Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immunosuppressant rapamycin inhibited proliferation of the H4IIEC hepatoma cell line. Rapamycin, but not its structural analog FK506, also inhibited the basal and insulin-stimulated activity of the p70 ribosomal protein S6 kinase. By contrast, insulin stimulation of the p85 Rsk S6 kinase and mitogen-activated protein (MAP) kinase activity were unaffected by drug. Rapamycin treatment of COS cells transfected with recombinant p70 S6 kinase completely inhibited the appearance of the hyperphosphorylated form of p70 S6 kinase concomitant with the inhibition of enzyme activity toward 40S subunits. Thus, rapamycin inhibits a signal transduction element that is necessary for the activation of p70 S6 kinase and mitogenesis but unnecessary for activation of p85 Rsk S6 kinase or MAP kinase.
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PMID:Rapamycin-induced inhibition of the 70-kilodalton S6 protein kinase. 138 Jan 82

A contribution of intracellular dehydration to insulin resistance has been established in human subjects and in different experimental systems. Here the effect of hyperosmolarity (405 mosmol/l) on insulin-induced mitogen-activated protein (MAP) kinase phosphatase (MKP)-1 expression was studied in H4IIE rat hepatoma cells. Insulin induces robust MKP-1 expression which correlates with a vanadate-sensitive decay of extracellular-signal-regulated kinase (Erk-1/Erk-2) activity. Hyperosmolarity delays MKP-1 accumulation by insulin and this corresponds to impaired MKP-1 synthesis, whereas MKP-1 degradation remains unaffected by hyperosmolarity. Rapamycin, which inhibits signalling downstream from the mammalian target of rapamycin (mTOR) and a peptide inhibiting protein kinase C (PKC) zeta/lambda abolish insulin-induced MKP-1 protein but not mRNA expression, suggesting the involvement of the p70 ribosomal S6 protein kinase (p70S6-kinase) and/or the eukaryotic initiation factor 4E-binding proteins (4E-BPs) as well as atypical PKCs in MKP-1 translation. Hyperosmolarity induces sustained suppression of p70S6-kinase and 4E-BP1 hyperphosphorylation by insulin, whereas insulin-induced tyrosine phosphorylation of the insulin receptor (IR) beta subunit and the IR substrates IRS1 and IRS2, recruitment of the phosphoinositide 3-kinase (PI 3-kinase) regulatory subunit p85 to the receptor substrates as well as PI 3-kinase activation, and Ser-473 phosphorylation of protein kinase B and Thr-410/403 phosphorylation of PKC zeta/lambda are largely unaffected under hyperosmotic conditions. The hyperosmotic impairment of both, MKP-1 expression and p70S6-kinase hyperphosphorylation by insulin is insensitive to K(2)CrO(4), calyculin A and vanadate, and inhibition of the Erk-1/Erk-2 and p38 pathways. The suppression of MKP-1 may further contribute to insulin resistance under dehydrating conditions by allowing unbalanced MAP kinase activation.
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PMID:Osmotic regulation of insulin-induced mitogen-activated protein kinase phosphatase (MKP-1) expression in H4IIE rat hepatoma cells. 1252 77

Expression of constitutively active Akt3 was found to increase the size of MCF-7 cells approximately twofold both in vitro and in vivo. A regulatable version of Akt1 (MER-Akt) was also found capable of inducing a twofold increase in the size of H4IIE rat hepatoma cells. Rapamycin, a specific inhibitor of mTOR function, was found to inhibit the Akt-induced increase in cell size by 70%, presumably via inhibition of the Akt-induced increase in protein synthesis. To determine whether Akt could be inhibiting protein degradation, thereby contributing to its ability to induce an increase in cell size, we conducted protein degradation experiments in the H4IIE cell line. Activation of MER-Akt was found to inhibit protein degradation to a degree comparable to insulin treatment. The effects of these two agents on protein degradation were not additive, thereby suggesting that they were acting on a similar pathway. An inhibitor of the phosphatidylinositol 3-kinase pathway, LY-294002, blocked both insulin- and Akt-induced inhibition of protein degradation, again consistent with the hypothesis that both agents were acting on the same pathway. In contrast, rapamycin did not block the ability of either agent to inhibit protein degradation. These results indicate that Akt increases cell size through both mTOR-dependent and -independent pathways and that the latter involves inhibition of protein degradation. These studies are also consistent with the hypothesis that insulin's ability to regulate protein degradation is to a large extent mediated via Akt.
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PMID:Akt promotes increased mammalian cell size by stimulating protein synthesis and inhibiting protein degradation. 1287 75

Sirolimus, and its antiproliferative capacity, was studied in vivo in three different syngenic rat tumours in the liver. Sirolimus is an inhibitor of the cytosolic mTOR-kinase, associated with the phosphoinositide-3-kinase/Akt pathway. After one week of daily sirolimus treatment, initiated on the day of tumour-cell inoculation, a dose-response relationship was shown at doses between 0.01 mg/kg/day and 1 mg/kg/day, decreasing tumour weight from 0.5+/-0.1 g in control rats (n=9) to 0.09+/-0.04 g for sirolimus 1 mg/kg (n=9). Treating established liver adenocarcinoma (n=15), sirolimus halved the tumour weight (1.4+/-0.2 g vs 0.7+/-0.1 g, p=0.005). Trough concentration in blood was 6.4+/-0.2 ng/ml after five days of daily treatment with 1 mg/kg sirolimus intraperitoneally. At this dose, there was no decrease in food consumption or rat weight, but decrease in weight of spleen, and increase in weight of liver (p<0.01). The three tumours studied, an nitrosoguanidin-induced adenocarcinoma, a Leydig cell sarcoma and a hepatoma, all responded, establishing sirolimus as a promising anticancer drug.
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PMID:Inhibition of mTOR suppresses experimental liver tumours. 1586 10

Small uncontrolled series have suggested that sirolimus favorably impacts renal function after orthotopic liver transplantation (OLT). We sought to retrospectively compare renal dysfunction between cohorts exposed to sirolimus-based and calcineurin inhibitor-based immunosuppression. We retrospectively studied 79 patients converted to sirolimus-based immunosuppression and 100 control subjects continued on calcineurin inhibitor-based immunosuppression after OLT at our institution from 2000 to 2005. We collected clinical, demographic, and medication history. Renal dysfunction was defined as two or more wk of creatinine > or =2.0 mg/dL. Cohorts were compared using Kaplan-Meier survival analysis and Cox proportional hazards modeling. Patients began sirolimus a median 83 d post-OLT and were followed on the medication for median 359 d. Patients in both the sirolimus and calcineurin inhibitor cohorts had median creatinine 1.2 mg/dL at study entry. Sirolimus-based immunosuppression was associated with a 1.8 (0.8-4.3, p = 0.17) hazards ratio for renal dysfunction. Adjusting for presence of hepatocellular carcinoma, combined kidney/liver transplantation, and age, the hazards ratio was 2.0 (0.8-4.8, p = 0.13). These point estimates were not substantially altered after subgroup analysis of sirolimus as the lone immunosuppressant, duration of exposure, and time between OLT and sirolimus conversion. In conclusion, our retrospective, controlled study showed that conversion to sirolimus after OLT did not protect against renal dysfunction. The effect of sirolimus on renal function will need to be prospectively evaluated in a prospective, randomized trial.
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PMID:Effects of sirolimus vs. calcineurin inhibitors on renal dysfunction after orthotopic liver transplantation. 1748 88

Sirolimus (SRL) is a macrolide antibiotic that has potent antifungal and immunosuppressive properties; preclinical studies suggest that SRL may possess a significant antiproliferative influence in vitro. Recently, several studies have documented a negative effect by SRL on both primary tumor growth and the proliferation of metastatic foci in various rodent models of hepatocellular carcinoma (HCC). Orthotopic liver transplantation (OLT) is increasingly becoming a viable treatment option for patients with end stage liver disease and concomitant HCC. As such, an immunosuppressive agent with antineoplastic activity is inherently attractive in the setting of OLT for malignancy. Regrettably, the cumulative experience with SRL-based immunosuppression in this patient population is limited. Herein, the authors review the experience to date with SRL as a primary immunosuppressive agent following OLT, and discuss the clinical implications of SRL-based therapy in OLT recipients with cirrhosis and cancer.
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PMID:Sirolimus and liver transplantation: clinical implications for hepatocellular carcinoma. 1756 62

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide with an annual occurrence of one million new cases. At present there is no effective treatment for HCC individuals that not amenable to curative therapies. Recent studies show the PI3K/Akt/mTOR signal pathway is involved in multiple cellular functions including proliferation, differentiation, tumorigenesis, and apoptosis. Rapamycin (a specific Mtor inhibitor) could lead to G(1) arrest of many malignant cell lines, and currently analogs of rapamycin are being investigated as a cancer chemotherapeutic adjuvant. This study investigated rapamycin and chemotherapeutic agent 5-fluorouracil (5-Fu) in combination treatment induced apoptosis and cell senescence in hepatocarcinoma cell line SMMC-7721 cells. Treating SMMC-7721 cells with rapamycin plus 5-Fu led to not only apoptosis but also cell senescence, and the senescent cells exhibited significantly less clonogenic potential than 5-Fu individually treated cells. Further study showed rapamycin plus 5-Fu-induced senescence-like growth arrest was accompanied by down-regulation of AP-1 and NF kappa B transcription activity. These results suggest that inhibitors of mTOR may have anticancer potential when used together with some other chemotherapeutic agents, and that down-regulation of AP-1 and NF kappa B transcription activity might take part in a senescence-like growth arrest program induced by rapamycin plus 5-Fu.
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PMID:Synergistic effect of mTOR inhibitor rapamycin and fluorouracil in inducing apoptosis and cell senescence in hepatocarcinoma cells. 1834 84

Sirolimus (SRL) is an mTOR inhibitor that has been shown, in contrast to calcineurin inhibitors (CNI), to inhibit cancers in experimental models. Since February 2005, we introduced SRL in liver transplant patients in group a, in whom the primary disease was hepatocellular carcinoma (HCC) associated with hepatitis B virus (HBV), hepatitis C virus (HCV), alcoholic or autoimmune liver cirrhosis, and group b, HCC-negative patients who developed posttransplantation cancers de novo. Of 18 patients in group a, 11 received SRL ab initio (subgroup a1), starting for 10 patients at 66.1+/-29.2 days after surgical healing and after 10 days in 1 case; the remaining 7 patients (subgroup a2) received SRL at 31.2+/-24.2 months. Three patients in group b, included 1 with Kaposi's sarcoma, 1 with bladder cancer, and 1 with thyroid cancer. In this group, SRL was introduced at 80.8+/-40.4 months. In all patients but one, who received a single 5 mg loading dose, SRL was started at 2 mg/d and adjusted to 6 to 8 ng/mL blood levels. CNI drugs, present as primary therapy, were gradually tapered to low levels and eventually stopped. The following observations were drawn from this initial experience: (1) 4/21 (19.0%) patients had to discontinue SRL because of early and late side effects: thrombocytopenia (n=2) and headache with leukopenia and leg edema associated with knee joint arthralgia (n=2); (2) 14 patients (11 in group a and 3 in group b) are still on SRL monotherapy; (3) 1 HCC recurrence and 1 de novo pancreatic adenocarcinoma were observed at 14 and 16 months, respectively (at the time of transplantation, both patients were beyond the MIlan HCC criteria), and (4) 1 patient, from subgroup a1, died after 99 days due to pneumonitis and possible relation to SRL lung toxicity. In conclusion, SRL appeared to be an effective immunosuppressant that could be used as monotherapy in liver transplant patients. Any conclusion on SRL anticancer effects can only come from randomized large studies after long follow-up.
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PMID:Sirolimus therapy in liver transplant patients: an initial experience at a single center. 1867 98

Living-donor liver transplantation (LDLT) is an effective treatment for patients with unresectable hepatocellular carcinoma (HCC). However, it remains controversial whether expanded listing criteria can be used for LDLT. We aimed to review results of LDLT for patients with HCC at our center. Patients with HCC were accepted for LDLT if there was no extrahepatic spread on computed tomography (CT) and positron emission tomography CT scan. Transarterial chemoembolization was performed before LDLT to control the tumors. Sirolimus or everolimus was used as part of the immunosuppressive protocol for all patients. Over the last 6 years, 35 of the 102 (34%) LDLT were performed at our center for HCC. Age (mean +/- SEM) was 55.3 +/- 1.3 years; 28 patients (80%) were men. Eight (23%) had LDLT performed in 2002 or 2003 (period 1), and 27 (77%) in 2004 to 2007 (period 2). Eleven (31%) were within and 23 (69%) were outside the Milan criteria. After 583 +/- 76 days follow-up, nine (25%) died, three of recurrent HCC. Three-year survival was significantly better in period 2 than in period 1 (90% vs 13%; P < .001). Although the 3-year survival for those within Milan criteria was better than those outside Milan criteria, the difference did not reach statistical significance (86% vs 57%; P = .26). Six (17%) had HCC recurrence, of whom five died. We concluded that reasonable medium-term survival can be obtained for patients with HCC. The experience level of the transplant team seemed to be the most important predictor of patient outcome.
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PMID:Experience of the transplant team is an important factor for posttransplant survival in patients with hepatocellular carcinoma undergoing living-donor liver transplantation. 1892 81

Rapamycin (RAPA) inhibits tumor growth and angiogenesis in hepatocellular carcinoma (HCC). The molecular mechanism underlying the antitumoral effects of RAPA remains unclear. Here we established a chemical-induced rat HCC model to investigate the signaling pathways mediating RAPA's antitumor activity. We found that RAPA exposure significantly diminished tumor growth, angiogenesis, and metastasis of HCC. Meanwhile, the antitumor drug dramatically decreased expression of HIF-1alpha and VEGF, either at mRNA or protein levels. Moreover, the low-dose of RAPA (1.5 mg/kg/day) was effective enough to markedly inhibit tumor progression of HCC. The preliminary results suggested that the antitumoral effects of RAPA might be at least partially mediated through downregulation of HIF-1alpha and VEGF, and low-dose RAPA-based regimens exhibited a promising future in treatment of HCC.
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PMID:Antitumoral activity of rapamycin mediated through inhibition of HIF-1alpha and VEGF in hepatocellular carcinoma. 1905 64


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