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Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition.

Caffa I, D'Agostino V, Damonte P, Soncini D, Cea M, Monacelli F, Odetti P, Ballestrero A, Provenzani A, Longo VD, Nencioni A - Oncotarget (2015)

Bottom Line: However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies.In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone.In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.

ABSTRACT
Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown. Here we report that starvation conditions increase the ability of commonly administered TKIs, including erlotinib, gefitinib, lapatinib, crizotinib and regorafenib, to block cancer cell growth, to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway and to strengthen E2F-dependent transcription inhibition. In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone. In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use.

No MeSH data available.


Related in: MedlinePlus

Gene expression and cell cycle regulation by starvation, crizotinib and their combination in H3122 cellsA, 6 × 105 H3122 cells were plated in 10 cm Petri dishes in regular medium. 24 h later, the cell medium was removed and cells were incubated for 24h either in regular medium (CTR) or in starvation medium. 24 h later cells were treated or not with 400 nM crizotinib for 24 h. Finally, total RNA was isolated and utilized for E2F1, E2F2 and RAD51 mRNA quantification by QPCR. B, Identification of upstream regulators of the en masse gene expression regulation by combined crizotinib plus starvation vs. crizotinib alone by IPA. C-E H3122 cells were treated as in A and utilized for either protein lysate generation or cell nuclei isolation and propidium iodide staining. C, phospho-RB (Ser807/811) and total RB were detected by immunoblotting. D, E, cell cycle was analyzed on a FACS Calibur by acquiring 10.000 events/sample.
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Figure 4: Gene expression and cell cycle regulation by starvation, crizotinib and their combination in H3122 cellsA, 6 × 105 H3122 cells were plated in 10 cm Petri dishes in regular medium. 24 h later, the cell medium was removed and cells were incubated for 24h either in regular medium (CTR) or in starvation medium. 24 h later cells were treated or not with 400 nM crizotinib for 24 h. Finally, total RNA was isolated and utilized for E2F1, E2F2 and RAD51 mRNA quantification by QPCR. B, Identification of upstream regulators of the en masse gene expression regulation by combined crizotinib plus starvation vs. crizotinib alone by IPA. C-E H3122 cells were treated as in A and utilized for either protein lysate generation or cell nuclei isolation and propidium iodide staining. C, phospho-RB (Ser807/811) and total RB were detected by immunoblotting. D, E, cell cycle was analyzed on a FACS Calibur by acquiring 10.000 events/sample.

Mentions: In order to determine what starvation would add to the TKI in terms of gene expression regulation, we compared the arrays corresponding to crizotinib alone to those corresponding to crizotinib plus starvation. Also in this case, the number of DEGs (264) was found to be very limited, which is in line with the notion that both types of treatment likely act on the same genetic and molecular mechanisms. We reasoned that these 264 DEGs could represent a core of genes that may explain the stronger anti-proliferative effect exerted by combined crizotinib and starvation compared to crizotinib alone. Using functional enrichment we observed that the DEGs of cells treated with crizotinib and starvation clustered in canonical pathways within the area of cell cycle control and DNA damage (Supplementary Table 4). Among these genes, it is worth to notice the presence of important cancer genes such as E2F1, E2F2, and RAD51, which combined starvation and crizotinib down-regulated to a higher extent compared to these treatments alone (Supplementary Table 4). Notably, the effect of crizotinib, starvation and their combination on E2F1, E2F2, and RAD51 could be readily verified by QPCR (Figure 4A).


Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition.

Caffa I, D'Agostino V, Damonte P, Soncini D, Cea M, Monacelli F, Odetti P, Ballestrero A, Provenzani A, Longo VD, Nencioni A - Oncotarget (2015)

Gene expression and cell cycle regulation by starvation, crizotinib and their combination in H3122 cellsA, 6 × 105 H3122 cells were plated in 10 cm Petri dishes in regular medium. 24 h later, the cell medium was removed and cells were incubated for 24h either in regular medium (CTR) or in starvation medium. 24 h later cells were treated or not with 400 nM crizotinib for 24 h. Finally, total RNA was isolated and utilized for E2F1, E2F2 and RAD51 mRNA quantification by QPCR. B, Identification of upstream regulators of the en masse gene expression regulation by combined crizotinib plus starvation vs. crizotinib alone by IPA. C-E H3122 cells were treated as in A and utilized for either protein lysate generation or cell nuclei isolation and propidium iodide staining. C, phospho-RB (Ser807/811) and total RB were detected by immunoblotting. D, E, cell cycle was analyzed on a FACS Calibur by acquiring 10.000 events/sample.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4494907&req=5

Figure 4: Gene expression and cell cycle regulation by starvation, crizotinib and their combination in H3122 cellsA, 6 × 105 H3122 cells were plated in 10 cm Petri dishes in regular medium. 24 h later, the cell medium was removed and cells were incubated for 24h either in regular medium (CTR) or in starvation medium. 24 h later cells were treated or not with 400 nM crizotinib for 24 h. Finally, total RNA was isolated and utilized for E2F1, E2F2 and RAD51 mRNA quantification by QPCR. B, Identification of upstream regulators of the en masse gene expression regulation by combined crizotinib plus starvation vs. crizotinib alone by IPA. C-E H3122 cells were treated as in A and utilized for either protein lysate generation or cell nuclei isolation and propidium iodide staining. C, phospho-RB (Ser807/811) and total RB were detected by immunoblotting. D, E, cell cycle was analyzed on a FACS Calibur by acquiring 10.000 events/sample.
Mentions: In order to determine what starvation would add to the TKI in terms of gene expression regulation, we compared the arrays corresponding to crizotinib alone to those corresponding to crizotinib plus starvation. Also in this case, the number of DEGs (264) was found to be very limited, which is in line with the notion that both types of treatment likely act on the same genetic and molecular mechanisms. We reasoned that these 264 DEGs could represent a core of genes that may explain the stronger anti-proliferative effect exerted by combined crizotinib and starvation compared to crizotinib alone. Using functional enrichment we observed that the DEGs of cells treated with crizotinib and starvation clustered in canonical pathways within the area of cell cycle control and DNA damage (Supplementary Table 4). Among these genes, it is worth to notice the presence of important cancer genes such as E2F1, E2F2, and RAD51, which combined starvation and crizotinib down-regulated to a higher extent compared to these treatments alone (Supplementary Table 4). Notably, the effect of crizotinib, starvation and their combination on E2F1, E2F2, and RAD51 could be readily verified by QPCR (Figure 4A).

Bottom Line: However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies.In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone.In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, University of Genoa, Genoa, Italy.

ABSTRACT
Tyrosine kinase inhibitors (TKIs) are now the mainstay of treatment in many types of cancer. However, their benefit is frequently short-lived, mandating the search for safe potentiation strategies. Cycles of fasting enhance the activity of chemo-radiotherapy in preclinical cancer models and dietary approaches based on fasting are currently explored in clinical trials. Whether combining fasting with TKIs is going to be potentially beneficial remains unknown. Here we report that starvation conditions increase the ability of commonly administered TKIs, including erlotinib, gefitinib, lapatinib, crizotinib and regorafenib, to block cancer cell growth, to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway and to strengthen E2F-dependent transcription inhibition. In cancer xenografts models, both TKIs and cycles of fasting slowed tumor growth, but, when combined, these interventions were significantly more effective than either type of treatment alone. In conclusion, cycles of fasting or of specifically designed fasting-mimicking diets should be evaluated in clinical studies as a means to potentiate the activity of TKIs in clinical use.

No MeSH data available.


Related in: MedlinePlus