Table 2.

Therapeutic targeting of RAGE and its ligands with implications in cancer treatment

RAGE/RAGE ligands as Therapeutic targets	Cancer model studied	Results observed	Functional effects/possible outcomes	References
A synergistic cytotoxic formulation of polyphenols - plumbagin and diosmin (anti-glycation or anti-AGE activity coupled with cancer cytotoxicity)	Human breast adenocarcinoma cell line-MDA-MB-231	Enhanced synergistic cytotoxic efficacy of the formulation comprising of Diosmin, which inhibits AGE formation considerably, even under supra- physiological concentrations of glycating sugars	Prevention and treatment of breast cancers	[248] - Patent
A composition containing an anti-AGE antibody (anti-carboxymethyl lysine monoclonal antibody)	Murine breast cancer tumour model	Reduction in cancer metastases by administration of an anti-carboxymethyl lysine monoclonal antibody	Prevention and treatment of cancer and metastasis	[249] - Patent
A cell binding agent with RAGE bindingability, linked to an anti-cancer drug	Endometrial & Ovarian cancer cell lines	Increase in efficacy and potency of the cytotoxic drug by coupling it with a RAGE binding agent	Treatment of gynaecological cancers	[250] - Patent
Pharmacological manipulation of AGEs using Metformin & a derivative of grape seed extract	Metastatic Breast cancer patients	Ongoing clinical trials	Analysis of the effects of AGE levels on ER + ve breast cancer and pharmacological intervention	[251] - Clinical trial
Pharmacological manipulation of AGEs using Metformin & a derivative of grape seed extract	Prostate cancer patients	Ongoing clinical trials	Analysis of the effects of AGE levels on prostate cancer and pharmacological intervention	[252] - Clinical trial
RAGE SiRNA	Human breast cancer cell lines MCF-7, Sk-Br-3 & MDA-MB-231	RAGE SiRNA inhibited cell proliferation, expression of NF-ķB, cyclin D1 and PCNA in all subtypes of breast cancer, with the most significant growth reduction in MDA-MB-231	Suppression of breast cancer growth, more pronounced in the aggressive type; RAGE & RAGE ligands can be potential therapeutic candidates for breast cancer management and therapy	[93]
S100B inhibitor—pentamidine (anti-protozoal agent)	Primary malignant Melanoma cells C8146A; C6 glioma cells	Binds S100B, inhibits S100B-p53 interaction & up regulates p53 expression; attenuated proliferation and migration of cancer cells	Inhibitors of S100-p53 interaction offer novel approach for treatment of glioma & melanoma	[108, 172]
S100A4 inhibitor—sulindac & calcimycin (NSAID)	Human colon cancer xenograft mouse model	Inhibited metastasis by interfering with β-catenin signalling, hence inhibiting S100A4	Modulators of β-catenin signalling might act as anti-metastatic agents	[146, 147]
S100B inhibitor—bidentate helical peptide based on TRTK-12	Melanoma xenograft mouse model and cell lines-Sk-Mel 5 and B16F10 cells	Binds S100B and causes mitigated tumour growth and rapid apoptosis in melanoma cells via inhibition of Akt and STAT-3 phosphorylation	Complete inhibition of melanoma growth in mouse model with no significant toxicity	[173]
S100B inhibitor—tasquinimod (quinoline-3-carboxamide derivative)	Tumour bearing mice & Metastatic castration-resistant prostate cancer patients	Block the interaction of S100A9 with RAGE and TLR4; down regulation of VEGF & CXCR4; Improves progression-free survival and reduces tumour growth in prostate cancer patients.	Effective control of metastases in prostate cancer patients	[174, 175]
Peptibody to S100A8 & S100A9	Murine cancer models (thymoma)	Resulted in depletion of myeloid derived suppressor cells (MDSC) & tumour regression via blockade of S100 Protein-MDSC interaction	Potential therapeutic candidate for curbing immune evasion by tumours-an emerging hallmark of cancer;S100A8/A9—diagnostic biomarker in renal cell carcinoma	[176, 177]
Antibodies to S100P- 2H8	Pancreatic carcinoma BxPC3 cell line & murine tumour model	Diminished tumour growth & metastasis; increased the sensitivity of tumour cells to gemcitabine	Therapeutic target for Pancreatic cancer; diagnostic biomarker for cancers in tissue & plasma of subjects	[90, 178]
Antibodies to S100A4- 5C3	Pancreatic MiaPACA-2 cell line and mouse xenograft model	Reduced cell migration, tumour growth & angiogenesis	Extracellular S100A4 inhibition for treatment of cancer & metastasis; S100A4—therapeutic target & prognostic biomarker in cancer	[110]
Cromolyn and 5-methyl Cromolyn Anti-histamine drug	Mice bearing syngeneic pancreatic ductal carcinoma (PDAC)	Disrupt S100P-RAGE interaction; reduced NF-ķB activity; reduction in both tumour growth & metastasis; improved efficacy of gemcitabine in PDAC	Treatment of pancreatic cancer in combination with gemcitabine	[179, 180]
HMGB1 inhibitor—methotrexate, folic acid antagonist	Murine macrophage- like cells (RAW 264.7)	Binds HMGB1 in RAGE binding region, blocks HMGB1/RAGE interaction and abrogates TNF-α release and mitogenic activity induced upon their interaction (both in vitro and in vivo)	Methotrexate an anti-folate drug, exhibits anti-inflammatory effect also as a HMGB1 inhibitor	[181]
HMGB1 inhibitor nifedipine, a calcium channel blocker	Mouse oral squamous carcinoma cell line SCC7	Impeding RAGE-HMGB1 interaction and migration in SCC7 cells by Nifedipine	Inhibition of tumour metastases	[112]
AGE inhibitor Nifedipine	Human renal tubular epithelial cells	Inhibition of AGE mediated increase in expression of RAGE, ICAM-1, TGF-β, ROS generation & stimulation of NF-ķB followed by nifedipine induced PPAR-γ activation in tubular cells	Anti-oxidative and anti- inflammatory agent against AGEs and RAGE expression	[182]
HMGB1 inhibitor - Vector with shRNA targeting HMGB1	Cancer cell lines and mice xenograft tumour models of ovarian, liver & bladder urothelial cancers	Suppression of proliferation, invasion & metastasis of cancers; via diminished expression of cyclin D1, PCNA, Bcl-2, MMP-2 &-9, p-Akt, Ki-67, NF-ķB and VEGF-C.	HMGB1- new therapeutic target for the treatment of ovarian, liver and bladder urothelial cancers	[183–185]
HMGB1 inhibitor - Ethyl pyruvate, anti-inflammatory agent	Cancer cell lines and mice xenograft tumour models of gastric, gall bladder, pancreatic, hepatocellular & mesothelioma	Abrogated HMGB1 release; inhibition of proliferation, migration, angiogenesis and induction of apoptosis, via upregulation of Bax, p53 and mitigated HMGB1, RAGE, Akt, p-Akt, Ki-67, MMP-9 expression, NF-ķB activation; Suppressed tumour growth & metastasis	HMGB1- as potential therapeutic target for treatment of tumour progression & metastasis of various cancers	[158, 186–188]
HMGB1 inhibitor—epigallocatechin gallate (EGCG), a polyphenol	Murine macrophage RAW264.7 cells; Human colorectal cancer cells- HCT-116, SW-480; Syngeneic mouse model.	Inhibition of HMGB1 release; exhibited strong anti-proliferative effects; potential chemo-preventive efficacy; Induced apoptosis via suppression of β-catenin signalling in head and neck cancers	Synergizes with common anti-cancer drugs, suitable as adjuvant in chemotherapy	[189–191]
HMGB1 inhibitor—Glycyrrhizin (GL), natural anti-inflammatory and anti-viral triterpene; triterpenoid saponin glycoside of glycyrrhizic acid	Mouse 3T3 fibroblasts Melanoma cell line B16F10 and mice bearing melanoma tumours	Binds directly to HMGB1, weak inhibition on its intranuclear DNA binding activity; inhibits HMGB1 mediated inflammation, proliferation, migration, angiogenesis & tumour regrowth caused by anti-cancer drugs inducing necrotic cell death like CAMEL peptide	By inhibiting HMGB1 release from necrotic cells, Glycyrrhizin favours improved efficacy of anti-cancer drugs causing necrotic cell death and serves to prevent tumour relapse	[192, 193]
AGE, RAGE, and HMGB1 inhibitor—quercetin, a flavonoid	Human breast adenocarcinoma cell line- MCF-7	Inhibition of (a) AGE formation, (b) expression of RAGE & HMGB1, (c) NF-ķB stimulation and (d) promotion of cancer cell death	Prevention and treatment of cancers	[194, 195]
AGE, HMGB1 inhibitor - curcumin	Hepatic stellate cells human umbilical vein endothelial cells cancer cells and mice tumour models	Blockade of AGE induced expression of RAGE by elevated PPARγ levels and mitigated oxidative stress inhibition of inflammation and HMGB1release; downregulation of cell surface receptor of HMGB1. chemo-sensitization of anti-cancer drugs like 5-fluorouracil and regulation of multiple signalling pathways involved in survival, growth, angiogenesis and metastases of cancers.	Indicative of the potential implication of curcumin as AGE, RAGE and HMGB1 inhibitor for the treatment of cancers.	[196, 197] [198, 199] [200, 201]