Table 1.
Animal studies reporting the effect of the KD on tumor growth and survival.
| Tumor | References | Animal species | Cell strain | KD ratio | CR | Study groups | Animal number | Tumor growth | Survival time | G, β-HB and BW | Conclusion |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Glioblastoma | Zhou et al. (16) | C57BL/6J; BALBc/J-SCID mice | U87-MG | 4:1 | Yes | SD; KD; KD-CR | n = 12–14 | KD vs. SD: ns | KD vs. SD: ns | KD-CR reduces G and BW; KD-CR elevates β-HB. | KD-CR has anti-tumor effect. |
| KD-CR vs. SD: inhibition | KD-CR vs. SD: increase | ||||||||||
| Stafford et al. (17) | C57BL/6 mice | GL261 | 8:1 | No | SD; KD | n = 20 | – | KD vs. SD: increase | G: ns; β-HB: increase; BW: ns. | KD improves survivability | |
| Abdelwahab et al. (8) | Albino C57BL/6 mice | GL261-Luc2 | 4:1 | No | SD; KD; SD + RT; KD + RT | n = 11–19 | Inhibition | KD vs. SD: increase; KD + RT vs. SD + RT: no data | G: decrease; β-HB: increase; BW: reduce. | KC enhances survival and slows tumor growth; additive effect of KD + RT | |
| Rieger et al. (18) | Athymic nude mice | U87MG | 3.14:1 | No | SD; KD; SD + CT; KD + CT | n = 5–7 | KD vs. SD: ns; KD + CT vs. SD + CT: inhibition | KD + CT vs. SD + CT: increase | G: ns; β-HB: increase; BW: ns. | No effect of KD alone; enhanced survival of KD + CT vs. SD + CT | |
| Woolf et al. (19) | Albino C57BL/6 mice | GL261-Luc2 | 4:1 | No | SD; KD | n = 6 | – | – | G: decrease; β-HB: increase; BW: reduce. | Alters the hypoxic | |
| Response, reduced tumor microvasculature | |||||||||||
| Lussier et al. (7) | Albino C57BL/6 mice | GL261-Luc2 | 4:1 | No | SD; KD | n = 12 | – | KD vs. SD: increase | G: decrease; β-HB: increase; BW: ns. | KD enhances survival | |
| De Feyter et al. (20) | Fischer rats | RG2, 9L | 4:1 | Yes | SD-CR; KD-CR | n = 10–11 | ns | ns | G: decrease; β-HB: increase; BW: reduce. | No effect | |
| Augur et al. (21) | VM/Dk mice | VM-M3 | 2.7:1 | No | SD; KD | n = 4–9 | – | ns | G: decrease; β-HB: increase; BW: reduce. | No effect | |
| Mukherjee et al. (22) | VM/Dk mice | VM-M3 | 4:1 | Yes | SD; KD-CR; SD + DON; KD-CR + DON | n = 10–15 | – | Increase | CR-KD ± DON decreases G and increases β-HB; BW: reduce. | KD-CR + DON prolong survival time | |
| Breast | Gluschnaider (23) | Transgenic FVB MMTV-PyMT mice | Spontaneous tumor development | 4:1 | No | SD; HFD; KD; MEDICA | n = 8–10 | KD vs. SD: inhibition | – | BW: ns. | Anti-tumor |
| Zhuang et al. (24) | BALB/c mice | 4T1 | 6:1 | Yes | SD; SD + Metformin; KD-CR; KD-CR + Metformin | n = 10 | Inhibition | – | G: decrease | KD-CR have anti-tumor effects; additive effect of KD + Metformin | |
| Hopkins et al. (11) | C57BL/6 mice | ES272 | 6:1 | No | SD; SD + PI3K inhibitors; KD; KD + PI3K inhibitors | n = 5 | Inhibition | – | – | No effect of KD alone, additive effect of KD + PI3K inhibitors | |
| Lung | Allen et al. (9) | nu/nu mice | NCI-H292, A549 | 4:1 | No | SD; KD; IR; IR + KD; CT; CT + KD; IR + CT; IR + CT + KD | n = 5–16 | Inhibition | KD + RT: prolongs survival; KD + RT/CT: prolongs survival | β-HB: increases | No effect of KD alone, enhanced anti-tumor effects of KD + CT/RT |
| Stemmer et al. (25) | C57BL/6 (Fgf21 WT and KO) mice | LLC1 | 3:1; 8:1 | No | SD; RP-KD; LP-KD | n = 8–15 | Inhibition | – | Low protein KD decreases G and increases β-HB. BW: ns. | LP-KD has anti-tumor effect | |
| Liver | Healy et al. (26) | C57BL/6N mice | DEN-induced hepatocellular carcinoma | 5:1 | No | SD; WD-L; WD-C; FD; KD | n = 6–12 | – | – | G: ns; BW: ns. | Anti-tumor |
| Byrne et al. (27) | C57BL/6N mice | DEN-induced hepatocellular carcinoma | 4:1 | No | SD; KD | n = 7 | ns | - | β-HB: increase; BW: increase. | No effect | |
| BRAF V600E-positive A375 melanoma | Xia et al. (15) | nu/nu mice | A375, A2058 (BRAF V600E) | 4:1; 6:1 | No | SD; KD | n = 8 | Increase | – | G: decreases; β-HB: ns; BW: ns. | Pro-tumor |
| SKMEL-2 cells melanoma | Xia et al. (15) | nu/nu mice | SK-MEL-2 (NRAS Q61R) | 4:1 | No | SD; KD | n = 7 | ns | - | G: decreases; β-HB: ns; BW: ns. | No effect |
| Colon | Tisdale et al. (28) | NMR1 mice | MAC16 | 1:1; 2:1 | No | SD; 68%fat KD ± 3-hydroxybutyrate; 80% fat KD ± 3-hydroxybutyrate | ns | 80% fat KD ± 3-hydroxybutyrate decreases tumor weight | - | G: ns; β-HB: increase; BW: reduce. | Anti-tumor |
| Beck and Tisdale (29) | NMR1 mice | MAC16 | 2:1 | No | SD; KD | n = 6–12 | KD decreases tumor weight | – | G: ns; β-HB: increase; BW: reduce. | Anti-tumor | |
| Hao et al. (30) | BALB/c nude mice | HCT-116 | 3:1 | No | SD; MKD; LKD | n = 12 | KD inhibits tumor growth | KD prolongs survival time | G: ns; β-HB: increase; BW: increase. | Anti-tumor | |
| Nakamura et al. (31) | CDF1 mice | Colon 26 | 3:1 | No | SD; KD | n = 5–10 | KD decrease tumor weight | – | β-HB: increase; BW: reduce. | Anti-tumor | |
| Kasumi and Sato (32) | BALB/c mice | Colon 26 | 4:1 | No | SD; KD | n = 6–8 | ns | KD prolongs survival time | G: ns; β-HB: increase; BW: reduce. | KD improves the prognosis | |
| Prostate | Freedland et al. (33) | SCID mice | LAPC-4 | 2:1 | No | Low fat; Western diet; no-carbohydrate ketogenic diet (NCKD) | n = 11 | ns | NCKD prolong survival time | G: increase; β-HB: increase; BW: increase. | Anti-tumor |
| Mavropoulos et al. (34) | Fox chase SCID mice | LNCaP | 2:1 | No | NCKD; LFD; MCD | n = 11 | NCKD decreases tumor volume | NCKD prolongs survival time | G: ns; β-HB: increase; BW: decrease. | Anti-tumor | |
| Kim et al. (35) | Athymic nude mice | LAPC-4 | 2:1 | No | SD ± MCT1 inhibitor; KD ± MCT1 inhibitor | ns | KD decreases tumor volume | KD prolongs survival time | G: ns; BW: ns. | Anti-tumor | |
| Pancreatic cancer | Shukla et al. (36) | Athymic nude mice | S2-013 | 2:1 | No | SD; KD | n = 9 | KD decreases tumor weight and tumor volume | – | G: decrease; β-HB: increase; BW: reduce. | Anti-tumor |
| Zahra et al. (10) | Athymic nude mice | MIA PaCa-2 | 4:1 | No | SD; KD; RT; KD + RT | n = 9–16 | KD + RT decreases tumor volume | KD + RT prolongs survival time | G: decrease; β-HB: increase; BW: reduce. | No effect of KD alone, additive anti-tumor effect of KD + CT | |
| Zhang et al. (37) | nu/nu mice | PANC-1 | 3:1 | No | SD; KD | n = 8 | KD decreases tumor weight | KD prolong survival time | G: decrease; β-HB: increase; BW: reduce. | Anti-tumor | |
| Kidney cancer | Liskiewicz et al. (14) | Eker (Tsc2+/−) rats | Spontaneous tumor development | 8:1 | No | SD; KD | n = 1–34 | KD increases renal tumor growth | – | G: decrease; β-HB: increase | Pro-tumor |
| Vidali et al. (38) | CD-1 nude mice | 786-O | 8:1 | No | SD; LCT-KD; MCT-KD | n = 5–6 | KD tends to slow down tumor growth, but with no significance. | KD reduces the overall survival | LCT-KD increases β-HB; BW: reduce. | KD might be contraindicated in the treatment of RCC patients presenting with Stauffer's syndrome | |
| Anaplastic thyroid cancer | Aggarwal et al. (39) | CD-1 nude mice | 8505C | No | SD; KD; SD + N AC; KD + NAC | n = 6 | KD or KD + NAC | – | G: decrease; β-HB: increase | Anti-tumor | |
| Neuroblastoma | Morscher et al. (40) | CD-1 nude mice | SH-SY5Y (non-NMYC amplified); SK-N-BE(2) (NMYC amplified) | 2:1 | Yes | SD; CR-SD; KD; CR-KD | n = 8–11 | CR-SD, CR-KD decrease tumor volume | CR-SD, CR-KD prolong survival time | CR-KD decreases G and BW; CR-KD increases β-HB. | No effect of KD alone; enhanced effects of CR-KD |
| Morscher et al. (41) | CD-1 nude mice | SH-SY5Y (non-NMYC amplified); | 2:1 | Yes | Cell line: SH-SY5Y (non-NMYC amplified) | n = 8–12 | KD + CT, CR-KD + CT decrease tumor volume | KD + CT, CR-KD + CT prolong survival time | CR-KD decreases G and increases β-HB; BW: reduce. | Antitumor effects of KD + CT; additive effect of CR on KD + CT | |
| SD; SD + CT; CR-SD + CT; KD + CT; KD-CR + CT | |||||||||||
| Morscher et al. (41) | CD-1 nude mice | SK-N-BE(2) (NMYC amplified) | 2:1 | Yes | Cell line: SK-N-BE(2) (NMYC amplified) | n = 8–12 | KD + CT: ns; CR-KD + CT decreases tumor volume | KD + CT: ns; CR-KD + CT prolongs survival time | CR-KD decreases G and increases β-HB; BW: reduce. | No effect of KD + CT; enhanced anti-tumor of CR on KD + CT | |
| SD; SD + CT; CR-SD + CT; KD + CT; KD-CR + CT | |||||||||||
| Aminzadeh-Gohari et al. (42) | CD-1 nude mice | SH-SY5Y (non-NMYC amplified); SK-N-BE(2) (NMYC amplified) | 8:1 | No | SD; LCT-KD; MCT-KD | n = 10–12 | LCT-KD and MCT-KD decrease tumor volume | MCT-KD prolongs survival time | G: decrease; β-HB: increase; BW: ns. | Anti-tumor | |
| Medulloblastoma | Dang et al. (43) | Ptch1+/−Trp53−/−mice | Spontaneous tumor development | 4:1 | No | SD; KD | n = 4 | ns | ns | BW: reduce. | No effect |
| Dang et al. (43) | NOD SCID mice | Medulloblastoma from Ptch1+/−Trp53−/− mice | 6:1 | No | SD; KD | n = 4 | ns | ns | G: decrease; β-HB: increase; BW: reduce. | No effect | |
| Gastric cancer | Otto et al. (6) | NMRI nude mice | 23132/87 | 2.7:1 | No | SD; KD | n = 12 | KD inhibits tumor growth | KD prolongs survival time | G: ns; β-HB: increase; BW: ns. | Anti-tumor |
| Systemic metastatic cancer | Poff et al. (12) | VM/Dk mice | VM-M3 | 4:1 | No | SD; SD + HBO2T; KD; KD + HBO2T | n = 8–13 | KD, KD + HBO2T inhibit tumor growth | KD, KD + HBO2T prolong survival time | G: decrease; β-HB: ns; BW: reduce. | Anti-tumor; enhanced antitumor effects of HBO2T on KD |
| Poff et al. (13) | VM/Dk mice | VM-M3 | 1.5:1 | No | SD; KD; KD + KE:KD + KE + HBO2T | n = 7–17 | KD, KD + KE, KD + KE + HBO2T inhibit tumor growth | KD, KD + KE, KD + KE + HBO2T prolong survival time | KD + KE, KD + KE + HBO2T decrease G and increase β-HB; BW: reduce. | Anti-tumor |
KD, ketogenic diet; CR, calorie-restricted; RT, radiotherapy; CT, chemotherapy; DON, 6-diazo-5-oxo-L-norleucine; RP, regular protein; LP, low- protein; WD-L, Western diet based on lard; WD-C, Western diet based on coconut oil; FD, fructose diet; NCKD, high-fat/no-carbohydrate ketogenic diet; LFD, low-fat/high-carbohydrate diet; MCD, high-fat/moderate-carbohydrate diet; NAC, N-acetylcysteine; HBO2T, hyperbaric oxygen therapy; KE, ketone ester; G, glucose; β-HB, b-hydroxybutyrate; BW, body weight.