Table 2.
Effects of perhexiline treatment in preclinical murine cancer models.
| Study | Cancer | Mouse Strain | Model | Treatment | Key Findings |
|---|---|---|---|---|---|
| Ren et al. (2015) [24] | BRCA | SCID | MDA-MB-468 xenograft, s.c. | Monotherapy PHX 400 mg/kg, intragastric, 5 days/week, 4 weeks. |
PHX significantly inhibited tumour growth, and decreased HER3 activation (pHER3). |
| Liu et al. (2016). [30] | CLL | Tcl-1Tg: p53−/− transgenic | Spontaneous CLL | Monotherapy PHX 8 mg/kg, i.p., every other day for 4 injections. |
PHX selectively eliminated CLL cells, significantly reduced leukemic burden and prolonged OS. |
| Wang et al. (2020) [32] |
CRC | BALB/c nude | HCT116, xenograft, s.c. dorsal flank | Monotherapy and combination therapy; CDDP 5 mg/kg, once/week, 4 weeks; PHX 8 mg/kg, every second day, 4 weeks. |
PHX monotherapy, and PHX and CDDP combination therapy reduced tumour progression. PHX and CDDP combination overcame resistance in CDDP-resistant cell line (HCT116/OXA). |
| CRC/GC | NSG | PDX, s.c., dorsal flank | Monotherapy and combination therapy; CDDP 5 mg/kg, once/week, 4 weeks; PHX 8 mg/kg, every second day, 4 weeks. |
PHX and CDDP monotherapy and combination therapy inhibited proliferation (Ki-67) and increased apoptosis (TUNEL). | |
| GC | BALB/c nude | HGC27 xenograft, s.c. dorsal flank | Monotherapy and combination therapy; CDDP 5 mg/kg, once/week, 4 weeks; PHX 8 mg/kg, every second day, 4 weeks. |
PHX monotherapy, and PHX and CDDP combination therapy reduced tumour progression. | |
| Kant et al. (2020) [34] | GBM | Nu/Nu nude | MES83 xenograft, s.c. (flank) and orthotopic (brain). | PHX monotherapy, 80 mg/kg, intragastric, 5 days/week, up to 24 days. | PHX accumulated in the brain. PHX significantly reduced growth of flank and orthotopic tumours, and increased overall survival. |
| Xu et al. (2018) [37] | HCC | Nu/nu nude | Hep3B, Huh7, and HepG2 xenograft, s.c.; H460 isogenic lung, s.c. |
Triple combination; PHX 30 mg/kg, i.p., daily; DPI 2 mg/kg, i.p., daily. |
Triple combination of HK2 knockdown, DPI and PHX significantly inhibited tumour growth, increased apoptosis, decreased AMPKα and phosphorylation of S6. |
| Brown et al. (2018) [36] | HCC | Liver specific inducible MYC oncogene (MYC-ON) | Spontaneous HCC | Monotherapy; PHX 8 mg/kg, i.p., 3/week, 5 weeks. |
PHX decreased incidence of HCC in NAFLD model. PHX reduced early apoptotic events in intrahepatic CD4+ T cells. |
| Xu et al. (2019) [38] | MM | NSG | OPM-2 (HK1−HK2+) and U266 (HK1+HK2+) xenografts, s.c., and P3X63Ag (HK1−HK2+), s.c. | Triple combination therapy; PHX 30 mg/kg i.p. daily; HK2-ASO1 50 mg/kg, s.c.; DPI 2 mg/kg or MET 250 mg/kg, i.p. daily. |
Triple combination of HK2-ASO1, DPI or MET, and PHX significantly inhibited tumour progression, and increased PARP-1 cleavage in OPM-2 (HK1−HK2+), but not U266 (HK1+HK2+) xenografts. Triple combination of murine HK2-ASO1, DPI or MET, and PHX significantly inhibited tumour progression in P3X63Ag (HK1−HK2+) murine MM cells, and prolonged OS. |
| Vella et al. (2015) [39] | NB | NOD-SCID (NOD.CB17-Prkdscid) | SK-N-BE(2) xenograft, s.c. | Monotherapy and combination therapy; PHX 1 or 3 mg/kg, intragastric, 5 days/week; CDDP 3 or 5 mg/kg, i.p., once/week. |
PHX monotherapy (1 or 3 mg/kg/dose) did not alter tumour growth. PHX (1 mg/kg) and cisplatin (3 mg/kg) combination reduced tumour growth. PHX (3 mg/kg) and cisplatin (5 mg/kg) combination reduced tumour growth, significantly increased progression-free survival, and inhibited cisplatin-induced increase in the NB cell differentiation marker, neurofilament 68 (NF68). |
| Rathore et al. (2021) [40] | OSS | Athymic nude | U2OS xenograft, s.c. | Monotherapy or combination therapy; PHX 8 mg/kg, intragastric, daily for 30 days; NCT-503 40 mg/kg, i.p., daily for 30 days. |
PHX monotherapy, but not NCT-503, moderately reduced tumour progression. PHX and NCT-503 combination therapy markedly reduced tumour progression resulting in sustained inhibition over 30 days. |
| Zhu et al. (2019) [33] | EOC | BALB/c nude | OVCAR (NKX2-8+/−) xenograft, i.p. | Monotherapy or combination therapy; CDDP 5 mg/kg every 3 days; PHX 3 mg/kg. |
PHX and CDDP combination therapy markedly reduced tumour progression resulting in sustained inhibition over 6 weeks, prolonged OS and induced apoptosis (TUNEL and activated caspase 3). |
| Schnell et al. (2015) [45] |
T-ALL | C57BL/6 | NOTCH1-induced murine T-ALL | Monotherapy; PHX 53.68 mg/kg. |
PHX reduced tumour burden (bone marrow cellularity and leukaemic infiltration, spleen weight and cellularity), and increased OS. |