A mathematical approach to study combined effects of toxicants in vitro: Evaluation of the Bliss independence criterion and the Loewe additivity model

Goldoni, Matteo; Johansson, Carolina

doi:10.1016/j.tiv.2007.03.003

Cited by 175 publications

(195 citation statements)

References 22 publications

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“…If the experimentally measured fractional inhibition of combined treatment is more than the expected Ebliss value, then the combination is considered to be synergistic, while if the experimentally combined effect is less than the expected Ebliss value, then the interaction is antagonistic. Otherwise, the combined effect is additive (12,13).…”

Section: Methodsmentioning

confidence: 99%

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds

et al. 2013

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Abstract. The epidermal growth factor receptor (EGFR) signaling pathway is widely activated in non-small cell lung cancer (NSCLC). However, only a subset of patients with NSCLC is sensitive to EGFR tyrosine kinase inhibitors (TKIs), particularly those with activating EGFR mutations. The mammalian target of rapamycin (mTOR) is another key intracellular kinase that plays an important role in the onset and progression of many types of human cancers and has been proven to be linked with primary resistance to EGFR inhibitors. We performed this study to investigate the combined inhibitory effect of the mTOR inhibitor RAD001 and the EGFR-TKI gefitinib in three EGFR wild-type NSCLC cell lines: A549 (PIK3CA wild-type), NCI-H460 (PIK3CA mutant) and NCI-H661 (PIK3CA wild-type). All cell lines demonstrate a poor response to gefitinib, but have a different genetic status for PIK3CA. We used MTT assays to measure cell proliferation. Flow cytometry was used to assess the effects on apoptosis and cell cycle arrest. Immunoblot analysis was used to evaluate the expression of downstream proteins. Treatment of RAD001 alone showed dose-dependent growth inhibition in all three cell lines. The combination of gefitinib and RAD001 resulted in synergistic growth inhibition in NCI-H460 cells, but only an additive inhibitory effect on A549 and NCI-H661 cells. Exposure to the combination of RAD001 and gefitinib led to a significant reduction in phosphorylated AKT levels in NCI-H460 cells; however, this was not noted in the other two cell lines. In conclusion, our data indicate that the dual inhibition of the EGFR/mTOR pathways may be a promising approach to treat EGFR wild-type NSCLC; however, this may be dependent on the PIK3CA mutation status.

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Section: Methodsmentioning

confidence: 99%

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds

et al. 2013

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“…To test the differences between experimental and theoretical points, we applied the method suggested by Goldoni and Johansson [26]. Briefly, the theoretical value was calculated by the experimental points of single dose-response curves [E(x) and E(y), respectively], and its SD was estimated by error propagation of experimental SD calculated separately on E(x) and E(y).…”

Section: E(xy) = E(x) + E(y) -E(x)*e(y)mentioning

confidence: 99%

“…Briefly, the theoretical value was calculated by the experimental points of single dose-response curves [E(x) and E(y), respectively], and its SD was estimated by error propagation of experimental SD calculated separately on E(x) and E(y). Finally, the significance of the differences between theoretical and experimental values was assessed by Student t tests [26]. For all non-linear fits, Origin 6.0 (Originlab, Northampton, USA) was used.…”

Section: E(xy) = E(x) + E(y) -E(x)*e(y)mentioning

confidence: 99%

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Monica

Galetti

Alfieri

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTThe epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib-resistance and able to maintain pS6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.

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“…For caspase-3/7 assays, a paired t-test was used to compare the effect of the drug combination to the effect of single agent pitavastatin. For trypan blue assays, a paired t-test was used to compare the observed effect of the drug combination to the expected additive effect calculated using the Bliss independence criterion (17).…”

Section: Methodsmentioning

confidence: 99%

ABT‑737 and pictilisib synergistically enhance pitavastatin‑induced apoptosis in ovarian cancer cells

Wolf¹,

Wolf²,

Richardson³

2017

Oncol Lett

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Abstract. There is considerable interest in redeploying drugs for use in combination with other oncology therapeutics. The single-agent activity of statins in ovarian cancer has been widely reported, however the drug concentration required to cause cell death is considerably higher than that achieved in patients receiving statin treatment for hypercholesterolemia. Unfortunately, statins can cause myopathy when administered in high doses. One solution to this is to identify drugs that could be used in combination with statins to reduce the dose required and those that may potentially reduce the incidence of adverse side effects. When the BH3 mimetic ABT-737, or the phosphatidylinositol 3-kinase inhibitor pictilisib, were combined with pitavastatin in cell growth assays using Ovcar-3 and Igrov-1 cells, the drug combinations were more effective than pitavastatin alone. In support of this, ABT-737 or pictilisib markedly increased cell death induced by pitavastatin in several ovarian cancer cell lines. The drugs were also synergistic in apoptosis assays. These observations suggested that either BH3 mimetics or pictilisib in combination with pitavastatin could be used in a subset of ovarian tumours, particularly those sensitive to BH3 mimetics, and phosphatase and tensin homolog inhibition, in the treatment of ovarian cancer.

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A mathematical approach to study combined effects of toxicants in vitro: Evaluation of the Bliss independence criterion and the Loewe additivity model

Cited by 175 publications

References 22 publications

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds

Combined inhibition of the EGFR and mTOR pathways in EGFR wild-type non-small cell lung cancer cell lines with different genetic backgrounds

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

ABT‑737 and pictilisib synergistically enhance pitavastatin‑induced apoptosis in ovarian cancer cells

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