Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects
Abstract
:1. Introduction
2. Overview of Perhexiline
3. Perhexiline Anti-Cancer Studies and Proposed Mechanisms
3.1. Perhexiline Activates the Intrinsic Apoptotic Pathway
3.2. Perhexiline Promotes Incomplete AMP-Activated Protein Kinase (AMPK) Activated Autophagy
3.3. Perhexiline Improves Chemotherapy Efficacy
3.4. Perhexiline Improves Anti-Androgen Therapy Efficacy
3.5. Perhexiline as Part of a Metabolic Inhibitor Strategy for Cancer
4. Perhexiline: More than Just CPT Inhibition
4.1. PI3K/Akt/mTOR
4.2. ErbB3 (HER3)
4.3. FYN
4.4. HES1
5. Preclinical Studies of Perhexiline-Mediated Tumour Clearance
6. Perhexiline Modulates Tumour-Infiltrating Immune Cells
7. Clinical Feasibility of Perhexiline as an Anti-Cancer Agent
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
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Study | Cancer | Cell Lines | Key Findings |
---|---|---|---|
Ramu et al. (1984) [27] | BCL | P388 P388/ADR | Re-sensitised DOX-resistant P388/ADR to DOX. |
Foster et al. (1988) [28] | BRCA | MCF-7 MCF-7/ADR | Re-sensitised DOX-resistant MCF-7/ADR to DOX. Increased intracellular DOX accumulation. |
Balgi et al. (2009) [29] | BRCA | MCF-7 | Induced autophagy. Inhibited mTOR signalling. |
Ren et al. (2015) [24] | BRCA | MDA-MB-468 | Inhibited growth. |
SK-BR-3 | Induced HER3 internalisation and degradation. | ||
AU565 | Synergistic with lapatinib. | ||
BT474 | Overcame lapatinib induced resistance. | ||
Rodriguez-Enriquez et al. (2015) [23] | BRCA CAC CRC Lung Fibroblast | MDA-MB-231 MDA-MB-468 MCF-7 HeLa COLO205 A-549 3T3 CCD-25Lu | Inhibited growth. |
Liu et al. (2016) [30] | CLL | Primary CLL, normal lymphocytes | Inhibited growth. Induced apoptosis. Did not decrease oxygen consumption. |
Batra & Alenfall (1991) [31] | CRC | HT-29 | Inhibited growth. |
Dhakal et al. (2022) [25] | CRC Fibroblast | COLO205 HCT116 HT-29 SW480 SW620 PDO HFF | Inhibited growth. Induced apoptosis. |
Wang et al. (2020) [32] | CRC GC | HCT116 DLD-1 HGC27 MGC803 GES-1 CCD841 | Induced apoptosis associated with decreased FAO, NADPH/NADP+ ratio, and mitochondrial transmembrane potential. Increased ROS levels. Synergistic with oxaliplatin. |
Zhu et al. (2019) [33] | EOC | OVCAR3, CAOV3, OV90 | Inhibited Akt/mTOR/S6K. Increased apoptosis |
Kant et al. (2020) [34] | GBM | PN19 MES83 T98G U251 | Anti-tumoral effects of PHX were independent of CPT and FAO inhibition. |
Agren et al. (2014) [35] | HCC | HepG2 | Inhibited growth. |
Brown et al. (2018) [36] | HCC | Murine and human CD4+ T cells | Rescued fatty acid-induced apoptosis. |
Xu et al. (2018) [37] | HCC | Hep3B Huh7 | Showed effects on glycolysis, OXPHOS and FAO. Inhibited growth. Induced apoptosis. Upregulated AMPK. |
Xu et al. (2019) [38] | MM | RPMI8226 OPM2 | Decreased viability. Induced apoptosis. |
Vella et al. (2015) [39] | NB | Increased expression of NDM29 ncRNA Downregulated ABC transporter (ABCA1, ABCA12) and solute carrier (SLC7A11) expression. Synergistic with cisplatin. | |
Rathore et al. (2021) [40] | OSS | NOS1 | Did not alter oxygen consumption. Inhibited cell proliferation, induced cell deat, and reduced total RSP6 and mTOR at higher concentration. Synergistic with NCT-503. |
Ghaffari et al. (2015) [41] | PC, SCC | PC-3, A-431 | Reduced viability. |
Flaig et al. (2017) [42] | PC | 22Rv1 MDV3100-resistant LNCaP TRAMPC1 | Combination treatments synergistically reduced proliferation. |
Itkonen et al. (2017) [43] | PC | LNCaP | Increased intracellular lipid accumulation. Decreased proliferation. Induced apoptosis and incomplete autophagy. Blocked proliferation in combination with MVD-3100 or ABI. |
Nassar et al. (2020) [44] | PC | LNCaP C4-2B 22RV1 | Decreased viability of cells. Downregulated expression of cell-cycle related genes CDK4, CDK6, AURKB, CCD20, CCND1, CCNE2, and E2F1 Increased G0–G1 cells. Increased cleaved PARP levels and apoptotic cells. Synergistic with AUY922. |
Schnell et al. (2015) [45] | T-ALL | HPB-ALL DND41 JURKAT CCRF-CEM CUTLL1 RPMI8402 | Induced strong anti-leukemic responses in T-ALL cells with and without NOTCH1 mutations. Anti-leukemic in primary human T-ALL. |
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. |
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Dhakal, B.; Tomita, Y.; Drew, P.; Price, T.; Maddern, G.; Smith, E.; Fenix, K. Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects. Molecules 2023, 28, 3624. https://doi.org/10.3390/molecules28083624
Dhakal B, Tomita Y, Drew P, Price T, Maddern G, Smith E, Fenix K. Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects. Molecules. 2023; 28(8):3624. https://doi.org/10.3390/molecules28083624
Chicago/Turabian StyleDhakal, Bimala, Yoko Tomita, Paul Drew, Timothy Price, Guy Maddern, Eric Smith, and Kevin Fenix. 2023. "Perhexiline: Old Drug, New Tricks? A Summary of Its Anti-Cancer Effects" Molecules 28, no. 8: 3624. https://doi.org/10.3390/molecules28083624