J. Akhter

In vitro and in vivo suppression of growth of hepatocellular carcinoma cells by albendazole

Tubulin protein is a major target of drug molecules, and consequently, tubulin inhibitors have attracted great attention as antimitotic antitumor agents for chemotherapeutic use. It has been shown that, the benzimidazole carbamate group of antiparasitics including albendazole act by inhibiting tubulin polymerization. In this study, albendazole was tested in culture against a range of human, rat and mice hepatocellular carcinoma (HCC) cells and in vivo against human SKHEP-1 tumor growth in nude mice. Albendazole induced a dose-dependent inhibition of [(3)H]thymidine incorporation in all cell lines examined and a dramatic decline in cell numbers in SKHEP-1 cells. The inhibitory effect of albendazole was evident at the 100 nM concentration and at 1000 nM, proliferation in all cell lines examined was inhibited by more than 80%, while, proliferation of HepG2, Hep3B and SKHEP-1 were suppressed by more than 90%, compared to control. Cell cycle analysis revealed that, depending on the dose employed, albendazole can arrest SKHEP-1 cells at both G0-G1 (250 nM) and G2-M (1000 nM) phases of the cycle. Albendazole treatment (300 mg/kg per day oral for 20 days) of nude mice inoculated subcutaneously with SKHEP-1, led to profound suppression of tumor growth. Immunohistochemical analysis of these tumors revealed that compared to control, those treated with albendazole have lower growth fractions. These findings demonstrate that albendazole strongly suppresses both in vitro and in vivo proliferation of HCC cells.

In vitro and in vivo inhibition of liver cancer cells by 1,25-dihydroxyvitamin D3.

Inhibitory effects of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) on the proliferation of a variety of cancer cell lines have been extensively reported. We have studied the effect of 1,25-(OH)2D3 (10(-11)-10(-6) M) on the proliferation of a number of human and rat liver cancer cell lines. Additionally, the effect of 1,25-(OH)2D3 (0.02-0.5 microg/kg per day) on the rate of growth of liver cancer cell line xenografts in nude mice was also investigated. In vitro, proliferation of Hep-3B, PLC/PRF/5, and SKHEP-1 cells was significantly inhibited by 1,25-(OH)2D3, while HTC and Novikoff cells were more resistant to the inhibitory effects of the drug. In vivo, treatment of SKHEP-1 tumor bearing nude mice with different doses of 1,25-(OH)2D3 significantly retarded tumor growth without the development of hypercalcemia.

Heat sink effect on tumor ablation characteristics as observed in monopolar radiofrequency, bipolar radiofrequency, and microwave, using ex vivo calf liver model.

AbstractThermal ablation of liver tumors near large blood vessels is affected by the cooling effect of blood flow, leading to incomplete ablation. Hence, we conducted a comparative investigation of heat sink effect in monopolar (MP) and bipolar (BP) radiofrequency ablation (RFA), and microwave (MW) ablation devices.With a perfused calf liver, the ablative performances (volume, mass, density, dimensions), with and without heat sink, were measured. Heat sink was present when the ablative tip of the probes were 8.0 mm close to a major hepatic vein and absent when >30 mm away. Temperatures (T1 and T2) on either side of the hepatic vein near the tip of the probes, heating probe temperature (T3), outlet perfusate temperature (T4), and ablation time were monitored.With or without heat sink, BP radiofrequency ablated a larger volume and mass, compared with MP RFA or MW ablation, with latter device producing the highest density of tissue ablated. MW ablation produced an ellipsoidal shape while radiofrequency devices produced spheres.Percentage heat sink effect in Bipolar radiofrequency : Mono-polar radiofrequency : Microwave was (Volume) 33:41:22; (mass) 23:56:34; (density) 9.0:26:18; and (relative elipscity) 5.8:12.9:1.3, indicating that BP and MW devices were less affected.Percentage heat sink effect on time (minutes) to reach maximum temperature (W) = 13.28:9.2:29.8; time at maximum temperature (X) is 87:66:16.66; temperature difference (Y) between the thermal probes (T3) and the temperature (T1 + T2)/2 on either side of the hepatic vessel was 100:87:20; and temperature difference between the (T1 + T2)/2 and temperature of outlet circulating solution (T4), Z was 20.33:30.23:37.5.MW and BP radiofrequencies were less affected by heat sink while MP RFA was the most affected. With a single ablation, BP radiofrequency ablated a larger volume and mass regardless of heat sink.

1α,25-Dihydroxyvitamin D3 and its analogues, EB1089 and CB1093, profoundly inhibit the in vitro proliferation of the human hepatoblastoma cell line HepG2

Background: 1α,25‐dihydroxyvitamin D3 (1,25[OH]2D3) has been shown to inhibit the proliferation of various cancer cells including colon, prostate, melanoma, osteosarcoma and breast cancer.

Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells.

Malignant peritoneal mesothelioma (MPM) is a rare neoplasm of the peritoneum, causally related to asbestos exposure. Nonspecific symptoms with a late diagnosis results in poor survival (<1 year). Treatment with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has improved survival in some patients (median 3–5 years). Hence, new therapies are urgently needed. MUC1 is a glycosylation-dependent protein that confers tumours with invasiveness, metastasis and chemoresistance. Bromelain (cysteine proteinase) hydrolyses glycosidic bonds. Therefore, we investigated the antitumour effect of bromelain on MUC1-expressing MPM cell lines. MUC1 expressions in cells were assessed using immunofluorescent probes with cells grown on cover slips and western blot analysis on cell lysates. The cell lines were treated with various concentrations of bromelain and after 4 and 72 h, their viability was assessed using standard sulforhodamine assays. The cells were also treated with combinations of bromelain and cytotoxic drugs (cisplatin or 5-FU) and their viability was assessed at 72 h. Finally, with western blotting, the effects of bromelain on cellular survival proteins were investigated. PET cells expressed more MUC1 compared with YOU cells. The cell viability of both PET and YOU cells was adversely affected by bromelain, with PET cells being slightly resistant. The addition of bromelain increased the cytotoxicity of cisplatin significantly in both cell lines. However, 5-FU with bromelain did not show any significant increase in cytotoxicity. Bromelain-induced cell death is by apoptosis and autophagy. Bromelain has the potential of being developed as a therapeutic agent in MPM.

Anti-Tumour and Chemosensitising Effect of a Combination of Bromelain + N-Acetyl Cysteine with Cisplatin or 5-Fu on Malignant Peritoneal Mesothelioma Cells

normally poor however, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy has increased survival in some patients. Hence, new therapies are needed. MUC1 is a glycosylation dependant protein associated with tumour invasiveness, metastasis and chemo resistance. Bromelain, a cysteine proteinase, hydrolyses glycosidic bonds, whilst N-Acetyl cysteine reduces disulphide bonds in glycoprotein. Hence, we investigated the anti-tumour effect of these agents in MUC 1 expressing MPM cell lines. Materials and Methods: The cell lines were treated to various concentrations of bromelain, NAC and combinations of NAC + bromelain, NAC + bromelain + cisplatin or 5-FU. Their cell viabilities were assessed at 48 hours with sulfhordamine B assay. Finally, with western blotting, the effect of NAC and the combination of NAC + bromelain on cellular survival proteins were investigated. Results: Combination of NAC (10 mM) with bromelain (75 ug/ml) showed 97% and 88% cell proliferation inhibition in YOU and PET cells, respectively. In triple combination, the addition of cisplatin to only 5.0 mM NAC and bromelain increased cytotoxicity in YOU cells but absent at 10.0 mM NAC concentration. However, in PET cells, triple combinations with cisplatin had no effect. The addition of 5-FU in triple combinations showed an increase in cytotoxicity with 5.0 mM NAC and bromelain in YOU cells. No increase in cytotoxicity was seen with addition of 10 mM NAC. In PET cells, the addition 5-FU to 5.0 mM NAC + 50 ug/ml bromelain, enhanced cytotoxicity significantly but was absent at all other combinations. Conclusion: The combination of bromelain and NAC may be developed as anti-tumour agents for treating MPM, with a possible role in combined therapy with current chemotherapeutic agents.