.14 in EAC control to 5.12 +/- 1.16 in EAC + ALE-treated group. Finally, in comparison to the EAC control, ALE was able to suppress in vivo DNA damage by abating the generations of 'tailed' DNA by 53.59% (98.65 +/- 2.31 vs 45.06 +/- 1.14, P < 0.001), and DNA single-strand breaks (SSBs) by 38.53% (3.14 +/- 0.31 vs 1.93 +/- 0.23, P < 0.01) in EAC-bearing murine liver. CONCLUSION: Our data indicate that, ALE is beneficial in restoring haematological and hepatic histological profiles and in lengthening the survival of the animals against the proliferation of ascites tumour in vivo. Finally, the chemopreventive efficacy of the ALE is manifested in limiting MT expression and in preventing DNA alterations in murine liver. The promising results of this study suggest further investigation into the chemopreventive mechanisms of the medicinal plant A. ilicifolius in vivo and in vitro.

Suppression of early stages of neoplastic transformation in a two-stage chemical hepatocarcinogenesis model: supplementation of vanadium, a dietary micronutrient, limits cell proliferation and inhibits the formations of 8-hydroxy-2'-deoxyguanosines and DNA strand-breaks in the liver of sprague-dawley rats.

Previous studies from our laboratory have demonstrated the potential anticarcinogenicity of vanadium, a dietary micronutrient in rat liver, colon, and mammary carcinogenesis models in vivo. In this paper, we have investigated further the antihepatocarcinogenic role of this essential trace element by studying several biomarkers of chemical carcinogenesis with special reference to cell proliferation and oxidative DNA damage. Hepatocarcinogenesis was induced in male Sprague-Dawley rats by chronic feeding of 2-acetylaminofluorene (2-AAF) at a dose of 0.05% in basal diet daily for 5 days a week. Vanadium in the form of ammonium metavanadate (0.5 ppm equivalent to 4.27 micromol/l) was supplemented ad lib to the rats. Continuous vanadium administration reduced relative liver weight, nodular incidence (79.99%), total number and multiplicity (P < 0.001; 68.17%) along with improvement in hepatocellular architecture when compared to carcinogen control. Vanadium treatment further restored hepatic uridine diphosphate (UDP)-glucuronosyl transferase and UDP-glucose dehydrogenase activities, inhibited lipid peroxidation, and prevented the development of glycogen-storage preneoplastic foci (P < 0.01; 63.29%) in an initiation-promotion model. Long-term vanadium treatment also reduced BrdU-labelling index (P < 0.02) and inhibited cell proliferation during hepatocellular preneoplasia. Finally, short-term vanadium exposure abated the formations of 8-hydroxy-2'-deoxyguanosines (P < 0.001; 56.27%), length:width of DNA mass (P < 0.01), and the mean frequency of tailed DNA (P < 0.001) in preneoplastic rat liver. The study indicates the potential role of vanadium in suppressing cell proliferation and in preventing early DNA damage in vivo. Vanadium is chemopreventive against the early stages of 2-AAF-induced hepatocarcinogenesis in rats.

Cell proliferation and hepatocarcinogenesis in rat initiated by diethylnitrosamine and promoted by phenobarbital: potential roles of early DNA damage and liver metallothionein expression.

Cell proliferation plays an important role in multistage chemical carcinogenesis. Again, several reports demonstrated that upregulation of metallothionein (MT) expression is associated with increased cell proliferation that may contribute to the pathogenesis of preneoplastic phenotype to frank malignancy. In this study, we evaluated the roles of early DNA damage, altered expressions of liver MT and Ki-67 nuclear antigen, and altered hepatic levels of zinc (Zn) and copper (Cu) on cell proliferation and the progression of hepatocarcinogenesis through premalignant, late premalignant and malignant transformation phases in male Sprague-Dawley rats. We have further studied the association between MT expression and cell proliferation in hepatocarcinogenesis. There was substantial induction of DNA single-strand breaks (SSBs) (P<0.001) and development of hepatocellular premalignant lesions along with significant decrease in hepatic levels of Zn and increase in Cu content following a single, necrogenic, intraperitoneal (i.p.) injection (200 mg/Kg body weight) of diethylnitrosamine (DEN) at week 4 of the experimental protocol. Moreover, DEN+phenobarbital (PB)-treatment significantly elevated MT-, Ki-67-, and BrdU-immunoexpressions along with their immunolabeling indices. Furthermore, positive correlations between MT- and Ki-67- labeling (P=0.0006) at various time intervals, as well as, between MT immunoreactivity and 5'-bromo-2'-deoxyuridine-labeling index (BrdU-LI) (P=0.0007) indicate that, MT expression might be associated with Ki-67 expression and cell proliferation thereby. The study suggests that DEN treatment may lead to alteration of Zn and Cu levels resulting in early DNA damage along with elevation of MT expression that may ultimately lead to hepatic cell proliferation. The results thus provide evidence in support of the role of MT as a potential positive regulator of cell growth during the early stages of hepatocellular transformation in rats.

Protective role of fish oil (Maxepa) on early events of rat mammary carcinogenesis by modulation of DNA-protein crosslinks, cell proliferation and p53 expression.

BACKGROUND: Fish oil is known to protect from many types of cancers of the colon, liver, breast, prostate and lung 123. The objective of the present study was to evaluate the role of fish oil [Maxepa, supplemented at a dose of 0.5 ml is equivalent to 90 mg eicosapentaenoic acid (EPA) and 60 mg docosahexaenoic acid (DHA)] on cell proliferation, expression of p53 tumor suppressor protein and DNA protein crosslinks (DPCs) in a defined model of chemical rat mammary carcinogenesis. Mammary carcinogenesis was initiated by a single, intravenous (i.v.) tail vein injection of 7,12 dimethylbenz(alpha)anthracene (DMBA) at a dose of 5 mg DMBA/2 ml corn oil/kg body weight in female Sprague-Dawley rats at 7 weeks of age. Fish oil supplementation was started daily, 2 weeks prior to DMBA injection and continued for 24 (31 weeks of animal age) weeks and 35 (42 weeks of animal age) weeks of post DMBA injection, for histopathological and immunohistochemical and for morphological studies, respectively. RESULTS: Our results indicate the chemopreventive effect of fish oil (Maxepa) on DMBA-induced rat mammary carcinogenesis. Administration of fish oil further showed a prominent reduction of cell proliferation (24.34%, P = 0.001); DPCs (25%, P < 0.001) and an increased expression of p53 protein (4.636 +/- 0.19, P < 0.001) in preneoplastic mammary tissue when compared to carcinogen control counterpart. Histopathological and morphological analyses were carried out as end-point biomarkers. CONCLUSION: Our study thus provides evidence for the anticarcinogenic effect of fish oil (Maxepa) in limiting mammary preneoplasia in Sprague-Dawley rats.

Molecular basis of vanadium-mediated inhibition of hepatocellular preneoplasia during experimental hepatocarcinogenesis in rats.

Carcinogen-induced early DNA lesions and metallothionein (MT) over-expression have been implicated in cell proliferation and thereby subsequent expression of premalignant phenotype of the cell. We have therefore investigated the chemopreventive potential of vanadium in a multi-biomarker approach, viz. 8-hydroxy-2'-deoxyguanosines (8-OHdGs), DNA single-strand breaks (SSBs), DNA-protein crosslinks (DPCs), chromosomal aberrations (CAs), in situ MT expression, and cell proliferation in rat liver preneoplasia. Hepatocarcinogenesis was induced in male Sprague-Dawley rats with a single, necrogenic, intraperitoneal (i.p.) injection of diethylnitrosamine (DEN) (200 mg/Kg body weight) at week 4 of the experimental protocol followed by promotion with phenobarbital (PB) (0.05% in basal diet), on and from week 8 and continued till 32 weeks in a long-term regimen. There was a significant and steady elevation of modified DNA bases 8-OHdGs (P < 0.0001; 90.69%) along with substantial increments of the extent of SSBs (P < 0.001) and CAs (P < 0.001) following DEN exposure. Supplementation of vanadium at a dose of 0.5 ppm abated the formations of 8-OHdGs (80.63%; P < 0.0001), SS-DNAs (P < 0.001) and SSBs/DNA unit (P < 0.01; 56.39%), DPCs (59.26%; P < 0.0001) and CAs (71.52%; P < 0.001) in preneoplastic rat liver studied at various time points. Low dose of vanadium treatment further reduced liver-MT immunoreactivity (P < 0.05) and BrdU-labeling index (P < 0.02) and a significant positive correlation (r = 0.92; r2 = 0.85; P = 0.0001) was noted between them. Continuous vanadium administration also decreased nodular incidence (66.67%) and nodule multiplicity (62.12%; P < 0.001) along with substantial improvement in the altered hepatocellular phenotype when compared to DEN + PB treatment alone. The study indicates that vanadium-mediated suppression of cell proliferation and resulting premalignant expression might be due to the observed reductions in hepatic 8-OHdGs, SSBs, DPCs, CAs, and MT immunoreactivity. Vanadium is chemopreventive for DEN-induced hepatocellular preneoplasia in rats.

Carcinogen-induced early molecular events and its implication in the initiation of chemical hepatocarcinogenesis in rats: chemopreventive role of vanadium on this process.

Carcinogen-induced formation of DNA adducts and other types of DNA lesions are the critical molecular events in the initiation of chemical carcinogenesis and modulation of such events by chemopreventive agents could be an important step in limiting neoplastic transformation in vivo. Vanadium, a dietary micronutrient has been found to be effective in several types of cancers both in vivo and in vitro and also possesses profound anticarcinogenicity against rat models of mammary, colon and hepatocarcinogenesis. Presently, we report the chemopreventive potential of vanadium on diethylnitrosamine (DEN)-induced early DNA damages in rat liver. Hepatocarcinogenesis was induced in male Sprague-Dawley rats with a single, necrogenic, intraperitoneal (i.p.) injection of DEN (200 mg/kg body weight) at week 4. There was a significant induction of tissue-specific ethylguanines, steady elevation of modified DNA bases 8-hydroxy-2'-deoxyguanosines (8-OHdGs) (P<0.0001; 89.93%) along with substantial increment of the extent of single-strand breaks (SSBs) (P<0.0001) following DEN exposure. Supplementation of 0.5 ppm of vanadium throughout the experiment abated the formations of O(6)-ethylguanines and 7-ethylguanines (P<0.0001; 48.71% and 67.54% respectively), 8-OHdGs (P<0.0001; 81.37%), length:width (L:W) of DNA mass (P<0.01; 62.12%) and the mean frequency of tailed DNA (P<0.001; 53.58%), and hepatic nodulogenesis in preneoplastic rat liver. The study indicates that 0.5 ppm vanadium is potentially and optimally effective, as derived from dose-response studies, in limiting early molecular events and preneoplastic lesions, thereby modulating the initiation stage of hepatocarcinogenesis. Vanadium is chemopreventive against DEN-induced genotoxicity and resulting hepatocellular transformation in rats.

Molecular basis of anticlastogenic potential of vanadium in vivo during the early stages of diethylnitrosamine-induced hepatocarcinogenesis in rats.

Carcinogen-induced DNA base modification and subsequent DNA lesions are the critical events for the expression of premalignant phenotype of the cell. We have therefore investigated the chemopreventive efficacy of a vanadium salt against diethylnitrosamine (DEN)-induced early DNA and chromosomal damages in rat liver. Hepatocarcinogenesis was induced in male Sprague-Dawley rats with a single, necrogenic, intraperitoneal injection of DEN (200mg/kg body weight). 8-Hydroxy-2'-deoxyguanosines (8-OHdGs), strand-breaks and DNA-protein crosslinks (DPCs) were measured by HPLC, comet assay and spectrofluorimetry, respectively. There was a significant and steady elevation of modified bases 8-OHdGs along with substantial increments of the extent of single-strand-breaks (SSBs), DPCs and chromosomal aberrations (CAs) following DEN exposure. Supplementation of vanadium as ammonium metavanadate (NH(4)VO(3), +V oxidation state) at a dose of 0.5ppm in terms of the salt weight throughout the experiment abated the formations of 8-OHdGs (P<0.0001; 79.54%), tailed DNA (P<0.05; 31.55%) and length:width of DNA mass (P<0.02; 61.25%) in preneoplastic rat liver. Vanadium treatment also inhibited DPCs (P<0.0001; 58.47%) and CAs (P<0.001; 45.17%) studied at various time points. The results indicate that the anticlastogenic potential of vanadium in vivo might be due to the observed reductions in liver-specific 8-OHdGs, SSBs and/or DPCs by this trace metal. We conclude that, vanadium plays a significant role in limiting DEN-induced genotoxicity and clastogenicity during the early stages of hepatocarcinogenesis in rats.

Vanadium limits the expression of proliferating cell nuclear antigen and inhibits early DNA damage during diethylnitrosamine-induced hepatocellular preneoplasia in rats.

Previous studies from our laboratory have shown that vanadium stabilizes xenobiotic metabolizing enzymes and antioxidant status and suppresses DNA-protein crosslinks during chemically-induced hepatocarcinogenesis in rats. In the present study, we have further investigated the in vivo antitumor potential of this micronutrient by determining the effect of 0.5 ppm vanadium in drinking water on biomarkers for the early stages of hepatocarcinogenesis; the biomarkers included gamma-glutamyl transpeptidase (GGT)-positive foci and glycogen-storage foci, in situ expression of proliferating cell nuclear antigen (PCNA), and genotoxic DNA damage assessed by the alkaline Comet assay. Histomorphometry also was assessed during the study. Hepatocarcinogenesis was induced by treating 4-week-old male Sprague-Dawley rats with a single, necrogenic, intraperitoneal (i.p.) injection of 200 mg/kg body weight diethylnitrosamine (DEN). Compared to the carcinogen control, vanadium administration over the 32 weeks of the experiment reduced the relative liver weight by 30%, the incidence of nodules by 69.34%, the total number and multiplicity of nodules by 80.77%, and remodeled the hepatocellular premalignant architecture towards a normal phenotype. Moreover, long-term vanadium treatment reduced the development of GGT foci by 76.2% (P < 0.001), decreased periodic acid-Schiff's reactivity by 59.49% (P < 0.01), and decreased PCNA expression, with the concomitant reduction in PCNA immunolabeling index by 93.36% (P < 0.001). Finally, vanadium inhibited early DNA damage (DNA strand-breaks) in DEN-treated rat hepatocytes as expressed in the Comet assay by a 60.04% reduction in the length:width value of DNA mass (P < 0.01) and a 51.54% reduction in the tail length of the DNA comets (P < 0.001). Our results indicate that continuous supplementation with 0.5 ppm vanadium suppresses hepatocellular neoplastic transformation in rats.

Chemopreventive effect of vanadium in a rodent model of chemical hepatocarcinogenesis: reflections in oxidative DNA damage, energy-dispersive X-ray fluorescence profile and metallothionein expression.

In the present study, we investigated the antitumour efficacy of vanadium in a defined rodent model of experimental hepatocarcinogenesis. Hepatic preneoplasia was induced in male Sprague-Dawley rats with a single, necrogenic, intraperitoneal injection of diethylnitrosamine (DEN) (200 mg/kg body weight) followed by promotion with phenobarbital (PB). The levels of modified DNA bases 8-hydroxy-2'-deoxyguanosine (8-OHdG), a potential marker involved in the initiation of carcinogenesis, were measured by high-performance liquid chromatography, whereas tissue trace element status and expression of metallothionein (MT), a Cu-Zn metalloprotein associated with neoplastic cell growth and subsequent development of premalignant phenotype of the cell, were studied by energy-dispersive X-ray fluorescence spectrometry and enzyme-coupled immunohistochemistry, respectively. There was a significant and steady elevation of modified bases (8-OHdG) along with substantial increase in MT immunoexpression and disturbance in trace element homeostasis following DEN exposure. Supplementation of vanadium at a dose of 0.5 ppm for four consecutive weeks strictly abated the formation of 8-OHdG (P < 0.0001; 81.28%) in preneoplastic rat liver. In a long-term DEN plus PB regimen, vanadium was able to limit in situ MT expression with a concomitant decrease in MT immunoreactivity (P < 0.05). Furthermore, vanadium treatment throughout the study restored hepatic levels of essential trace elements and decreased nodular incidence (58.34%) and nodule multiplicity (P < 0.001; 66.89%) in rats treated with DEN plus PB. Taken together, the study provides evidence in support of the chemopreventive potential of vanadium in limiting neoplastic transformation during the preneoplastic stages of hepatocarcinogenesis in rats.

Multiple myeloma: monoclonal antibodies-based immunotherapeutic strategies and targeted radiotherapy.

Multiple myeloma (MM) is an incurable B-cell malignancy of terminally differentiated plasma cells. Besides conventional treatments, several targeted therapies are emerging for MM. We review recent developments in monoclonal antibodies (MoAbs) and (radio)immunoconjugates-based targeted immunotherapeutic (serotherapies) strategies, as well as skeletal targeted radiotherapy (STR) in MM. MoAbs-based strategies include the targeting of cytokines and their receptors as well as toxins, drugs or radionuclide delivery to MM cells. Both targeted radioimmunotherapy (RIT) and STR have proved efficient in the treatment of radiosensitive tumours. We conclude that there is a need for more mechanistic investigations of drug action to identify novel therapeutic targets in myeloma cells, as well as in the bone marrow microenvironment.

Vanadium inhibits the development of 2-acetylaminofluorene-induced premalignant phenotype in a two-stage chemical rat hepatocarcinogenesis model.

In recent years, research on the biological influence of micronutrients in cancer has grown enormously. Among these, vanadium, a dietary micronutrient present in mammalian tissues has received considerable attention as a limiting agent. In the present study, attempts have been made to investigate the in vivo antitumour potentials of this micronutrient at the 0.5 ppm dosage in drinking water in a defined model of a two-stage experimental rat hepatocarcinogenesis. The chemopreventive effect of vanadium was assessed by studying certain biomarkers, such as development of gamma-glutamyltranspeptidase (GGT)-positive foci, levels of some essential trace elements, in situ expression of proliferating cell nuclear antigen (PCNA) and chromosomal aberrations. Hepatocarcinogenesis was induced in male Sprague-Dawley rats by chronic feeding of 2-acetylaminofluorene (0.05% in basal diet) on and from week 4. Vanadium administration throughout the experiment reduced the relative liver weight, nodular incidence (66.70%), total number and multiplicity (79.93%) and restored hepatic levels of selenium (Se) and iron (Fe) (P < 0.001) when compared to the carcinogen control. Moreover, long-term vanadium treatment significantly abated the expressions of GGT (P < 0.001) and PCNA with concomitant reduction in PCNA immunolabeling index (P < 0.001; 36.62%). Finally, the anticlastogenic potential of vanadium was reflected through its ability to inhibit early chromosomal aberrations (P < 0.001; 45.17%) in 2-AAF-challenged rat hepatocytes. Our results suggest that supplementary vanadium at a dose of 0.5 ppm, when administered continuously throughout the study, than administered either in the initiation or promotion phase alone, is very much effective in suppressing neoplastic transformation in vivo. We conclude the significant role of vanadium in limiting cell proliferation and chromosomal aberrations during the preneoplastic stages of hepatocarcinogenesis in rats.

Vanadium induces apoptosis and modulates the expressions of metallothionein, Ki-67 nuclear antigen, and p53 during 2-acetylaminofluorene-induced rat liver preneoplasia.

Our previous studies have shown that vanadium, a dietary micronutrient, has an inhibitory effect against experimentally induced rat hepatocarcinogenesis. In this study, we evaluated the role of vanadium on some potential protein expression markers of carcinogenesis, such as metallothionein (MT), an intracellular metal-binding protein linked with cell proliferation and apoptosis, Ki-67 nuclear antigen, and p53 tumor suppressor during 2-acetylaminofluorene (2-AAF)-induced (0.05% in basal diet) rat liver preneoplasia. In a short-term regimen, supplementation of vanadium at a dose of 0.5 ppm effectively suppressed the formation of DNA 'comets' (29.55%; P < 0.02), thereby indicating its nongenotoxicity at this particular dose. Vanadium administration throughout the study reduced relative liver weight (RLW), nodular incidence (57.15%), total number, and multiplicity (48.45%) with restoration of hepatic zinc (Zn), magnesium (Mg), selenium (Se), copper (Cu), iron (Fe), and calcium (Ca) contents when compared to the carcinogen control. Moreover, treatment with vanadium significantly abated the expressions of MT and Ki-67, studied at four sequential time points. An increased immunopositivity of p53 protein (1.03 +/- 0.23%; P < 0.02) was found in vanadium-treated rat liver with an elevated apoptotic-labeling index (AI; P < 0.001) as documented by TUNEL assay. Furthermore, a positive correlation between MT expression and Ki-67 labeling along with a strong negative correlation between MT immunoreactivity and AI (r = -0.9000, P = 0.0004 at week 24) at various time intervals suggest that, vanadium-mediated suppression of MT and Ki-67 expressions may be associated with induction of apoptosis. The results thus provide evidence for the first time in support of the potential role of vanadium on induction of p53 and apoptosis with concurrent suppression of MT and Ki-67 in order to have an understanding, in part, of the chemopreventive mechanism of this trace element in limiting neoplastic transformation in a defined model of experimental rat hepatocarcinogenesis.

Vanadium suppresses sister-chromatid exchange and DNA-protein crosslink formation and restores antioxidant status and hepatocellular architecture during 2-acetylaminofluorene-induced experimental rat hepatocarcinogenesis.

Vanadium is an important regulator of cellular growth, differentiation, and cell death, and thus has received increasing attention to be an effective cancer chemopreventive agent. In the present study, attempts have been made to investigate the in vivo antineoplastic effect of this micronutrient at the 0.5 ppm dosage in drinking water, by monitoring hepatic nodulogenesis and hepatocellular phenotype followed by antioxidant status and atomic absorption spectrometric estimation of some essential biometals during the multistage of carcinogenesis induced by 2-acetylaminofluorene (2-AAF; 0.05% in basal diet). Finally, sister-chromatid exchange (SCE) and DNA-protein crosslink (DPC) formation, as potential biomarkers were estimated to find out the suppressive effect of vanadium at the molecular level. The results showed that vanadium administration throughout the experiment reduced the relative liver weight, nodular incidence (48.40%), total number, and multiplicity (63.91%), and altered the size of visible persistent nodules (PNs) with concurrent restoration of hepatic glutathione (P < 0.01), glutathione-S-transferase (P < 0.001) and manganese-dependent superoxide dismutase (P < 0.001) activities as well as, hepatic zinc and copper contents (P < 0.001) when compared to the carcinogen control. Moreover, vanadium treatment significantly reduced SCE frequency (50.24%) and DPC coefficient (P < 0.001; 21.30%). Our results, thus, strongly suggest that supplementary vanadium at a dose of 0.5 ppm, when administered continuously throughout the study, than administered either in the initiation or promotion phase alone, is very much effective in suppressing neoplastic transformation during 2-AAF-induced in vivo rat hepatocarcinogenesis.