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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

Fasting potentiates regorafenib in vivo activity in HCT116 xenograftsA-C, Six- to eight-week-old BALB/c athymic mice (nu+/nu+) were injected s.c. with 2 × 106 HCT116 cells. When tumors become palpable, mouse were randomly assigned to one of four arms (six mice per treatment arm): control, normal diet; regorafenib (normal diet with regorafenib); fasting; fasting+regorafenib. Mouse weight (C) and tumor size (A) were monitored daily (A, at day +21: CTR vs. regorafenib: p<0.01; CTR vs. fasting: p<0.01; regorafenib vs. regorafenib +fasting: p<0.05; fasting vs. regorafenib+fasting: p<0.01). After three weeks from the beginning of treatment, mice were euthanized and tumor masses were excised and weighted (B). *: p<0.05; **: p<0.01; ***: p<0.001.
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Figure 6: Fasting potentiates regorafenib in vivo activity in HCT116 xenograftsA-C, Six- to eight-week-old BALB/c athymic mice (nu+/nu+) were injected s.c. with 2 × 106 HCT116 cells. When tumors become palpable, mouse were randomly assigned to one of four arms (six mice per treatment arm): control, normal diet; regorafenib (normal diet with regorafenib); fasting; fasting+regorafenib. Mouse weight (C) and tumor size (A) were monitored daily (A, at day +21: CTR vs. regorafenib: p<0.01; CTR vs. fasting: p<0.01; regorafenib vs. regorafenib +fasting: p<0.05; fasting vs. regorafenib+fasting: p<0.01). After three weeks from the beginning of treatment, mice were euthanized and tumor masses were excised and weighted (B). *: p<0.05; **: p<0.01; ***: p<0.001.

Mentions: Based on these premises, we sought for the proof-of-concept that starvation would increase the efficacy of TKIs also in vivo, using, to this end, well-established xenografts cancer models. In H3122 xenografts, both cycles of fasting and crizotinib effectively reduced tumor growth with no difference in terms of efficacy between the two approaches (Figure 5 A, B). However, the combination TKI+fasting was more effective than either type of treatment alone (Figure 5A, B). Notably, as observed in vitro, the combination of fasting with crizotinib was the only intervention to result in a significant reduction in phospho-ERK levels, whereas fasting alone was found to increase phospho-ERK in vivo, too (Figure 5C). Notably, although fasted mice did exhibit transient weight losses, they fully recovered their weight between one cycle and the next one (Figure 5D). Similar results were obtained with regorafenib in xenografts of the colorectal cancer cell line, HCT116 (Figure 6). After a three-week treatment, both regorafenib and cycles of fasting achieved a substantial reduction in tumor growth compared to the controls (Figure 6A, B). However, again, combined fasting and regorafenib were significantly more active than either type of treatment alone. Finally, also in this animal model, the weight lost by fasted animals was fully recovered between one treatment cycle and the following one (Figure 6C).


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)

Fasting potentiates regorafenib in vivo activity in HCT116 xenograftsA-C, Six- to eight-week-old BALB/c athymic mice (nu+/nu+) were injected s.c. with 2 × 106 HCT116 cells. When tumors become palpable, mouse were randomly assigned to one of four arms (six mice per treatment arm): control, normal diet; regorafenib (normal diet with regorafenib); fasting; fasting+regorafenib. Mouse weight (C) and tumor size (A) were monitored daily (A, at day +21: CTR vs. regorafenib: p<0.01; CTR vs. fasting: p<0.01; regorafenib vs. regorafenib +fasting: p<0.05; fasting vs. regorafenib+fasting: p<0.01). After three weeks from the beginning of treatment, mice were euthanized and tumor masses were excised and weighted (B). *: p<0.05; **: p<0.01; ***: p<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Fasting potentiates regorafenib in vivo activity in HCT116 xenograftsA-C, Six- to eight-week-old BALB/c athymic mice (nu+/nu+) were injected s.c. with 2 × 106 HCT116 cells. When tumors become palpable, mouse were randomly assigned to one of four arms (six mice per treatment arm): control, normal diet; regorafenib (normal diet with regorafenib); fasting; fasting+regorafenib. Mouse weight (C) and tumor size (A) were monitored daily (A, at day +21: CTR vs. regorafenib: p<0.01; CTR vs. fasting: p<0.01; regorafenib vs. regorafenib +fasting: p<0.05; fasting vs. regorafenib+fasting: p<0.01). After three weeks from the beginning of treatment, mice were euthanized and tumor masses were excised and weighted (B). *: p<0.05; **: p<0.01; ***: p<0.001.
Mentions: Based on these premises, we sought for the proof-of-concept that starvation would increase the efficacy of TKIs also in vivo, using, to this end, well-established xenografts cancer models. In H3122 xenografts, both cycles of fasting and crizotinib effectively reduced tumor growth with no difference in terms of efficacy between the two approaches (Figure 5 A, B). However, the combination TKI+fasting was more effective than either type of treatment alone (Figure 5A, B). Notably, as observed in vitro, the combination of fasting with crizotinib was the only intervention to result in a significant reduction in phospho-ERK levels, whereas fasting alone was found to increase phospho-ERK in vivo, too (Figure 5C). Notably, although fasted mice did exhibit transient weight losses, they fully recovered their weight between one cycle and the next one (Figure 5D). Similar results were obtained with regorafenib in xenografts of the colorectal cancer cell line, HCT116 (Figure 6). After a three-week treatment, both regorafenib and cycles of fasting achieved a substantial reduction in tumor growth compared to the controls (Figure 6A, B). However, again, combined fasting and regorafenib were significantly more active than either type of treatment alone. Finally, also in this animal model, the weight lost by fasted animals was fully recovered between one treatment cycle and the following one (Figure 6C).

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