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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

Starvation conditions synergistically increase the antiproliferative effects of TKIs in cultured cancer cellsHCC827 (EGFR mutated, exon 19 EGFR deletion), H3122 (ALK+ NSCLC), SKBR3, BT474 (HER2+ breast cancer), or HCT116 (colorectal cancer) cells were plated in 96 well plates in regular culture medium. 24 h later, the cell medium was removed and cells were incubated either in regular medium (CTR) or in starvation medium (starvation). 24 h later, 10 nM gefitinib (gef), 100 nM erlotinib (erl), 400 nM crizotinib (criz), 100 nM lapatinib (lap), or 300 nM regorafenib (reg) were added where indicated. 72 h later, viability was detected by CellTiter96 Aqueous1. CIs for the combinations TKI-starvation are indicated within each panel. G-I, 4×105 HCC827, 1×105 H3122, 5×104 HCT116 cells/dish were plated in 10 cm dishes and treated with erlotinib, gefitinib, crizotinib, or regorafenib as in A-F. 5 days later, cell medium was removed and cells were cultured for two additional days in regular culture medium. Thereafter, cells were fixed, stained with SRB and imaged.
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Figure 1: Starvation conditions synergistically increase the antiproliferative effects of TKIs in cultured cancer cellsHCC827 (EGFR mutated, exon 19 EGFR deletion), H3122 (ALK+ NSCLC), SKBR3, BT474 (HER2+ breast cancer), or HCT116 (colorectal cancer) cells were plated in 96 well plates in regular culture medium. 24 h later, the cell medium was removed and cells were incubated either in regular medium (CTR) or in starvation medium (starvation). 24 h later, 10 nM gefitinib (gef), 100 nM erlotinib (erl), 400 nM crizotinib (criz), 100 nM lapatinib (lap), or 300 nM regorafenib (reg) were added where indicated. 72 h later, viability was detected by CellTiter96 Aqueous1. CIs for the combinations TKI-starvation are indicated within each panel. G-I, 4×105 HCC827, 1×105 H3122, 5×104 HCT116 cells/dish were plated in 10 cm dishes and treated with erlotinib, gefitinib, crizotinib, or regorafenib as in A-F. 5 days later, cell medium was removed and cells were cultured for two additional days in regular culture medium. Thereafter, cells were fixed, stained with SRB and imaged.

Mentions: Experiments were conducted to ascertain whether culture conditions mimicking the metabolic consequences of fasting (i.e. low glucose - 0.5 g/l - and low serum -1% FBS) would potentiate the growth-inhibiting activity of TKIs in current clinical use, including the EGFR TKIs erlotinib (Tarceva) and gefitinib (Iressa), the ALK TKIs crizotinib (Xalkori) and TAE684, the HER2/EGFR TKIs lapatinib (Tykerb) and CP724714, and the multitarget TKI regorafenib (Stivarga) (Figure 1 and Supplementary Figure 1). These compounds were tested in appropriate cellular models, which included the NSCLC cells with mutated EGFR, HCC827, the NSCLC cells carrying the EML4-ALK translocation, H3122, the breast cancer cells with amplified HER2, BT474 and SKBR3, and the regorafenib-sensitive colorectal cancer cells HCT116, by measuring viability with the MTS-based assay CellTiter96 Aqueous 1. After a four-day treatment, starvation conditions were sufficient to slow cancer cell growth in SKBR3, BT474, and HCT116 cells (Figure 1D-F), but not in HCC827 and H3122 cells (Figure 1A-C), although extending the starvation period from four to six days visibly affected cell growth in the latter two cell lines, too (Figure 1G, H). In all of the cellular models, a synergistic potentiation of the TKI activity by starvation was readily evident and was documented by the calculation of CIs (Figure 1A-I, Supplementary Figure 1A, B). Measuring cell viability with an alternative assay, the sulforhodamine B colorimetric assay [17], yielded similar results and readily revealed a cooperation between starvation conditions and TKIs, too (data not shown).


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)

Starvation conditions synergistically increase the antiproliferative effects of TKIs in cultured cancer cellsHCC827 (EGFR mutated, exon 19 EGFR deletion), H3122 (ALK+ NSCLC), SKBR3, BT474 (HER2+ breast cancer), or HCT116 (colorectal cancer) cells were plated in 96 well plates in regular culture medium. 24 h later, the cell medium was removed and cells were incubated either in regular medium (CTR) or in starvation medium (starvation). 24 h later, 10 nM gefitinib (gef), 100 nM erlotinib (erl), 400 nM crizotinib (criz), 100 nM lapatinib (lap), or 300 nM regorafenib (reg) were added where indicated. 72 h later, viability was detected by CellTiter96 Aqueous1. CIs for the combinations TKI-starvation are indicated within each panel. G-I, 4×105 HCC827, 1×105 H3122, 5×104 HCT116 cells/dish were plated in 10 cm dishes and treated with erlotinib, gefitinib, crizotinib, or regorafenib as in A-F. 5 days later, cell medium was removed and cells were cultured for two additional days in regular culture medium. Thereafter, cells were fixed, stained with SRB and imaged.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Starvation conditions synergistically increase the antiproliferative effects of TKIs in cultured cancer cellsHCC827 (EGFR mutated, exon 19 EGFR deletion), H3122 (ALK+ NSCLC), SKBR3, BT474 (HER2+ breast cancer), or HCT116 (colorectal cancer) cells were plated in 96 well plates in regular culture medium. 24 h later, the cell medium was removed and cells were incubated either in regular medium (CTR) or in starvation medium (starvation). 24 h later, 10 nM gefitinib (gef), 100 nM erlotinib (erl), 400 nM crizotinib (criz), 100 nM lapatinib (lap), or 300 nM regorafenib (reg) were added where indicated. 72 h later, viability was detected by CellTiter96 Aqueous1. CIs for the combinations TKI-starvation are indicated within each panel. G-I, 4×105 HCC827, 1×105 H3122, 5×104 HCT116 cells/dish were plated in 10 cm dishes and treated with erlotinib, gefitinib, crizotinib, or regorafenib as in A-F. 5 days later, cell medium was removed and cells were cultured for two additional days in regular culture medium. Thereafter, cells were fixed, stained with SRB and imaged.
Mentions: Experiments were conducted to ascertain whether culture conditions mimicking the metabolic consequences of fasting (i.e. low glucose - 0.5 g/l - and low serum -1% FBS) would potentiate the growth-inhibiting activity of TKIs in current clinical use, including the EGFR TKIs erlotinib (Tarceva) and gefitinib (Iressa), the ALK TKIs crizotinib (Xalkori) and TAE684, the HER2/EGFR TKIs lapatinib (Tykerb) and CP724714, and the multitarget TKI regorafenib (Stivarga) (Figure 1 and Supplementary Figure 1). These compounds were tested in appropriate cellular models, which included the NSCLC cells with mutated EGFR, HCC827, the NSCLC cells carrying the EML4-ALK translocation, H3122, the breast cancer cells with amplified HER2, BT474 and SKBR3, and the regorafenib-sensitive colorectal cancer cells HCT116, by measuring viability with the MTS-based assay CellTiter96 Aqueous 1. After a four-day treatment, starvation conditions were sufficient to slow cancer cell growth in SKBR3, BT474, and HCT116 cells (Figure 1D-F), but not in HCC827 and H3122 cells (Figure 1A-C), although extending the starvation period from four to six days visibly affected cell growth in the latter two cell lines, too (Figure 1G, H). In all of the cellular models, a synergistic potentiation of the TKI activity by starvation was readily evident and was documented by the calculation of CIs (Figure 1A-I, Supplementary Figure 1A, B). Measuring cell viability with an alternative assay, the sulforhodamine B colorimetric assay [17], yielded similar results and readily revealed a cooperation between starvation conditions and TKIs, too (data not shown).

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