Table 3.

Glucose transporters as target in anticancer therapy.

Methods for Inhibition of Glucose Transporters	Therapeutic Effects and Mode of Action
Inhibitors of GLUTs
(1) WZB117	(1) It inhibits cancer growth and sensitizes colon and breast cancer cells to conventional chemotherapeutics agents and radiation. It also inhibits GLUT1 and glucose transport into cancer cells, decreases the levels of intracellular ATP and glycolytic enzymes.
(2) WZB27 and WZB116	(2) These inhibitors reduce basal glucose uptake and cell proliferation, induce apoptosis, and arrest the cell cycle in G1/S phase.
(3) BAY-876	(3) This inhibitor decreases uptake of glucose by a triple-negative breast cancer cell lines.
(4) Glutor	(4) It targets GLUT1, GLUT2, and GLUT3. Glutator inhibits glucose uptake, glycolysis, and efficiency suppresses the growth of various human cancer cell lines. Dual inhibition of glutaminolysis and glycolysis has a positive therapeutic effect in the treatment of ovarian cancer, and the administration of a dual-specific inhibitor of GLUT1 and GLUT3 and the inhibitor of glutamine metabolism may synergistically inhibit cancer cell growth.
(5) Fasentin	(5) Inhibitor of GLUT1, which binds directly to GLUT1 and inhibits glucose uptake, increases apoptosis in prostate cancer, multiple myeloma cells, and acute promyelocytic leukemia cells. It sensitizes theses cancer cells to FAS ligand-death receptor signaling.
(6) Oxime-based inhibitors	(6) They bind to GLUT1, inhibiting glucose transport and cell proliferation in H1299 lung cancer cells.
(7) Polyphenols	(7) Apigenin significantly inhibits the expression of GLUT1 and enhances the chemosensitivity of laryngeal carcinoma HEp-2 cells to cisplatin, inhibiting proliferation of pancreatic cancer cells. Narigenin inhibits basal and insulin-stimulated glucose uptake, causing inhibition of proliferation of cancer cells. Resveratrol decreases expression of GLUT1 in cancer. Hespertin downregulates GLUT1 and impairs translocation of GLUT4 from intracellular compartment into the plasma membrane. Kaempferol decreases expression of GLUT1. Phloretin is a GLUT2 inhibitor, which retards tumor growth and induces apoptosis in leukemia, melanoma, and colon cancer cells, and also sensitizes cancer cells to paclitaxel. Quercetin is a GLUT2 inhibitor, causing inhibition of glucose absorption by this glucose transporter. It reduces the risk of lung cancer and other cancers. Silibinin, also known as silibin, is a GLUT4 inhibitor. Investigations of silibinin influence on prostate cancer revealed its relative safety as an anticancer agent.
(8) Adriamycin, camptothecin, and etoposide	(8) decrease of GLUT3 expression in HeLa cells, causing their deaths. They do not interact with GLUT protein directly; they are DNA-damaging anticancer agents.
(9) STF-31	(9) It was first used as selective target VHL-deficient renal cell carcinoma cells. This inhibitor inhibits cell proliferation and induces apoptosis in breast cancer cell lines, blocks glucose uptake, and/or glycolysis. It acts only on cancer cells, and does not influence normal cells. Renal cell carcinoma is rescued from the cytotoxic effects of this inhibitor if these cells express a high level of GLUT2. This inhibitor selectively kills renal cell carcinomas cells by its binding to the GLUT1.
MicroRNAs (MiRNAs)
They act as negative post-transcriptionally regulators of gene expression	MicroRNA-195-5p targeting expression of GLUT3, inhibits uptake of glucose and growth of bladder cancer cells. MicroRNA-7-5p suppresses oncogenes in the MCF-10A mammary epithelial cells. MicroRNA-125a-5p targeting expression of GLUT1, plays a role as tumor suppressor and regulator of glucose metabolism in several cancers, mainly in thyroid carcinoma.
Short hairpin RNA (shRNA)
Their role is the silencing of glucose transporters	Silencing of GLUT1 expression with an shRNA decreases uptake of glucose in a triple-negative (MDA-MB-468 and Hs578T) and in SK-BR3 cell lines, and also decreases the growth of MDA-MB-468 cells. Silencing of GLUT4 by a GLUT4 shRNA decreases glucose uptake in MCF-7 and MDA-MB-231 breast cancer cells, impairing cell proliferation and viability of these cancer cells.
Antisense cDNA
Transfection of antisense cDNA into cancer cells	This procedure reduces invasiveness of cancer cells, transfection of GLUT1 antisense cDNA reduces the level of GLUT1 mRNA and cell proliferation in human leukemia cells, decreases glucose uptake and GLUT1 mRNA level in the MKN45 gastric cancer cell line, reduces invasiveness of rhabdosarcoma and glioblastoma cell lines, decreases glucose uptake and level of GLUT1 mRNA and GLUT1 protein, as well as decreases proliferation of HEp-2 laryngeal carcinoma cells. GLUT5 knockdown by antisense oligonucleotide decreases the uptake of glucose and proliferation of MCF-7 and MDA-MB-231 breast cancer cells.
Antibodies anti-GLUT1
	This procedure inhibits the growth of head and neck squamous cell cancer cells (Cal27), induces their apoptosis, and sensitizes these cells to chemotherapy (cisplatin), inhibiting proliferation by 50% in the non-small cell lung carcinoma, and by 75% in breast cancer cell lines. In these cells, the induction of apoptosis was observed. Administration of anti-GLUT1 potentiates the antiproliferative effects of cisplatin, paclitaxel, and gefitinib.
Carbohydrate-drug conjugates (Glycoconjugates)
	Glufosfamide shows a broad spectrum of antitumor activity. After hydrolysis or glucosidase-mediated cleavage of glucose in cancer cells, the phosphoramide mustard is liberated, which is the anticancer active drug. Several glycoconjugates for GLUT targeting were synthesized, as an example of these cytotoxic molecules may be chlorambucil, methane sulfonate, paclitaxel, and others. In addition, other glucose transporters are investigated, such as GLUT2, GLUT3, and GLUT12, as carrier proteins for conjugates. Adriamycin (doxorubicin) conjugated with a glucose analogue and succinic acid is designed to target cancer cells through GLUT1. It inhibits cancer cells. However, it is effective against different solid tumors in clinical applications, and its use is limited due to systemic toxicity and multidrug resistance. Paclitaxel is widely used for the treatment of breast, ovarian, and lung carcinomas. Its clinical application is reduced due to its low water solubility. Oxiplatin is a platinum antitumor prodrug, which is commonly used as a chemotherapeutic agent. It was investigated in experiments with cancer cells, such as human colon cancer (HT29) and breast cancer (MCF-7). Its multiple side effects limit its use.
Inhibitors of SGLTs
	There are several new antidiabetic drugs that inhibit SGLTs. Dapagliflozin decreases uptake of specific SGLT tracers, Me-4FDG in mice with pancreatic cancer. Canagliflozin and dapagliflozin decrease cancer viability in the mouse xenograft model, and canagliflozin reduces tumor growth by increasing necrosis. SGLT2 inhibitors may be anticancer drugs used in pancreatic cancer. Inhibitors of SGLT1 and SGLT2 may be used in anticancer therapy in the case of prostate, ovarian, and brain cancers. Inhibition of SGLT2 may be a therapeutic target for early-stage lung adenocarcinoma (LADC). Selective targeting of SGLT2 with inhibitor canagliflozin greatly decreases tumor growth and increases survival in animal models, and patients-derived xenografts of LADC. Targeting SGLT2 in lung cancer may decrease lung cancer progression in the early stages of development.