Abstract
Background The potential for ketogenic diets or administration of exogenous ketone bodies to treat or prevent to cancer remains encouraging. Of particular interest is the possibility that, whatever the effect of a nutritional intervention alone, the diet might enhance the effect of existing cancer drugs, thereby requiring lower doses and a reduction in toxicity and side effects.
Methods SW480, a human cell line derived from colon, was treated with ketone bodies (sodium 3-hydroxy butyrate (common name, □-hydroxy butyrate) or with sodium acetoacetate in the presence or absence of rapamycin. Cells were incubated for 96 hours in DMEM with 10 mM glucose medium. HSF2617, a human epithelial fibroblast line served as control and cells were subjected to similar treatment as the SW480 cells. Cell proliferation and glucose consumption were determined with standard reagents.
Results The ketone bodies inhibited proliferation of SW480 cells in culture. Rapamycin also inhibited proliferation and its action was enhanced by the ketone bodies although there was little synergistic effect under these conditions. Human fibroblast controls were not inhibited by the ketone bodies. Both SW480 and control lines showed consumption of glucose during a 96 hour incubation period, suggesting that normal controls can switch to ketogenic metabolism while the cancer cells, which proliferate poorly, cannot. Results are consistent with recent reports of a mouse model showing the synergy of rapamycin and a ketogenic diet (Zou Y, et al. (2020) PLoS ONE 15 (5)) as well as earlier publications describing additive or synergistic effects of ketogenic diets with other modalities of cancer treatment.
Conclusions The results show that the growth of a cancer cell line in culture can be inhibited by the addition of ketone bodies or rapamycin to the growth medium. The combination of treatments was found to be additive, consistent with results from a previously published mouse model. The data demonstrate the potential for a strategy whereby doses of anti-cancer agents that have detrimental or toxic side-effects can be reduced if coupled to an appropriate source of ketone bodies.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
Email: Anna Miller – anna.miller{at}downstate.edu;
Eugene J Fine – eugene.fine{at}einsteinmed.org;
Bo Lin – bo.lin{at}downstate.edu
Matthew R. Pincus ; matthew.pincus{at}downstate.edu
Richard D Feinman – richard.feinman{at}downstate.edu
List of Abbreviations
- DMSO
- Dimethyl sulfoxide
- 3-HB
- DL-3-hydroxybutyrate (commonly referred to as ⍰⍰-hydroxy butyrate)
- IRS-1
- Insulin Receptor Substrate-1
- NaAcAc
- Sodium acetoacetate
- mTOR
- Mammalian target of Rapamycin
- PDH
- pyruvate dehydrogenase complex
- PI3K
- Phosphoinositol triphosphate kinase
- SCOT
- succinyl-CoA:acetoacetate CoA transferase