Table 1.
List of metabolic pathway drugs which were evaluated clinically.
| Drug | Target molecule | Mode of action in different cancer types |
|---|---|---|
| AZD3965 AR-C155858 |
MCT1 | Inhibition of lactate transporter and glycolysis in CRC (235) and LC (236). |
| WZB117 Silibinin Cytochalasin B Fasentin, phloretin, STF-3, Dapagliflozin |
GLUT SGLT |
Downregulates GLUT1 expression in CRC (235), Inhibits glucose uptake in cells preferentially expressing GLUT1 or GLUT4 and inhibits active transport of glucose into cells by SGLT1 and SGLT2 in LC (382–385), Inhibit glucose reabsorption in the kidney in BC (386) |
| 2-DG Lonidamine Bromopyruvate |
HK | Sensitizes CRC cells to TRAIL-induced apoptosis (310). Inhibits glycolysis in hypoxic cancer cells and inhibits mitochondrial pyruvate oxidation in BC (302) and LC (302, 309, 387). |
| Metformin, Mito-Metformin |
Mitochondrial electron transporter complex 1 | AMPK activation, PKM2 inhibition, and ATP depletion in CRC (388, 389) Inactivates phosphorylation of the E1 alpha-subunit of PDC and inhibits alpha-ketoglutarate dehydrogenase in BC (390). |
| Dichloroacetate AZD7545 |
PDK | Fostering oxidative phosphorylation in BC (391). Increases oxidative phosphorylation, thereby increasing Krebs cycle intermediate concentration in LC (392, 393) |
| CPI-613 ME-344 |
PDH | Inactivate phosphorylation of the E1 alpha-subunit of PDC; and inhibits alpha-ketoglutarate dehydrogenase and decreases mitochondrial ATP production in BC (394, 395). |
| Indoximod, Epacadostat, BMS-986205, KHK2455, Epacadostat, INCB001158 |
Indoleamine 2,3 dioxygenase (IDO1) |
Increases tryptophan concentration and activates T cell-mediated immunity In BC (106, 396). Induces host immune system mainly T-cell mediated response in BLC (397, 398). |
| 3PO PFK3 PFK158 |
PFKFB3 | Reduces glucose uptake and ATP production in LC (399, 400). |
| Bromop-yruvate | GAPDH | Inhibit glycolysis, thereby suppressing the production of ATP and inducing cell death in LC (401, 402). |
| Shikonin | PKM2 | Inhibits cell aerobic glycolysis in LC (403). |
| FX11 Quinoline-3-sulfonamide Oxamate GNE-140 PSTMB |
LDH | Inhibits the ability of LDH to convert pyruvate into lactate in LC (237, 404–407). |
| Enasidenib Ivosedinib GSK864 GSK321 |
IDH | Potent IDH1 inhibitor used in LC and approved in relapsed/refractory IDH2 mutant AML (408, 409). |
| Lonidamine SiRNA |
VDAC1 | Induces apoptosis by rewiring tumor cell metabolism, reduces cancer stem cells, and induces differentiation in LC (410, 411). |
| Simvastatin | 3-hydroxy-3-methylglutaryl coenzyme A reductase | Inhibit conversion of HMG-CoA to mevalonate, the rate limiting step of steroidogenesis in PC (412). |
| INCB001158 | Arginase | Induces proliferation of cytotoxic T-cells and natural killer (NK) cells that kill the tumor cells In BLC (413). |
| L-NMMA | Nitric oxide synthase | Inhibits NOS in BLC (397). |
| ADI-PEG20 | Arginine deiminase | Starves tumor cells by arginine depletion in BC (414). |
| CB-839 | Glutaminase | Inhibits hydrolysis of glutamine in BC (415) |
| DON, BPTES, Acivicin, Azaserine | GLS1 | Inhibits Gln metabolism in CRC (416, 417) and reduces glucose uptake in PC (418). |
| L-aspartate + Rapamycin | ASNs, mTOR | Inhibits asparagine biosynthesis in CRC (112) |
| TVB-3166, TVB-2640, Omeprazole, Conjugated Linoleic Acid (CLA), Orlistat, C75, cerulenin, and C93, 3-aryl-4 hydroxyquinoline-2(1H)-one derivatives, GlaxoSmithKline produced GSK837149 |
FASN | Inhibits de novo palmitate synthesis in CRC (343). Supresses denovo lipogenesis in BC (82, 344, 345). Form a covalent bond with the enzyme FASN and inhibits its function, thereby inhibiting lipogenesis in PC (419–421). |
| SB-204990 and simvastatin | ATP citrate lyase |
RNA interference and inhibits proliferation and survival of tumor cells in PC (422). |
| Ficlatuzumab | FGF | Inhibits glucose uptake and blocks HGF activity in CRC (106). |
| RO5126766 | RAF/MEK | Downregulates GLUT1 expression in CRC (133). |
| Metformin, 5-aminoimidazole-4-carboxamide-1-b-ribofuranoside (AICAR), A-769662, PT1, and OSU-53 |
AMPK | Reduces the expression of gluconeogenic enzymes, decreases AMP/ATP ratio, and activates AMPK in PC (421, 423–425). |
| Mercaptopurine | Hypoxanthine–guanine phosphoribosyltransferase, amidophosphoribosyltransferase, Inosine-5'-monophosphate dehydrogenase | Acute lymphatic leukemia (347, 348) |
| Fluorouracil | Thymidylate synthase | Colon, esophageal, gastric, rectum, breast, biliary tract, stomach, head and neck, cervical, pancreas and renal cell cancer (302, 359) |
| Thioguanine Carboplatin Oxaliplatin |
DNA | Acute non-lymphocytic leukemias (347, 350) Testicular tumors, ovarian tumors, and bladder cancer CRC (426) |
| Gemcitabine | Ribonucleoside-diphosphate reductase, thymidylate synthase, UMP-CMP kinase | Ovarian, lung, breast, and pancreas cancer (361, 362) |
| Pemetrexed | Thymidylate synthase, Bifunctional purine biosynthesis protein PURH, Dihydrofolate reductase, Trifunctional purine biosynthetic protein adenosine 3 | Mesothelioma, NSCLC (427) |