In vitro evidence for a new therapeutic approach in renal cell carcinoma

Pittoggi, Carmine; Martis, Gianni; Mastrangeli, Giorgia; Mastrangeli, Bruno; Spadafora, Corrado

doi:10.1590/s1677-55382008000400012

Cited by 13 publications

(15 citation statements)

References 16 publications

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“…RPV and EFV are toxic against pancreatic cancer cells at lowest concentrations. We found EC50s of EFV (31.5μmol/l and 49.0μmol/l) which are comparable to published concentrations that show anti-cancer cell activity in vitro (range 10–60μmol/l) [3–5, 7, 11–13]. In BxPC-3 cells the lower toxic NNRTI concentrations induced apoptosis and the higher concentrations necrosis, whereas in the Panc-1 cells no increase of apoptosis was found.…”

Section: Discussionsupporting

confidence: 81%

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Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

et al. 2015

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BackgroundCancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo.MethodsCytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data.ResultsThe in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5μmol/l (= 9944ng/ml), Nevirapine 239μmol/l (= 63786ng/ml), Etravirine 89.0μmol/l (= 38740ng/ml), Lersivirine 543μmol/l (= 168523ng/ml), Delavirdine 171μmol/l (= 78072ng/ml), Rilpivirine 24.4μmol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162–15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856–8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients.ConclusionAll studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer.

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Section: Discussionsupporting

confidence: 81%

“…Published data report a toxic effect of EFV and NVP against cancer cells, whereas EFV is toxic at lower concentrations than NVP [4, 5, 7]. As a new generation of NNRTI has been developed, the question raised whether these drugs are also toxic against cancer.…”

Section: Resultsmentioning

confidence: 99%

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

et al. 2015

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“…Nevirapine did not cause non-specific necrotic cell death or apoptosis in any of the tested cells, and the decrease in cell growth was correlated with accumulation of cells in the G1/G0 phase of the cell cycle, with a concomitant decrease in the S phase (Mangiacasale et al, 2003;Landriscina et al, 2005;Sciamanna et al, 2005). Although it has been suggested that an inhibition of endogenous non-telomeric RT by nevirapine is responsible for the interference with cell cycle progression Mangiacasale et al, 2003;Landriscina et al, 2005;Sciamanna et al, 2005;Landriscina et al, 2008;Pittoggi et al, 2008), the mechanisms underlying the anti-proliferative effects of nevirapine are poorly understood. Furthermore, while the effects of nevirapine on cell cycle progression have been studied in a number of cell types, the effect of nevirapine upon human hepatocytes, a target for nevirapine-induced toxicities has not been examined.…”

Section: Introductionmentioning

confidence: 90%

“…Several studies have shown that exposure to nevirap-of cell growth in a variety of mouse and human cell lines (Mangiacasale et al, 2003;Landriscina et al, 2005;Sciamanna et al, 2005;Landriscina et al, 2008;Pittoggi et al, 2008). Nevirapine did not cause non-specific necrotic cell death or apoptosis in any of the tested cells, and the decrease in cell growth was correlated with accumulation of cells in the G1/G0 phase of the cell cycle, with a concomitant decrease in the S phase (Mangiacasale et al, 2003;Landriscina et al, 2005;Sciamanna et al, 2005).…”

Section: Introductionmentioning

confidence: 90%

Differential responses of human hepatocytes to the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine

Fang

Beland

2013

J. Toxicol. Sci.

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-Nevirapine is a non-nucleoside reverse transcriptase (RT) inhibitor used for the treatment of AIDS and the prevention of mother-to-child transmission of HIV-1. Despite its therapeutic ben--ity. The present study examined the effects of nevirapine on cell growth and death in human hepatocyte HepG2 cells and THLE2 cells and the possible pathways involved in these effects. The concentrations of nevirapine inhibiting 50% cell growth were similar for both cell lines. Nevirapine (0-250 μM) treatment caused a slight increase in the amount of lactate dehydrogenase released into the medium. Apoptotic cell death did not contribute to the decrease in viable cells. Exposing of HepG2 cells to nevirapine caused cells, the percentage of cells in G1/G0 phase was increased and cellular senescence was induced in a concentration-dependent manner. Endogenous non-telomeric RT activity was not detected in either cell line. Western blot analysis indicated lower levels of p53 and phospho-p53 (ser15) in HepG2 cells as compared -ment. These data demonstrate that nevirapine inhibits cell growth, induces cell cycle arrest at different phases, and has different effects on cellular senescence in HepG2 cells and THLE2 cells. The differential responses appear to be related to differences in the basal levels of p53 in the HepG2 cells and THLE2 cells.

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“…RCC tissue specimens were cultured by several different methods as previously described (Besch et al, 1983;Kim et al, 2008;Pittoggi et al, 2008) in DMEM medium (GIBCO, US) containing 1% penicillin, 1% streptomycin, 1% amphotericin B, 0.5% L-Glutamide and 20% fetal cattle serum. A portion of the primary culture and second generation cells were cryopreserved in liquid nitrogen.…”

Section: Primary Rcc Culturementioning

confidence: 99%

Heat-Shock Protein 70 as a Tumor Antigen for in vitro Dendritic Cell Pulsing in Renal Cell Carcinoma Cases

Meng

Sui²,

Tian³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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Immunological functions of heat shock proteins (HSPs) have long been recognized. In this study we aimed to efficiently purify HSP70 from renal cell carcinoma and test it as a tumor antigen for pulsing dendritic cells in vitro. HSP70 was purified from renal cell carcinoma specimens by serial column chromatography on Con A-sepharose, PD-10, ADP-agarose and DEAE-cellulose, and finally subjected to fast protein liquid chromatography (FPLC). Dendritic cells derived from the adherent fraction of peripheral blood mononuclear cells were cultured in the presence of IL-4 and GM-CSF and exposed to tumor HSP70. After 24 hours, dendritic cells were phenotypically characterized by flow cytometry. T cells obtained from the non-adherent fraction of peripheral blood mononuclear cells were then co-cultured with HSP70-pulsed dendritic cells and after 3 days T cell cytotoxicity towards primary cultured renal cell carcinoma cells was examined by Cell Counting Kit-8 assay. Dendritic cells pulsed in vitro with tumor-derived HSP70 expressed higher levels of CD83, CD80, CD86 and HLA-DR maturation markers than those pulsed with tumor cell lysate and comparable to that of dendritic cells pulsed with tumor cell lysate plus TNF-α. Concomitantly, cytotoxic T-lymphocytes induced by HSP70-pulsed dendritic cells presented the highest cytotoxic activity. There were no significant differences when using homologous or autologous HSP70 as the tumor antigen. HSP70 can be efficiently purified by chromatography and induces in vitro dendritic cell maturation in the absence of TNF-α. Conspecific HSP70 may effectively be used as a tumor antigen to pulse dendritic cells in vitro.

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In vitro evidence for a new therapeutic approach in renal cell carcinoma

Cited by 13 publications

References 16 publications

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells

Differential responses of human hepatocytes to the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine

Heat-Shock Protein 70 as a Tumor Antigen for in vitro Dendritic Cell Pulsing in Renal Cell Carcinoma Cases

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