Bioenergetic alteration in gastrointestinal cancers: The good, the bad and the ugly

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.