Drug Repurposing for Tooth Regeneration: The Promising Premises.

Drug repurposing which identifies new therapeutic use(s) for drugs currently in use is a brand-new avenue of research interest worldwide. It circumvents the high-end monetary and time investment usually associated with contemporary drug discoveries. In the field of dentistry, recent studies in drug repurposing focuses in attaining dentin repair or reduction of bone resorption associated with apical periodontitis. Metformin, an anti-diabetic drug has shown pro-osteogenic properties. Aspirin a known anti-inflammatory agent with anticoagulant action is found to modulate the differentiation of dental pulp cells. The significant role of glycogen synthase kinase-3 inhibitors in activating the Wnt/-beta cat signaling pathway of mesenchymal pulp stem cells may pave the way to the pharmacological treatment of dental caries in near future. It is to be noted here that further preclinical and clinical studies are warranted for the regular therapeutic use of these potential drugs in clinical dentistry. Copyright:

INTRODUCTION

Drug repurposing can also be termed as drug repositioning. It is concerned with the recognition of new pharmacological indications of existing/failed/old/investigational/already marketed/Food and Drug Administration approved drugs and their utilization in the treatment of diseases other than the drug's proposed therapeutic use. Drug repositioning mitigates the exponential cost and high failure risk and long duration of development in traditional drug discovery.[123] The two main strategies of drug repositioning are on-target and off-target. In on-target strategy, for a new therapeutic indication an established pharmacological action of a drug is applied. Here, the biological target is the same, whereas diseases are different. Whereas in the off-target profile, both targets and indications are novel.[4] There are two main methods for drug repositioning. One is an experimental method, and the other a computer simulation method. An experiment-based approach involves the screening of original drugs through experimental analysis. Computer simulation involves virtual screening of public databases using computational biology and bioinformatics/cheminformatics tools, and is based on molecular interactions between drug molecules and protein targets.[567] Since the discovery of new drugs is usually associated with high risk, high level of financial and time investment, drugs currently in the market when repurposed for dental applications also becomes an interesting arena.

METFORMIN

Metformin (N, N-dimethyl l-biguanide) is the first-line drug for type 2 diabetes treatment.[8] It has an anti-inflammatory activity besides its hypoglycemic effect.[9] It was evident from clinical trials that, topical metformin is a potential ancillary in periodontal therapy.[10] Increased infiltration of monocytes/macrophages has been observed in the progression of apical periodontitis. The significant chemokine responsible for monocyte recruitment is found to be the monocyte chemoattractant protein-1 otherwise known as C-C motif chemokine ligand-2 (CCL-2). Repressing CCL-2 expression and thereby chemotaxis of macrophages/monocytes can dampen the disease progression.[11] Enhanced activity of inducible nitric oxide synthase (NOS) is another factor in developmental apical periodontitis. Accelerated inflammation by activated macrophages results due to generation of nitric oxide by (NOS).[121314] Metformin pharmacologically modulates the iNOS/NO pathway[15] thereby attenuating the progression of apical periodontitis.[13] Metformin additionally suppresses iNOS expression induced by Lipopolysaccharide (LPS). LPS being a major virulence factor of endodontic pathogens influences the pathogenesis of apical periodontitis. Proinflammatory cytokines such as tumor necrosis factor and interleukin-1a (IL-1a) are released by the induction of macrophages by LPS. Consequently, breakdown of the extracellular matrix is triggered leading to bone resorption associated with apical periodontitis.[16] Metformin in addition mediates suppression of' LPS-induced inflammatory signaling and resultant production of inflammatory mediators through AMPK dependent and independent pathways.[17] Thus, the regulation of iNOS expression, NO production, and suppression of LPS-induced inflammatory signaling leading to suppression of monocyte recruitment, etc., makes metformin a potential agent as root canal medicament with positive effects on both monocytes and osteoblasts thus contributing toward host response modulation.

ASPIRIN

Multipotent stem cells in dental pulp are of prime importance in the regenerative capacity of pulp-dentine complex, especially in trauma or caries induced dental tissue loss.[18] Osteogenic effects when brought about by employing biomolecules, helped in achieving odontogenic differentiation of dental pulp cells (DPCs).[19] Wnt/beta-catenin signaling pathway was targeted through pharmacological approach to bring about dentine repair and in vivo dentine formation.[20] Gene expression connectivity mapping (CMap) which identifies the regulation of gene expression by small molecules,[21] specifies aspirin as a molecule which induces odontogenic differentiation. Aspirin, an anti-inflammatory agent and antiplatelet agent are a linchpin candidate for drug repurposing owing to its thoroughly represented human safety profile.[22] Aspirin induces stem cell differentiation[23] and many recent studies demonstrate its ability to regulate osteogenic differentiation of DPCs.[24] Improved osteogenic differentiation of' SHEDS and the regulation of (TERT)/Wnt/beta-catenin pathway in both in vitro and in vivo studies was demonstrated by Aspirin, even at low concentrations.[25] Reduction in levels of inflammatory cytokines IL-6 and matrix metalloproteinase-9 and induced odontogenic differentiation was brought about by Aspirin even at a concentration of 0.05 Mm evidences its regulation of odontogenic genes DMP-1 and DSPP.[26] The anti-inflammatory potential along with induction of odontogenic differentiation in DPCs, thus make Aspirin a promising agent in vital pulp therapies. Future works thus have to target on efficient delivery methods of this drug for in vivo scenarios.

GLYCOGEN SYNTHASE KINASE-3 INHIBITORS

Glycogen synthase kinase-3 (GSK3) is a protein kinase. It is concerned with the production of a vast variety of proteins in numerous pathways.[27] Targeted GSK-3 inhibition has evidenced therapeutic benefits since the pathogenesis and progression of various ailments including diabetes, obesity, cancer[28], and Alzheimer's disease are influenced by this Kinase.[2829] The activation of the Wnt pathway, retention of Rex-1, Oct-3/4, Nanog and pluripotent state-specific transcription factors and preservation of undifferentiated embryonic stem cells phenotypes are all made possible by attaining GSK-3 inhibition through 6-bromoindirubin-3'-oxime.[30] Tideglusib a GSK-3 antagonist demonstrates a tooth repair potential based on this inhibitory effect as reported recently by Neves et al.

Mode of action is thought to be activation of Wnt/§-cat signaling pathway of' pulpal mesenchymal stem cells. If reproducible in in-vivo studies, this holds a possibility of pharmacological treatment for loss of dental tissue.[20] The potential of tideglusib (or other GSK-3 molecules) in achieving regeneration of the teeth are in initial trial phases. Tivantinib is another GSK3 inhibitor which is an antiproliferative agent, currently in phase III trials for the treatment of the lung and hepatocellular carcinomas.[31] In vivo investigations aimed at delivering tivantinib adsorbed on collagen sponges into exposed pulpal lesions are being carried out currently.

CONCLUSION

Drug repurposing with a long-recorded history through serendipitous observations provides a new boulevard in developing new therapeutic approaches based upon existing/approved drugs. This drug repositioning strategy, in an era of precision and integrated medicine, thus gains significance in the field of dentistry too. To attain beneficial results through drug repositioning in dentistry, a meticulous understanding of the nuances coupled with a comprehensive approach is called for. Novel researches in drug repurposing can thus revamp the existing chemotherapeutics in dentistry and are to be emphasized both from a prognostic and economical perspective.

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Conflicts of interest

There are no conflicts of interest.