Table 4.
Promising novel bioenergetics targeting drugs for gastrointestinal cancer therapy
| Inhibitor | Target | GI model | Consequence | Clinical trial | Ref. |
| Targeting glucose transportation | |||||
| Genistein | HIF1A, GLUT1 and HK2 | GC, ESCA, HCC, CCA, PCA, and CRC cell lines | Inhibited cancer cell proliferation, cell cycle progression, migration, invasion, angiogenesis, stemness, spheroid formation, EMT, and promoted apoptosis | CRC patient, phase I/II (NCT10985763), and PAC patient, phase I/II (NCT02336087, NCT00376948 and NCT00882765) | [131-140] |
| Apigenin | HIF1A, GLUT1 and HK2 | GC, ESCA, HCC, CCA, PCA, and CRC cell lines | Inhibited cancer cell proliferation, colony-forming, cell cycle progression, migration, invasion, angiogenesis, and induced apoptosis | CRC patient, phase II (NCT00609310) | [141-146] |
| WZB117 | GLUT1 | HCC, CCA, PAC, and CRC cell lines, and xenograft models | Reduced glucose uptake, inhibits cell proliferation, and invasion, and enhanced chemosensitivity | None in GI cancers | [148-151] |
| STF-31 | GLUT1 | PAC and CRC cell lines, and xenograft model | Reduced cancer stem cell properties, such as stemness, and inhibits cell proliferation, viability, and tumor growth | None in GI cancers | [152,153] |
| BAY-876 | GLUT1 | ESCA, PCA, and CRC cell lines, and xenograft mouse models | Reduced cancer cell proliferation, tumor growth, and glucose uptake, while also increased chemosensitivity | None in GI cancers | [154-156] |
| Targeting glucose metabolism | |||||
| 2-Deoxy-D-glucose (2-DG) | HK2 | GC, ESCA, HCC, PAC and CRC cell lines, xenograft models, and rat HCC and hamster PAC models | Inhibited cell proliferation, tumor growth, and promoted chemosensitivity | PAC patient, phase I (NCT00096707) | [159-165] |
| 3-Bromopyruvate (3-BrPA) | HK2 | GC, HCC, PCA, and CRC cell lines, and rabbit, transgenic mouse and xenograft mouse models | Inhibited cellular ATP generation, cell proliferation, and tumor growth. Also induced mitochondrial depolarization, reduced animal serum VEGF levels, and promoted cell death and chemosensitivity | HCC patient, case report[170] | [167-170] |
| Lonidamine (LND) | HK2 | HCC, CCA, and CRC cell lines, hamster CCA model, and GC and CRC patients | Inhibited cell proliferation, migration, invasion, and cell cycle progression. Increased chemosensitivity, patient overall response rate, and duration of disease progression in GC patients. However, was ineffective and toxic in advanced CRC patients | GC patient, phase II[172], CRC patients, phase II[176,177] | [174-179] |
| 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) | PFKFB3 | HCC, PAC, and CRC cell lines, and transgenic and xenograft mouse models | Inhibited glucose uptake, cell proliferation, tumor growth, angiogenesis, fibrogenesis, and promoted cell death | None in GI cancers | [182-184] |
| 1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PFK15) | PFKFB3 | GC, HCC, PAC, and CRC cell lines, xenograft models, and HCC rat model | Inhibited cell proliferation, migration, invasion, cell cycle progression, tumor growth, and enhanced cell death | None in GI cancers | [185-189] |
| 1-pyridin-4-yl-3-[7-(trifluoromethyl)-quinolin-2-yl]-prop-2-en-1-one (PFK158) | PFKFB3 | None in GI cancers | None in GI cancers | Solid tumor patients, phase I (NCT02044861) | [190] |
| Shikonin | PKM2 | GC, ESCA, HCC, CCA, PCA, and CRC cell lines, and xenograft mouse models | Inhibited cell proliferation, migration, invasion, cell cycle progression, tumor growth, and enhanced cell death | None in GI cancers | [192-197] |
| TT-232 | PKM2 | HCC, PAC, and CRC cell lines, and xenograft mouse models | Inhibited cell proliferation, tumor growth, and enhanced cell death | None in GI cancers | [198-200] |
| Targeting lactate biosynthesis | |||||
| Dichloroacetate (DCA) | PDK | GC, ESCA, HCC, PAC, and CRC cell lines, xenograft models, and B6C3F1 mice | Reduced lactate production, cell proliferation, migration, and increased chemosensitivity. Showed synergistic anti-cancer effects in HCC. However, promoted hepatocarcinogenesis in B6C3F1 mice | CRC patient, phase I (NCT00566410) | [203-207] |
| Compound 24c | LDHA | PAC cell lines, and xenograft model | Suppressed cell proliferation, colony formation, enhanced cell apoptosis, arrested cell at G2 phase, repressed xenograft growth, and re-programmed cancer metabolism, with minimal impact on mouse weight | None in GI cancers | [210] |
| 1-(Phenylseleno)-4-(Trifluoromethyl) Benzene (PSTMB) | LDHA | HCC and CRC cell lines | Inhibited cell proliferation, reduced cell viability, attenuated LDHA activity, lowered lactate levels, and induced mitochondria-mediated apoptosis | None in GI cancers | [211] |
| Oxamate | LDHA | GC, ESCA, HCC, PCA, and CRC cell lines | Suppressed LDHA activity, lactate production, cell proliferation, migration, MMP9 expression, pro-inflammatory cytokines, EMT transition, and AKT/ERK/mTOR signaling pathways, while enhanced apoptosis, senescence, protective autophagy, and metabolic rewiring | None in GI cancers | [212-218] |
| Galloflavin | LDHA | HCC, PCA, and CRC cell lines | Reduced ATPase activity and expression levels of heat shock proteins, inhibited cell proliferation, lactate production, pro-inflammatory cytokines, and EMT transition, while promoting apoptosis and senescence | None in GI cancers | [215,218-220] |
| FX11 | LDHA | HCC, PCA, and CRC cell lines, and xenograft mouse models | FX11 reduced lactate production and ATP levels, suppressed cell proliferation, migration, invasion, and xenograft tumor growth, while enhancing apoptosis. However, in a PCA patient-derived mouse xenograft model, FX11 was only effective in attenuating tumor growth in the presence of mutant TP53 | None in GI cancers | [221-225] |
| Gossypol (AT-101) or its derivatives | LDHA | GC, ESCA, HCC, PAC and CRC cell lines, GC and xenograft mouse models, and ESCA patient | Reduced cell viability, suppressed cell proliferation, migration, and tumor growth, down-regulated cancer stem cell markers CD133, Nanog, LC3, and YAP-1, enhanced apoptosis, protective autophagy. and complete response rate/prognosis | ESCA patient, phase I/II (NCT00561197) | [226-240] |
| Targeting lactate transportation | |||||
| AZD3965 | MCT1/2 | GC, ESCA, HCC, CRC cell lines | Inhibited cell proliferation and tumor growth, while increasing intracellular lactate concentration, TCA-related metabolites, mitochondrial metabolism, and chemosensitivity. Also decreased intracellular pH | None in GI cancers | [242-246] |
| AR-C155858 | MCT1/2 | GC, PAC, and CRC cell lines, and xenograft mouse models | Inhibited cell proliferation, spheroid forming ability, and tumor growth, while decreased glycolysis and increased intracellular lactate concentration, TCA-related metabolites, mitochondrial metabolism, and chemosensitivity | None in GI cancers | [247-249] |
| Targeting mitochondrial OXPHOS | |||||
| Metformin | Mitochondrial complex I | GC, ESCA, HCC, CCA, PAC, and CRC cell lines, xenograft models, and ESCA, HCC, CCA, PCA and CRC patients | Suppressed cell proliferation, migration, cell cycle progression, and tumor growth while increasing chemosensitivity and cell death. Also re-programmed the tumor immune microenvironment in ESCA patients | ESCA patient, phase II (ChiCTR-ICR-15005940), HCC patient, phase I (CTRI/2018/07/014865), CCA patient, phase Ib (NCT0249674), PCA patient, phase II (NCT01210911 and NCT01167738), and CRC patient, phase II (NCT01312467, NCT03047837, and NCT01941953) | [252-265] |
| Tamoxifen | Mitochondrial complex I | GC, ESCA, HCC, CCA, PAC and CRC cell lines, CRC murine model, and ESCA, HCC and PAC patients | Inhibited cell proliferation, tumor growth, metastasis, and increased chemosensitivity. However, no prolonged survival benefits have been observed in HCC patients, and in some cases, there may even be a higher risk of death | ESCA patient, phase I (NCT02513849), PAC patient, phase II[272-274], and HCC patient, phase III (NCT00003424) | [267-273,277] |
| IM156 | Mitochondrial complex I | GC and CRC patients | Considered tolerable in human subjects, with stable disease being the most common response. Combinatorial therapy may be necessary for improved efficacy | GC and CRC patients, phase I (NCT03272256), and PAC patient, phase Ib (NCT05497778) | [278] |
| IACS-010759 | Mitochondrial complex I | PAC cell lines, and CCA, PAC, and CRC patients | Reduced cell viability and generally well tolerated, but may induce neurotoxicity, peripheral neuropathy, and behavioral/physiological changes in mice. Increased blood lactate levels | CCA, PAC, and CRC patient, phase I (NCT03291938) | [279,280] |
| Atovaquone | Mitochondrial complex III | GC, HCC, PAC and CRC cell lines, and xenograft models | Reduced OXPHOS, oxygen consumption rate, cell viability, cell proliferation, and cell cycle progression. Inhibited tumor growth and enhanced cell death | None in GI cancers | [283-285] |
| Targeting TCA cycle | |||||
| CPI-613 | PDH and KGDHC | GC, ESCA, PAC and CRC cell lines, xenograft mouse models, and GC mouse model | Inhibited cell proliferation, cell viability, tumor growth, and metastasis, while increased cell death and chemosensitivity. In PAC patients, also increased the overall response rate | PAC patient, phase I (NCT01835041) and III (NCT03504423), HCC and CCA patients, phase I/II (NCT01766219), and CRC patients, phase I (NCT05070104 and NCT02232152) | [287-291] |
GI: Gastrointestinal; ESCA: Esophageal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; CCA: Cholangiocarcinoma; PAC: Pancreatic cancer; CRC: Colorectal cancer; LDHA: Lactate dehydrogenase subunit A; MCT1/2: Monocarboxylate transporter family 1/2; HIF1A: Hypoxia inducible factor 1A; GLUT1: Glucose transporter 1; HK2: Hexokinase 2; PFKFB3: Fructose-2,6-biphosphatase 3; PKM2: Pyruvate kinase isozyme M2; PDK: Pyruvate dehydrogenase kinase; PDH: Pyruvate dehydrogenase; KGDHC: Alpha-ketoglutarate dehydrogenase complex; EMT: Epithelial-mesenchymal transition; OXPHOS: Oxidative phosphorylation.