Table 1 Alleviation of cancer metastasis using metabolic enzyme inhibitors.

Glycolysis inhibitors

Lonidamine (LND),

Mitochondria-targeted lonidamine (Mito-LND),

2-Deoxyglucose (2-DG)

HK1, HK2

LND/Mito-LND induces ROS and autophagy to block lung cancer migration amd invasion. Mito-LND inhibits p-P70S6K and p-AKT to suppress EMT. 2-DG abrogates NQO1/PKLRdependent glycolysis and tumor metastasis by reversing EMT.

Lonidamine

(Phase II/III);

2-deoxyglucose

(Phase I/II)

NCT00435448

NCT00096707

NCT00188929

[111, 146, 147]

3-Bromopyruvate (3-BrPA)

GAPDH

3-BrPA inhibits GAPDH, acetyl-CoA production and attenuates NQ01/ PKLR signaling axis-enhanced tumor glycolysis and metastasis via EMT.

N.A.

N.A.

[111]

3PO,

PFK-158 (3PO derivative)

PFKFB3

3PO treatment leads to PFKFB3 inactivation and lowered lactate levels. Blockage of glycolysis by targeting PFKFB3 could suppress the migration and invasion of HNSCC cells and reduce growth of both primary and metastatic melanoma tumors.

ACT-PFK-158

(Phase I)

NCT02044861

[116,117,118]

Dexamethasone

G6PC

Dexamethasone restores gluconeogenesis and inhibits HCC growth and angiogenesis by enhancing G6PC and PEPCK expression.

Phase I/II/III

NCT00695201

NCT00403065

NCT00316927

NCT00176293

[138]

Chlorogenic acid,

AD4-015

G6PT

G6PT blockers represses tumor metastasis by suppressing the expression of MMP-2 and MMP-9.

Chlorogenic acid

(Phase I/II/III)

NCT03751592NCT02245204NCT02728349NCT03758014

[139, 140]

TCA cycle inhibitors:

AG-120 (Ivosidenib),

AG-881,

AGI-5198,

AGI-5027

Mutant IDH1

IDH1 inhibitors suppressed 2-HG levels in IDH1-mutant cells. IDH1 inhibtors inhibited SNAIL-dependent EMT and invasive ability of IDH1-mutant cells.

AG-120

(Approved for AML)

AG-881

(Phase I)

NCT02073994NCT02989857NCT02481154

[125, 148]

AG-221 (Enasidenib),

AG-881,

AGI-6780

Mutant IDH2

IDH2 inhibitors suppressed 2-HG production in IDH2-mutant cells to inhibit liver progenitor cell expansion, development of premalignant biliary lesions, and progression to metastatic IHCC.

AG-221

(Approved for AML; Phase I/II)

NCT02273739NCT03515512NCT02481154

[125, 149, 150]

Lipid metabolism inhibitors:

Omeprazole

FASN

Omeprazole significantly decreased cancer cell invasion and metastasis to the lung and the expression of at least two prometastatic genes, MMP-9 and CXCR4.

N.A.

N.A.

[128, 151]

Cholesterol metabolism inhibitors:

N.A.

Simvastatin,

Pravastatin

HMGCR

Statins inhibit cholesterol biosynthesis and protein prenylyation. Pravastatin treatment greatly reduced the occurrence and extent of spontaneous lung metastasis by decrease the expression of several MMPs including MMP-2, pro-MMP-2, TIMP-2, MMP-14, and MMP-9.

Simvastatin

(Phase II/III);

Pravastatin

(Phase II/III)

NCT03324425

NCT01038154

NCT00433498

NCT01418729

[60, 129, 152]

SAM cycle inhibitors:

DZNep,

Adenosine dialdehyde

SAHH

DZNep and adenosine dialdehyde increased SAH-to-SAM ratio and blocked EZH2-mediated H3K4me3 and transcription of SNAIL and PRC2, leading to reversal of EMT.

N.A.

N.A.

[131, 132]

Nucleotide metabolism inhibitors:

MY-5445,

Sildenafil,

Tadalafil

PDE5

Accumulation of cGMP by PDE5 inhibition upregulates cAMP-dependent PKA activity resulting in a reduction of CSCs involved in metastasis and resistance development.

Sildenafil

(Phase I/II/III);

Tadalafil

(Phase II)

NCT02466802

NCT01817751NCT00142506

[90]