Table 1.
Some of the preclinical studies for the effect of ketogenic diet on cancer (tumor) cells.
| Cancer Type | Cell Line | Animal Model | KD Ratio |
Study Group | Mechanism and Results of the Studies Compared with SD | Ref. |
|---|---|---|---|---|---|---|
| Glioblastoma | T98G, U87MG, NIH3T3, A172, LNT-229, U251MG | athymic nude mice | 3:1 | SD, KD | KD resulted in a significant increase in BHB (KB), but it had no effect on glioma cell lines, TP, BG levels, or survival → no effect. | [75] |
| U87MG | athymic nude mice | 3:1 | SD ± CT, KD ± CT | KD alone: increase in KBs but no effect on TP or survival; KD+CT: increase the activity of CT drug → increase survival. | [252] | |
| GL261-Luc2 | albino C57BL/6 mice | 4:1 | SD ± RT, KD, KD ± RT | KD alone: increase in BHB (KB) and survival; KD+RT: enhance antitumor additive effect from RT alone → increase survival. |
[22] | |
| GL261-Luc2 | albino C57BL/6 mice | 4:1 | SD, KD | The expression of VEGF receptor, MMP-2 and vimentin were reduced in tumors from animals on KD, and significantly reduced in the peritumoral edema. | [142] | |
| Medullo-blastoma | Spontaneous tumor development | Ptch1/-Trp53/mice | 4:1 | SD, KD | KD reduced the insulin level and increased the KB level in mice but there was no effect on the TP or survival. | [253] |
| Medulloblastoma from Ptch1/-Trp53/mice | NOD SCID mice | 6:1 | SD, KD | KD reduced the insulin level and increased the KB level in mice but there was no effect on the TP or survival. | [253] | |
| Prostate cancer | LAPC-4 | athymic nude mice | 2:1 | SD ± MCT1 inhibitor, KD ± MCT1 inhibitor |
MCT1 inhibitor did not affect TP and increased necrotic fraction; KD decreased TP compared to SD and decreased the necrotic fraction. |
[254] |
| Spontaneous tumor development | transgenic Hi-Myc mice | 2:1 | SD, KD | KD worked as a protumor (preventive). | [255] | |
| Colon cancer | colon 26 | CDF1 mice | 3:1 | SD, KD | KD increased KB and decreased TP and plasma IL-6 levels compared with tumor-bearing mice taking SD. | [245] |
| colon 26 | BALB/c mice | 4:1 | SD, KD | The KD group showed an increase in survival and better health status, no effect on TP → KD good as a potential preventive therapy. | [246] | |
| Pancreatic cancer | S2-013 | athymic nude mice | 2:1 | SD, KD | KD caused reduced TP and inhibition of muscle and body weight loss by decreasing BG, glycolytic flux in tumor cells and increasing KB, which diminished glutamine uptake, overall ATP content, and survival of the pancreatic cancer cell lines, while inducing apoptosis of it. | [247] |
| PANC-1 | nu/nu mice | 3:1 | SD, KD | KD decreased TP and increased the survival rate by reducing energy supplies to cells, which damage the tumor microenvironment → antitumor effect. | [248] | |
| MIA PaCa-2 | athymic nude mice | 4:1 | SD ± RT, KD ± RT | KD increased radiation sensitivity in a pancreatic cancer compared with radiation alone. | [249] | |
| Breast cancer | Spontaneous tumor development | transgenic FVB MMTV-PyMT mice | 4:1 | SD, KD | KD decreased TP by suppressing tumorigenesis; this may perhaps reflect the inherent tumor-suppressive efficacy of free LCFA or their respective CoA-thioesters by suppressing their esterification into lipids due to limiting insulin and glycerol-3-phosphate. | [250] |
| 4T1 | BALB/c mice | 6:1 | SD ± metformin, CR-KD ± metformin |
KD enhanced the cytotoxic effect of metformin on tumor growth by decreasing ATP production and inhibiting survival signaling pathways. | [256] | |
| ES-272 | C57BL/6 mice | 6:1 | SD ± PI3K inhibitors, KD ± PI3K inhibitors |
KD enhanced PI3K inhibitors to decrease TP in tumor cell → increased the antitumor effect. | [27] | |
| Lung cancer | LLC1 | C57BL/6 (Fgf21 WT and KO) mice | 3:1, 8:1 | low-fat diet (SD), regular protein KD, low protein KD | Regular protein KD had no effect on TP but low protein KD showed decreased TP, i.e., an antitumor effect by the extreme increase of fibroblast growth factor 21 levels because of protein starvation. | [251] |
| TC-1_luc | BALB/c mice | 4:1 | SD, KD, KD + mABs | KD increased BHB that slowed TP and induced a T cell-dependent anticancer effect. | [185] | |
| NCI-H292, A549 | nu/nu mice | 4:1 | different experiments with different IR doses, but overall: SD ± RT, KD ± RT, SD + RT/CT, KD + RT/CT |
KD enhanced the antitumor effect of RT that decreased TP compared with RT alone by a mechanism that may involve increased oxidative stress. | [257] | |
| Melanoma | A375, A2058 (BRAF V600E) | nu/nu mice | 4:1, 6:1 | SD, KD | KD decreased glucose level and increased AcA, leading to increased TP → protumor effect. | [258] |
| RET melanoma | C57BL/6JolaHsd BALB/c mice | 4:1 | SD, KD, KD + mABs | KD increased BHB that slowed TP and induced a T cell-dependent anticancer effect and KD had synergistic antitumor effects when combined with a combination of immunostimulatory mAbs. | [185] | |
| Kidney cancer | 786-O | CD-1 nude mice | 8:1 | SD, LCT-KD, MCT-KDs |
KD reduced TP, but mouse survival was dramatically reduced due to massive weight loss in the KD group. | [259] |
| RENCA-luc | BALB/c mice | 4:1 | SD, KD, KD + mABs | KD delayed the progression of TP, preventing tumor outgrowth in some mice and smaller tumors were observed in others. | [185] | |
| Spontaneous tumor development | Eker (Tsc2) rats | 8:1 | SD, KD | KD promoted TP by recruiting ERK1/2 and mTOR, which are correlated with the accumulation of oleic acid and the overproduction of growth hormone. | [260] | |
| Liver cancer | DEN-induced hepatocellularcarcinoma | C57BL/6N mice | 4:1 | SD, KD | KD had no effect on TP. | [261] |
| DEN-induced hepatocellularcarcinoma | C57BL/6N mice | 5:1 | low-fat/low-sucrose diet, KD, western diets, fructose diet | KD and a low-fat/low-sucrose diet feeding decreased TP compared with a high-sucrose diet; this effect correlated with sugar intake and was independent of excess adiposity or insulin resistance. | [262] | |
| Uterus cancer | HeLa | nu/nu mice | 3:1 | SD, KD | KD showed an increase in TP and decreased survival because HeLa tumors actively consumed KB as an energy source. | [248] |
| Patient-derived xenograft | nude mice | 6:1 | SD ± PI3K inhibitors, KD ± PI3K inhibitors | KD had no effect on TP alone but an enhanced antitumor effect of KD+PI3Kinhibitors compared with CD + PI3K. | [27] | |
| Acute myeloid leukemia | MLL-AF9 Ds-Red | C57BL/6 mice | 6:1 | SD ± PI3K inhibitors, KD ± PI3K inhibitors | KD alone decreased the survival → protumor effect, but enhanced survival in KD + PI3K inhibitors group compared with CD + PI3K inhibitor. |
[27] |
| Bladder cancer | Patient-derived xenograft | nude mice | 6:1 | SD ± PI3K inhibitors, KD ± PI3K inhibitors | KD alone decreased TP, and with PI3K inhibitors had an additive antitumor effect because the efficacy of PI3K inhibition can be limited in the presence of insulin feedback and in KD reduced levels of phosphorylated insulin receptor, decreasing the levels of tumor proliferation, increasing apoptosis, and enhancing PI3K inhibitors activity | [27] |
2-DG: 2-deoxyglucose, AcAc: acetoacetate, BHB: b-hydroxybutyrate, CD: control diet, CHO: carbohydrate, CR-CD: calorie-restricted control diet, CR-KD: calorie-restricted ketogenic diet, CT: chemotherapy, DEN: diethylnitrosamine, DON: 6-diazo-5-oxo-L-norleucine, HBOT: hyperbaric oxygen therapy, IR: ionizing radiation, KD: ketogenic diet, KE: ketone ester, KO: knock out, LCT: long-chain triglyceride, LFD: low-fat diet, MCT: medium-chain triglyceride, MCT1: monocarboxylate transporter 1, NCKD: non carbohydrate ketogenic diet, PI3K: phosphatidylinositol-3 kinase, RT: radiotherapy, TP: tumor progression, WT: wild-type.