Review of Drug Repositioning in Cancer Therapeutics

 

Seema B. Kharwade²*, Dipti B. Ruikar¹, Snehal S. Manekar², Nikita P. Shahane¹

¹P.R. Pote Patil College of Pharmacy, Amravati - 444604, MS, India.

²Dr. Rajendra Gode Institute of Pharmacy, Amravati - 444602, MS, India.

*Corresponding Author E-mail: seemabkharwade@gmail.com

 

 

INTRODUCTION:

Drug repositioning also known as drug repositioning, reprofiling, redirecting, switching recent concept emerged in 2004. Thor and Ashburn offered the first definition. It is the process of determining a drug's novel therapeutic usage or uses, if any for old/existing/ available drug. Drug repositioning is the practice of giving already available medications new applications outside of their intended therapeutic indications¹. Better treatment alternatives for a disease or medical condition may be provided by repurposing an existing medicine for new indications². Drug repositioning strategies come with a lot of benefits and cons, one of which is that they can assist combat the attrition that is currently occurring in the area of novel drug discovery³.

 

The original definition with concept of drug repurposing has been extended further to include active substances that failed during the clinical phase of their development either due to their toxicity or insufficient efficacy, as well as withdrawal of drug from the market because of safety profile. However, it should not include substances that have not yet been subjected to clinical investigation. Any structural modification of the drug is not covered under the concept of drug repositioning.

 

Drug repurposing is bases on two main primary scientific bases: (1) the discovery, the finding through the human genome elucidation, that some diseases share sometimes common biological targets and (2) the concept of pleiotropic drugs⁴. One of the important part of drug repurposing is complex interplay between diseases, drugs and targets with in silico approaches (data mining, machine learning, ligand based and structure-based approaches)⁵.

 

Traditional Approach:

The timeline for any new drug to go through enough number of trials including preclinical and clinical trials to obtain approval can be years, or even decades too. There are two strategies or method of drug repurposing. First one is on-target and other is off-target. In on-target drug repurposing strategy the known mechanism with pharmacological action of a drug molecule is applied to a new therapeutic indication. In this strategy, the approaches of biological target drug is same, but the disease is different⁶.

 

Fig. 1: Flow chart for showing the strategies of Drug repurposing on-target as well as off-target

 

Minoxidil (Rogaine) is one of the examples of an on-target profile. Minoxidil produces two different therapeutic effects by acting on the same target. Minoxidil has an antihypertensive vasodilator property by opening the potassium channels which leads to widening or dilation blood vessels. This pharmacological action causes increase in blood supply, oxygen and nutrients to the hair follicles and this action helps its use in the treatment of male pattern baldness (androgenic alopecia). With this Minoxidil was came in mean stream as one of the option for the treatment of hair loss and remain less potent antihypertensive⁶.

 

Several widely used prominent repurposed drugs known medications with new uses table of repurposing drugs including with chemical structure and example^4,7. Drug repurposing in oncology has the high potential to profit benefit a large number of patients by allowing them to receive novel, expiated, fast-tracked tailored treatments. Innovative phenotypic concept and omic assays, patient-specific testing, well-defined primary cancer cells novel with help of screening methods, patient-derived grafts, and machine-learning algorithms to speed up discovery could accelerate yield new drugs for multiple treatments based on the principle of polypharmacology and refined phenotyping, with tumor cell heterogeneity taken into account. Organizations will benefit when repurposed therapies demonstrate Scheme Improved efficacy, safety, and cost over standard treatment. Patients, public and private 2 presents the classical drug development pathway and drug re-purposing, described in this review. However, clinical trial efficacy remained the same.

 

Table 1: Table of repurposing drugs with chemical structure and example

Drug name with formula	Original indication	Disease name	Chemical Structure
Cycloserine C3H6N2O2	Urinary tract infection	Tuberculosis
Aspirin C9H8O4	Analgesia	Colorectal cancer antiplatelet aggregation drug
Gemcitabine C9H11F2N3O4	Antiviral	Cancer
Minoxidil C9H15N5O	Hypertension	Hair loss
Zidovudine C10H13N5O4	Cancer	AIDS
Topiramate C12H21NO8S	Epilepsy	Obesity
Thalidomide C13H10N2O4	Nausea	Leprosy and multiple myeloma
Phentolamine C17H19N3O	Dermal necrosis hypertension	Autism
Galantamine C17H21NO3	Polio and paralysis	Alzheimer
Duloxetine C18H19NOS	Depression	Stress urinary incontinence
Sunitinib C22H27FN4O2	GIST, renal cell carcinoma	Pancreatic tumors
Finasteride C23H36N2O2	Benign prostatic hyperplasia	Hair loss
Sildenafil C22H30N6O4S	Angina	Erectile dysfunction, Pulmonary arterial hypertension
Raloxifene C28H27NO4S	Osteoporosis	Breast cancer
Imatinib C29H31N7O	Chronicmyelogenous leukemia	Gastrointestinal tumors

 

Drug Repurposing Approaches:

Drug repurposing approaches included – Molecular docking, transcription signature, similarity analysis, network analysis, data mining, machine learning, knock down gene signature, retrospective studies, meta-analysis, cell culture studies, protein signature and xenografts⁷.

 

Fig. 2: Drug repurposing approaches

 

Cancer Related Drugs: Metformin:

Metformin drug to treat diabetes patients mostly type 2 diabetes patients. Metformin is a cytostatic agent, whose primary ingredient was guanidine in which Metformin found in extract of a plant root extract⁹. The use of metformin as a cytostatic cancer therapy is growing. It was noted that diabetic patients taking metformin daily had lower chances rate of breast¹⁰. The other cancers, which was further supplemented by studies showing cells from diabetic patients receiving metformin do not grow well in culture¹⁰. Metformin has shown the increasing role in cytostatic effects.

 

Metformin was introduced as a remarkable success adjunct therapy for cancers and for different types of cancers, some of which have reported. The standard recommended dose Metformin 500mg/day for the lung adenocarcinoma was recently trailed in patients of lung adenocarcinoma along with erlotinib, afatinib or Gefitinib. Addition of metformin to standard chemotherapy regimen increased the progression-free survival (PFS) by about a third; it is nearly doubled overall survival of the patient¹¹.

 

Metformin also improved PFS and OS in advanced, previously untreated non-small cell lung cancer (NSCLC). The PFS and OS for metformin-treated patients were especially improved in those with KRAS mutations. This suggests that determining molecular subgroups should be used to guide therapy in the future, especially in light of the paucity of direct KRAS inhibitors. Tumor cells have an enhanced metabolic need for glucose. Metformin might be useful in chemotherapy as it is lowering the blood glucose concentration which specifically starve tumor cells. This leads to decreased proliferation and metastasis of tumor cell¹². Normal murine mammary cells study indicated that metformin shown highest effect on hormone receptor positive luminal cells and decreased the total number of cells, progenitor capacity and DNA damage. Metformin also showed antiproliferative response in the patients of breast cancer when dose increased from 500 mg/day to 1500 by day 6¹³.

 

Thalidomide and Derivatives in Cancer:

Early morning sickness was treated with thalidomide. In 1962, it was discontinued globally following the discovery of a link between it and serious birth abnormalities. It was first used in cancer treatment to reduce inflammation. Subsequently, it demonstrated the capacity to stop certain cancer cells from proliferating. Mantle cell lymphoma, multiple myeloma, and myelodysplastic syndromes linked to the deletion 5q abnormalities are all treated with thalidomide¹⁴. By attaching to cereblon, a protein involved in limb development, it demonstrated anticancer activity¹⁵. This has been connected to the severe teratogenicity consequences of early pregnancy thalidomide use. Additionally, thalidomide specifically degrades T-cell repressors, activating them and increasing their release of IL-2. In order to combat cancer cells, this strengthens the immune system¹⁶.

 

Available Drug Repurposing Drugs:

Clinical trial efficacy, on the other hand, remains a major bottleneck for successful medication development. This, we believe, is due in part to the heterogeneity of primary tumours and metastases, as well as the variable, often subpar assays commonly used, such as 'cell death on a dish.' To improve the success rates of clinical trials, better and more informed phenotypic assays are required. Several promising approaches based on clinical symptoms, genomic and transcriptomic data, as well as databases (e.g. SIDER, PharmGKB) have been developed and new ones are quickly being introduced. Future repurposing of pharmaceuticals for numerous oncological indications will be facilitated by rapidly evolving computational approaches that combine different "-omics" and multi-network multi-layered data sets. Repurposing medications in combination with other agents has been shown to be effective.

 

Table 2: Table of Available Drug Repurposing Drugs

Drug name	Original indication	Disease name	Reference
(SymmetrelTM) Amantadine	Dopamine agonist	Parkinson disease	17
(AntabuseTM) Disulfiram	Aldehyde dehydrogenase inhibitor	Alcoholism	18,19
(StromectolTM) Ivermectin	Anthelmintic drug	Parasite infections	20
(VoltarenTM) Diclofenac	NSAID	Pain
(TagametTM) Cimetidine	Anti-histamine; H2-histamine receptor antagonist	Dyspepsia, heartburn, peptic ulcers	27,28,29
(Acetylsalicylic acid) Aspirin	Salicylate	Pain, fever	20,31,32
(EllenceTM) Epirubicin	Anthracycline	Node-positive breast cancer	33,34
(GlucophageTM)Metformin	Biguanide	Diabetes type II	35,36
(ImazalilTM) Enilconazole	Fingicide	Fungal infections	37
(CelexaTM) Citalopram	Selective serotonin reuptake inhibitor	Depression	37
(RezulinTM) Troglitazone	Thiazolidinedione	Diabetes	37

 

CONCLUSION:

We consider this review as a selective of approaches compilation, and argue how, taken together, they could bring drug repurposing to the next level of trial. Repurposing medications in conjunction with other treatments has the potential to enhance cancer patient outcomes. To be cautious, repurposing pharmaceuticals from medicine to veterinary indications might be quite useful, but it can also have detrimental environmental consequences, depending on the size of deployment: Ivermectin usage by veterinarians on farm and range animals, for example, might have unintended consequences. The drug repositioning(DR) approach resulting in to significant reduction in cost of R&D, possibilities chances of successful result, time required shorter during research and investment risk become lower, it has market demands increasing due to these beneficial outcome advantages for scientists for discovery, researchers, consumers and pharmaceutical companies, drug discovery program for almost all diseases of human due to novel approaches of accelerate the process repositioning strategy started the application.

 

AUTHOR CONTRIBUTIONS:

Approved for publication all authors listed have made a substantial, direct and intellectual contribution to the work.

 

CONFLICT OF INTEREST STATEMENT:

The review was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest as the authors declare.

 

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Received on 09.05.2022                    Modified on 03.08.2023

Accepted on 12.06.2024                   ©AJRC All right reserved