Table 2.
Overview of the candidate drugs selected for in vitro validation.
| Drug | Approved as cancer drug | Metabolic targets (Recon 2.04) | Main metabolic targets | Non-metabolic main targets | Indication | Mode of action | Use in cancer research |
|---|---|---|---|---|---|---|---|
| Fluvastatin | No | HMGCR, CYP3A4, SLC15A1, CYP2C8, SLCO1B1, CYP2C9, CYP2C19 | HMGCR | – | Hypercholesterolemia |
HMG-CoA reductase Inhibitor |
Anti-proliferative effects in breast cancer (Garwood et al. [76]), could prevent the onset of renal cancer (Horiguchi et al. [12]), potential synergistic effects with gemcitabine (Bocci et al. [77]) and cisplatin (Taylor-Harding et al. [78]) |
| Ellagic Acid | No | CYP2E1, CA6, SQLE, CA12, CA3, CA9, CYP1A1, CA1, CA4, CA5B, CA5A, CA7, CA2, CA14 | CA6, SQLE, CA12, CA3, CA9, CA1, CA4, CA5B, CA5A, CA7, CA2, CA14 | CSNK2A1, GSK3B, PRKACA, PRKCA, PRKCB, SYK | Phytochemical abundant in fruits and vegetables | Squalene epoxidase (SQLE) inhibitor) | Apoptotic and anti-angiogenic effects in cancer cells (Losso et al. [60]) |
| Icatibant | No | ANPEP | – | BDKRB2 |
Orphan drug used for hereditary angioedema treatment (Cicardi et al. [79]) |
Alanyl Aminopeptidase protein (ANPEP) Inhibitor |
– |
| Terbinafine | No | CYP19A1, SQLE, CYP11A1, CYP2D6 | SQLE | – | Antifungal agent |
Possibly by targeting SQLE |
Demonstrated anticancer effects in vitro (Chien et al. [80]; Lee et al. [81]) |
| Tioconazole | No | CYP2E1, CYP19A1, CYP51A1, CYP3A4, CYP2C8, CYP2C19 | – | – | Antifungal agent | Inhibits the ergosterol synthesis | Desensitises cancer cells to chemotherapy (P.-F. Liu et al. [65])) |
| Lovastatin | No | HMGCR, CYP3A4, SLCO1A2, CYP2D6, CYP2C8, SLCO1B1, CYP2C9 | HMGCR | HDAC2, ITGAL, NR1I2 | Hypercholesterolemia | Mevalonate pathway and cholesterol synthesis inhibitor | Anti-proliferative properties in cancers (Agarwal et al. [82]; Martirosyan et al. [83]), |
| Gemcitabine | Yes | TYMS, CMPK1, RRM1 | TYMS, CMPK1, RRM1 | – | Pyrimidine analogue | – | Inhibits DNA replication (Noble and Goa, [84]) and has been approved for the treatment of several cancers |
| Cladribine | Yes | RRM1, RRM2, RRM2B | RRM1, RRM2, RRM2B | POLA1, POLE, POLE2, POLE3, POLE4 | Purine analogue | Ribonuclease reductase inhibitor | Used in the treatment of hairy cell leukaemia (Bryson and Sorkin, [85]) |
| Butenafine | No | SQLE | SQLE | – | Antifungal | SQLE inhibitor | Reduces cancer proliferation (Cirmena et al. [86]) |
| Cerulenin | No | FASN | FASN | – | Antifungal | FASN inhibitor | Induces apoptosis in human breast cancer (Liu et al. [87]; Thupari et al. [88]) and in A375 melanoma cell line (Ho et al. [89]). Suppression of colon cancer metastasis in mice liver (Murata et al. [90]) |
| Atovaquone | No | DHODH, CYP2C9 | – | – | Ubiquinone analogue used for malaria | DHODH inhibitor | Inhibits oxidative phosphorylation in cancer (Fiorillo et al. [61]), (Ashton et al. [91]) |
| Tamoxifen | Yes | CYP19A1 CYP1B1, EBP, CYP3A4, CYP2B6, CYP2D6, CYP2C8, ABCB11, CYP2C9 | EBP | ESR1, ESR2, GPER1, PRKCA, PRKCB, PRKCD, PRKCE, PRKCG, PRKCI, PRKCQ, PRKCZ | Anti-oestrogen | – | Developed to treat breast cancer (Buckley and Goa [92]) |
12 candidate drugs for repurposing in melanoma were selected for experimental validation. Half of the drugs are already FDA-approved as anticancer agents. Metabolic targets represent inhibited targets in the generic metabolic reconstruction Recon 2.04. The main metabolic targets in addition to non-metabolic targets were identified from the manually curated database Drug Repurposing Hub. Indication, mode of action, and use in cancer research were retrieved from Drug Bank and from literature.