RAGE targeted diagnostic and therapeutic interventions studied in cancer

RAGE targeted intervention/treatmentCondition/diseaseTumour pertinent effects studiedReferences
Nanoparticles
DADS-RAGE-SLN: RAGE-antibody conjugated, DADS laden SLNBreast cancerDADS-RAGE-SLN elicited substantial rise in pro-apoptotic proteins and parallel reduction in anti-apoptotic proteins with enhanced anti-tumour activity and selective toxicity in MDA-MB-231 breast cancer cells[114]
Novel nano-therapeutics targeting RAGEBreast cancerTarget specificity and potent cytotoxicity in TNBC[115]
CML-HSA conjugated, RAGE targeted multi-modal nanoparticles (64Cu-Cy5-G4-CML)Prostate cancerSufficient RAGE targeting established with 64Cu-Cy5-G4-CML in LNCaP and DU145 prostate cancer cells, mice xenografts and human samples, confirming the feasibility of RAGE-targeted cancer imaging with AGE-conjugated nanoparticles[116]
Nucleic acid-based drugs
An aptamer-based RAGE antagonistColo-rectal cancerDecreased cancer cell proliferation, migration and angiogenesis via inhibition of S100B-dependent and -independent stimulation of RAGE/NF-κB/VEGF-A signalling in HCT116 colorectal cancer cells[48]
Genetic ablation of RAGE—by shRNA and *CRISPR/Cas9 techniquesGliomaSuppression of growth, invasion and immune evasion of cancer cells by abrogation of galectin-3 and MMP9 expression, and AKT and ERK 1/2 activities in murine glioma model[117]
RAGE-specific siRNA transfectionPancreatic cancerElicited apoptotic cell death and gemcitabine-mediated cytotoxicity via suppression of PI3K/AKT/mTOR cues in both resistant and non-resistant MIA PaCa-2 pancreatic cancer cells[118]
Nanomedicines/antibody-based drugs
A monoclonal antibody (mAb; IgG 2A11)—RAGE inhibitorPancreatic cancerMitigated autophagy and enhanced the cytotoxic efficacy of gemcitabine in murine pancreatic tumours[119]
RAGE-targeted ADCEndometrial cancer (EC)RAGE over-expression in EC adversely correlated with patient survival; RAGE-ADC: 100-fold more effective in EC cells than non-malignant cells; 200-fold more cytotoxic than the drug alone; non-toxic to normal mouse model and substantial tumour growth suppression in mouse xenograft model of EC[120]
RAGE-targeted ADCOvarian and prostate cancerDemonstrated the efficacy of RAGE-ADC against high RAGE-expressing ovarian and prostate cancer cells in vitro and in vivo mice models[121]
RAGE antagonist
FPS-ZM1, a high-affinity RAGE-specific blockerBreast cancerEstablished the efficacy of FPS-ZM1 in blocking the AGEs-induced interaction between CAFs and breast cancer cells, by inhibiting RAGE; AGE-driven IL-8 rise in CAFs, promoting elicitation of invasive/malignant features in cancer cells, was inhibited via blockade of RAGE-ROS-ERK 1/2-AKT-c-Fos signal cascade[62]
Pharmacophore
3-Styrylchromone derivative: 7-methoxy-3-hydroxy-styrylchromone (a papaverine-mimetic and a novel α-glucosidase inhibitor)Colon cancer

Anti-inflammatory, anti-proliferative and anti-cancer effects in colon cancer cells via suppression of HMGB1-RAGE-ERK 1/2 signalling

Augmented pro-apoptotic Bax and caspase-3/7 expression in HCT116 cells

Individual and synergistic augmentation of the above mentioned effects with DNA damaging agents in cancer cells

[83]
Phyto-compounds
Curcumin, quercetin, withaferin A—natural phytochemicals with anti-glycation activityMany cancers including breast, colon and prostateInhibition of various molecular signalling pathways involved in RAGE-driven cues; potentiality in the prevention of diabetes-induced cancers[122]
Scutellarein—a flavone from the plant Chrysanthemum indicumColon cancerReduced cell viability and enhanced apoptosis via rise in cdc4 and fall in RAGE protein expression, coupled with an upsurge in RAGE ubiquitination in colon cancer cells[123]
Quercetin—a flavonoid and AGE inhibitorPancreatic cancerInduced cell cycle arrest, apoptosis and gemcitabine sensitivity via attenuation of RAGE expression in resistant MIA PaCa-2 pancreatic cancer cells[118]
Papaverine—an opiate alkaloidFibrosarcoma

Elicited considerable suppression of RAGE-reliant cell proliferation, invasion and migration, RAGE-reliant NF-κB activation and RAGE expression in HT1080 human fibrosarcoma cells

Identified as a potent RAGE inhibitor by optimized-peptide strategy of transformation to small molecules

[124]
Clinical trials involving AGEs-RAGE axis (with implications in cancer)
Azeliragon—oral RAGE inhibitor, in combination with dexamethasone, a corticosteroid (phase I trial), in patients with malignant gliomaGlioma and glioblastoma

To mitigate inflammation, thereby reducing the side effects of chemotherapy

To inhibit RAGE pathway, thereby reducing cerebral edema post-surgery in patients with glioblastoma

To decrease the dose of dexamethasone required by concurrent administration with azeliragon

[125]
Azeliragon or TTP488, formulated as a 5 mg hard gelatin capsule (phase I and II trials), in patients with refractory pancreatic cancerMetastatic pancreatic cancerTo assess the safety and efficacy of azeliragon in patients resistant to first-line treatment of metastatic pancreatic cancer[126]
Azeliragon or TTP488 (phase I and II trials), in women with early breast cancerNon-metastatic breast cancer and cancer-related cognitive decline

To evaluate the impact of azeliragon in attenuation of cardiac toxicity from chemotherapy in women with early breast cancer

To target RAGE pathway for subsequent attenuation of anthracycline-associated cardiotoxicity and chemotherapy-associated cognitive decline

To assess the safety of azeliragon when given along with chemotherapy

[127]
CX-01 in combination with azacitidine (phase I trial), in patients with MDS and AMLMDS and AML

To treat relapsed or resistant MDS and AML

To enhance the cytotoxic effects of azacitidine on MDS and AML hematopoietic stem cells by impeding the interaction of HMGB1-RAGE and HMGB1-TLR4, and chemokine CXCR4 axis

[128]
Grape seed extract (oligomeric procyanidin complex) in combination with vitamin D (phase I trial), in patients with solid cancersSolid cancers (gastrointestinal, lung, breast, prostate, lymphoma and cancer of the lymph nodes)

To identify plant-based compounds for safe reduction of systemic inflammation in patients with advanced cancer

To curb various inflammatory markers including AGEs and sRAGE in the patients

[129]
Vitamin D—50,000 IU D3 (phase IV trial), in women with PCOSPolycystic ovarian syndrome; vitamin D deficiency

To evaluate the beneficial clinical impact of vitamin D treatment on PCOS with impaired metabolic concomitance

Vitamin D augmented serum sRAGE levels in PCOS afflicted women

[130]
DPP-IV inhibitors (sitagliptin) in patients with type 2 diabetes mellitusDiabetes mellitus

To evaluate the impact of DPP-IV inhibitors on cancer frequency and the underlying AGE-RAGE cues in Japanese patients with diabetes

Might work as a cancer protective agent in diabetes by blocking the AGE-RAGE axis

[131]
Relationship between dietary AGEs, inflammation and oxidative stress in breast cancer patientsBreast cancer

To compare dietary AGE intake and serum AGE levels in healthy individuals and in patients with breast cancer

To assess the levels of serum carboxymethyl lysine (AGEs), RAGE and sRAGE in the patients

[132]
A low AGE dietary intervention in breast cancer survivorsBreast cancerTo assess the effect of a low AGE diet on weight (BMI), known (IL-6 and CRP) and novel (AGE and RAGE) prognostic biomarkers, and hence post-cancer prognosis[133]

DADS: diallyl-disulphide; SLN: solid-lipid nanoparticle; Cy5: Cyanine5 dye; shRNA: short hairpin RNA; CRISPR: clustered regularly interspaced short palindromic repeats; siRNA: small RNAi; ADC: antibody-drug conjugate; Bax: Bcl-2 associated X protein; MDS: myelo-dysplastic syndrome; AML: acute myeloid leukemia; PCOS: polycystic ovary syndrome; DPP-IV: dipeptidyl peptidase 4; BMI: body mass index; CRP: c-reactive protein; *CRISPR/Cas9: a unique genome editing technology, which aids in editing specific parts of the genome by removing, adding or altering sections of the DNA sequence