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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 1  |  Page : 33-43

Repurposing of a muscle relaxant drug thiocolchicoside as an anticancer agent


Department of Biotechnology, Progressive Education Society’s, Modern College of Arts, Science and Commerce, Ganeshkhind, Pune, Maharashtra, India

Date of Submission14-Oct-2020
Date of Decision24-Nov-2020
Date of Acceptance24-Nov-2020
Date of Web Publication16-Mar-2021

Correspondence Address:
Dr. Amrita Srivastav
Department of Biotechnology, Progressive Education Society’s, Modern College of Arts, Science and Commerce, Ganeshkhind, Pune 411053, Maharashtra.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mgmj.mgmj_87_20

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  Abstract 

Introduction: Conventional methods of drug discovery have somehow proved to be ineffective in terms of lengthy design, limited efficacy amongst multiple other reasons. Considering that “time” is an important factor in the process of drug discovery, it becomes necessary to look for newer methods. Drug repurposing can be considered as a suitable option in such scenarios; to treat cancer or diseases with rapid pathogenesis. Amongst the various types of cancer, breast cancer and more precisely triple-negative breast cancer (TNBC) has become a prevalent form. Objectives: To overcome the challenges of conventional methods, several bioinformatic tools may be used, particularly those involved in molecular docking (CASTp, Discovery Studio, AutoDock Tools, etc.). Materials and Methods: Thiocolchicoside is a semisynthetic drug that was traditionally used as an anti-inflammatory and analgesic. In this article, we repurpose thiocolchicoside to act mainly on the NF-kB pathway. RANK and RANKL are frequently detected in the oncogenic process and together they participate in cancer development through TRAF6 activating the NF-kB pathway. Molecular docking of thiocolchicoside against TRAF6-RANK can exhibit the potency of this drug against breast cancer. Results: It was observed that cell viability was decreased when different drug concentrations were used against TNBS cell lines in vitro as compared with the control sample. The cell viability observed was 100% in the control sample, 95.93% in 15.625 µM drug concentration, 62.33% in 31.25 µM, 55.56% in 62.5 µM, 53.66% in 125 µM, 44.17% in 250 µM, and 39.84% in 500 µM. Conclusion: Repurposing a drug with the help of molecular docking is an effective method of drug development that reduces the time and cost factor due to its already known safety. Molecular docking of thiocolchicoside against TRAF6-RANK exhibits its inhibitory effect, and it can be effectively used as an anticancer drug.

Keywords: Docking, repurposing, thiocolchicoside, triple-negative breast cancer


How to cite this article:
Medhi S, Narvekar S, Srivastav A. Repurposing of a muscle relaxant drug thiocolchicoside as an anticancer agent. MGM J Med Sci 2021;8:33-43

How to cite this URL:
Medhi S, Narvekar S, Srivastav A. Repurposing of a muscle relaxant drug thiocolchicoside as an anticancer agent. MGM J Med Sci [serial online] 2021 [cited 2021 Oct 21];8:33-43. Available from: http://www.mgmjms.com/text.asp?2021/8/1/33/311390




  Background Top


The process of drug discovery begins with the diagnosis of a disease, which depicts certain symptoms. A drug is a chemical or combination of chemicals or even a protein that reduces these symptoms with minimal side effects. A desirable drug should be affordable, profitable to drug companies, and have a low chance of showing drug resistance. The conventional approach of drug discovery is a time-consuming process,[1] taking about 12–15 years to be approved considering different levels of trials to be done before the drug could finally be launched in the markets. Apart from this, the expenditure on this process is a deal in billions. The safety of the drug can also be questionable. The success rate is also low through this method. Hence, it became necessary to find new ways of drug discovery. Computer-aided drug discovery (CADD) is a virtual shortcut to the drug discovery process. CADD has played an important role in discovering many available pharmaceuticals drugs that have obtained FDA approval and have reached the market.

Drug repositioning or drug repurposing is the technique of discovering alternate uses of drugs outside the scope of the medical indications for the drug or compounds that already exist.[2] The drug candidates that are chosen are usually marketed drugs or those that have failed in a clinical trial for reasons other than safety. The clinical trials conducted for these drugs are cheaper, faster, and also carry less risk than conventional drug development methods. This is possible because the safety profiles of these drugs are already known.

The rationale behind drug repositioning is based on the ability of small molecules to target distinct proteins in cells.[3] In this manner, we can track specific pathways involved in the pathogenesis of the disease detected. In this case, different pathways involved in cancer initiation or progression that may be unrelated to each other can, thus, be targeted by the same molecule. This concept is known as “polypharmacology” and it is slightly different from the traditional approach where the goal is to identify one drug solely for one target, with the purpose of high selectivity and enhanced efficacy.[4] The major aim, in this case, is also to reduce toxicity and prevent any kind of drug resistance from being developed in the individual being treated.

There are two general approaches to drug repositioning: discovering new indications for an existing drug and identifying effective drugs for a disease.[5],[6] The development of new cancer drugs is extremely costly, and there is a huge gap between the resources invested for the process of drug development and their convertibility into longer survival for patients with cancer. However, with CADD, as the data of a drug are already available, repurposing becomes easier, saving both time and money, giving hope to patients with rare cancers to be treated in time.

Molecular docking is one of the primary approaches when it comes to CADD. It is one of the most common methods and has proved to be effective with time. Different programs and software that have been developed are based on varying algorithms to perform the required molecular docking studies. The docking process involves two basic steps: (1) prediction of the ligand conformation, (2) its position and orientation within sites of the target protein. The desired outcome of molecular docking is to detect the off-target effects of existing drugs and compounds. A docking program consists of two main components: the sampling algorithm and the sampling function. The sampling algorithm generates different ligand binding modes or conformations. The scoring function ranks these conformations based on the binding energy evaluations.[7] Different docking software include DOCK, MCDOCK, Target fishing dock (TarFisDock), MEdock, DOCK6.0, AutoDock, AutoDockVina, etc.

Breast cancer is one of the most progressive types of cancer known. The increasing numbers of patients with this type of cancer are the reason for the fast and ongoing research that is being conducted in this field. Breast cancer portrays many types based on the receptors present in the cancer cells. The patients are tested for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as these are expressed by the breast cancer cells. Interestingly, the TNBC cells are ER negative, PR negative, and HER2 negative, which is one of the greatest barriers when it comes to designing drugs against these receptors. Facts state that “approximately 10–15% of breast carcinomas are known to be of the TNBC subtype, which constitutes approximately 80% of all basal-like tumors.”[8] The HER2-negative tumors are poorly differentiated and associated with a higher recurrence rate. This also shows an overall decrease in survival capacities. Hormone therapies simply do not work well in this case due to the already mentioned absence of the three receptors. Endocrine therapy or trastuzumab (Herceptin) does not benefit women with TNBC. Currently, there is no preferred standard form of chemotherapy for triple-negative breast cancer. TNBC is usually treated with surgery, radiation therapy, and chemotherapy.

Thiocolchicoside is a semisynthetic derivative of colchicine that is a naturally occurring anti-inflammatory glycoside.[9] This originates from the flower seeds of Superba gloriosa.[10] It has been in use as a skeletal muscle relaxant with anti-inflammatory and analgesic effects. The previous indications for which it has been used include orthopedic, rheumatologic, and traumatic conditions. Thiocolchicoside has, hence, been considered efficient and safe for the treatment of patients with inflammation and pain. Through this article, we try to showcase the use of an innovative strategy to repurpose the clinically approved drug thiocolchicoside for cancer therapy. The anti-inflammatory effect of thiocolchicoside acts by modifying the NF- κB pathway.[11] This pathway is involved in inflammation as well as tumorigenesis.[12] NF-κB is a transcription factor present in an inactivated state in the cytoplasm and when activated it moves to the nucleus and mediates the transcription of hundreds of genes. Various factors can activate the NF-κB pathway, including tumor necrosis factor.[13] So if the NF-κB pathway can be modulated, we can stop the cell proliferation, leading to tumor growth. Hence, we can repurpose the drug thiocolchicoside against cancer.

The oncogenic events and the tumor microenvironment are the two main factors that govern an oncological process. The tumor microenvironment includes cytokines, extracellular matrix components, interactions with fibroblasts, endothelial cells, immune cells, and various specific cell types depending on the location of the cancer cells. RANKL and RANK are among these glycoproteins. They are the members of TNF and TNFR superfamilies. RANK is frequently expressed by cancer cells, in contrast with RANKL, which is frequently detected in the tumor microenvironment and together they participate in every step in cancer development.[14] Their activities are regulated by osteoprotegerin (OPG, a soluble decoy receptor) and its ligands, and by LGR4, a membrane receptor that is able to bind RANKL. RANKL works through RANK to provide proliferative and survival signals and thereby promotes the final stages of lactating mammary gland development.[15] TRAF6 plays an important role in intracellular signal transduction, as it can activate the function of NF-κB.[16] It belongs to a family of proteins that play an important role in the regulation of inflammation, antiviral responses, and apoptosis.[17] TRAF6 can also mediate the signaling from the Toll/IL-1 family, CD40, and RANK. Binding of TRAF6 to RANK activates the pathway that leads to NF-κB activation, as seen in [Figure 1]. Overexpression of TRAF6 can induce several human cancer types.[18] TRAF6 proteins can be treated as drug target proteins for differentiation therapy against cancers.[19]
Figure 1: RANK-RANKL pathway leading to NF-κB activation from KEGG pathway database

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  Data and methods Top


In silico molecular docking

Molecular docking was the main technique adopted in this study. This technique involved evaluating the binding affinities of the potential ligand molecule to the protein target. Based on this, a suitable model could be selected and the intricacies of their interactions could be established further.

Drug selection

The NCBI has a wide range of research papers and review articles from various notable journals. After reviewing the literature on drug repurposing, already repurposed drugs, and the current research based on the same lines, a suitable drug thiocolchicoside was selected. The absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of the drug were studied from the DrugBank database. The structure data file (SDF) structure of the drug was downloaded from PubChem [Figure 2]. The DrugBank database is a unique bioinformatics and cheminformatics resource that combines detailed drug data with comprehensive drug target (i.e. sequence, structure, and pathway) information. PubChem is organized as three interconnected databases: Substance, Compound, and BioAssay. Each PubChem Compound record (accession CID) has a web page called a “Compound Summary” that recaps all information known about a particular chemical.
Figure 2: Three-dimensional structure of the drug; prepared for docking

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Target protein selection

RANK–RANKL signaling plays an important role in cancer. The pathway was studied on the KEGG pathway database. Receptor activator of NF-kB ligand (RANKL) binds to RANK and activates this NF-κB pathway. After reading the paper published in the British Journal of Pharmacology, it is suggested that thiocolchicoside suppressed the osteoclastogenesis induced by RANKL, and by breast cancer and multiple myeloma cells; the manuscript published in Cancer Prev Res suggested that thiocolchicoside exhibited the anticancer the effect through downregulation of the NF-κB pathway and its regulated gene products linked to cancer, and the TRAF6-RANK protein complex was selected as the target protein for docking while hypothesizing that if the drug binds to RANK it may stop the further pathway. The TRAF6-RANK complex protein structure was downloaded from the Protein Data Bank (PDB) in PDB format [Figure 3].
Figure 3: Target protein TRAF6-RANK complex on RCSB PDB, ID 1LB5

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Prediction of binding sites

The binding sites of the protein were predicted by using CASTp and Discovery studio. CASTp is a server that gives us the pockets present on the protein surfaces and voids buried in the interior of the proteins. We can see the binding sites of the receptor predicted by using CASTp in [Figure 4].
Figure 4: Binding sites of the receptor predicted by using CASTp

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Docking preparation

The drug was cleaned and converted into a 3D format by using MarvinView. Marvin is a toolkit by ChemAxon that is built to draw, edit, publish, render, import, and export chemical structures as well as to convert between various chemical and graphical file formats. This 3D format was saved as Mol2 format. The protein structure was opened in the Discovery studio. It was cleaned; the water molecules, heteroatoms, and the actual bound ligand were deleted.

Docking procedure

For starting the process of docking, AutoDock was used. The ligand was opened, and then the root of this ligand was detected by using the torsion tree option. Thereafter, we can set the number of torsions that are allowed on this ligand, determining the degree of rotation at the binding molecule. We can further edit this molecule and add the polar hydrogen bonds to this molecule. For preparing the binding site, we use the grid to fit into the region where binding needs to occur. This site is also where the original ligand existed, which had now been cleaned. For executing the commands so that docking occurs, we can use AutoDock Tools and select the Lamarckian output method. Alternatively, this can be done by using the Command prompt. Using these methods, we can see the model built between our ligand (drug) and the receptor (target protein). Docking analysis may be further done by using the AutoDock Tool, which includes the macromolecule option. This will show us the hydrogen bonds formed and also the binding energies of different models generated by using the program algorithm. The same result may be viewed by using Discovery Studio, where we can distinguish the bonds formed as well.

In vitro analysis

To establish the results generated in silico, the same procedure was performed in vitro. The TNBC cell line MDA-MB-231 was sourced from the National Centre for Cell Science (NCCS), Pune. For this experiment, approval from the Institutional Biosafety and Ethical Committee was obtained. The cell lines were cultured in L15 medium at the time of purchase. Eventually, they were cultured in (Dulbecco’s Modified Eagles Medium (DMEM). To acclimatize them, they were initially cultured in 50% L15 medium and 50% DMEM. The cell line was then gradually adapted to be subcultured in DMEM. Subculturing was done by using the Trypsin-EDTA dissociation method. The cells were rinsed with complete media (DMEM and FBS) thereafter and were split into two to three other flasks. The culture flasks were then stored in a CO2 incubator.

Meanwhile, the drug concentrations were prepared. The drug thiocolchicoside was used. The strength of each capsule was 4mg. The molecular weight was noted to be 563.618g/mol. Varying concentrations of this drug were made, which includes 500, 250, 125, 62.5, 31.25, and 15.625µM.

Cell counting was done before the cells were plated into the 96-well plates for MTT assay. Cell counting was done by using a hemocytometer and trypan blue. The hemocytometer was cleaned, dried, and assembled with a coverslip. A small amount of cell suspension was added along with trypan blue in a 1:1 ratio. This was transferred to the edge of the counting chambers by using capillary action. The hemocytometer was placed under an inverted microscope, and the cells were viewed at 100× magnification. The quadrants were focused on, and the numbers of cells in each section were recorded. The average number of cells were taken and multiplied by the dilution factor.

Twenty thousand cells were plated per well in a 96-well plate. One control and six test lines were plated. The cells were incubated for 24h. After 24h, the existing medium was removed from the wells and then different concentrations of the drug were introduced in each well. The incubation period for this was around 24h, to see the effect of the drug. The next day, 10 µL of MTT reagent was added. The cells were incubated for three hours. After incubation, the purple color was visible. To this, 100 µL DMSO was added. The cells were incubated for another 30min. After this, absorbance was recorded at 570nm by using a microplate reader.


  Results Top


In this section, the results of the in silico methods and the implications that they have on the in vitro studies are exhibited. CASTp and Discovery Studio showed the possible binding sites of the protein, making it easier to understand where the ligand could bind. The binding sites after sufficient cleaning were docked by using AutoDock Tools using a suitable drug molecule. Out of all the predicted sites mentioned in the software, only two of them showed successful docking with hydrogen bonds. The final docked conformations were selected based on the binding energy and the number of hydrogen bonds between the ligand and the target protein.

For site 1, the binding energy for the ninth conformation was the lowest: −5.11 [Table 1] and [Figure 5]. This was considered because it suggests a higher efficiency of binding. Hydrogen bonds were formed at Leu 457, Thr 463, and Asn 467, as shown in [Figure 6]. The interactions at site 1 are seen in [Figure 7].
Table 1: RMSD table for site 1: conformation 9 with binding energy −5.11

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Figure 5: Conformation 9 of site 1

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Figure 6: Docking and interactions between the drug and protein at site 1. Hydrogen bonds were formed at Leu 457, Thr 463, and Asn 467.

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Figure 7: 2D diagram of interactions at site 1

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For site 3, the binding energy for the fifth conformation was the least but there was an unfavorable donor–donor bond. For the seventh conformation, the energy was −6.71 [Table 2] and [Figure 8]. Hydrogen bonds were formed at ILE 352 and ILE 354 [Figure 9]. The interactions are well illustrated in [Figure 10].
Table 2: RMSD table for site 3: conformation 7 with binding energy −6.71

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Figure 8: Conformation 7 of site 3

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Figure 9: Docking and interactions between the drug and protein at site 3. Hydrogen bonds were formed at ILE 352 and ILE 354

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Figure 10: 2D diagram of interactions at site 3

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After an in vitro analysis of the same analysis was conducted for the same experimental setup, the following results were seen [Figure 11]. On the basis of the results, the drug shows concentration-dependent inhibition of the growth of cancer cells [Figure 12]. The viability of the cells was found to be the least in 500 µM drug concentration, 39.84%, as compared with the control, showing 100% viability as seen in [Table 3]. As a concentration higher than 500 µM is not tried, it cannot be confirmed whether the ceiling effect is achieved with this concentration.
Figure 11: 96 micro-well plate with result 1 of MTT assay. Control—extreme left, drug concentration from 500 to 15.625 μM—left to right

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Figure 12: Cell viability percentage graph of MTT assay

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Table 3: Cell viability with respect to drug concentration

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  Discussion Top


Increasing costs, high failure rates, poor safety, and a lengthy process to develop anticancer drugs have necessitated the search for new approaches to drug discovery, out of which drug repurposing becomes a promising procedure.[20] Once the drug is designed, it has to go through preclinical trials and phases of clinical trials, which take years to approve the drug. CADD has proved to be a useful method for drug development, which has reduced the costs and time for drug discovery. The molecular docking technique predicts the binding mode as well as the extent to which the query ligand (drug) and the receptor (target protein) can bind to each other. TNBC is one of the most aggressive types of breast cancers. As hormone therapy does not benefit women with TNBC, the only option is a combination of surgery, chemotherapy, and radiation therapy. Innovative therapies such as targeted therapies and immunotherapies are prevalent but are highly expensive, so there is a high demand for the use of already clinically approved noncancer drugs, off-patent, and with known targets, as possible cancer treatments.[21] Pantziarka et al.’s Repurposing Drugs in Oncology (ReDO) project targets the potential use of licensed noncancer cures as sources of new cancer strategies. The ReDO project has used a literature-based approach to recognize licensed noncancer drugs, with published evidence of anticancer activity. At present, ReDO data consist of 268 drugs in its database (ReDO_DB).[22] Regarding this, clinical trials.gov[23] was searched for ongoing or completed clinical studies on drug repurposing and TNBC. Scientists are working to give a comprehensive overview on three parameters related to drug repurposing[24]: (1) preclinical studies: number of studies per drug and pharmacological activity; (2) clinical studies: study type, country, study period, population studies, exclusion criteria, age, follow-up, arms, treatments, and outcomes; and (3) clinicaltrials.gov: number of studies per drug. About 188 preclinical studies references,18 clinical references (25–30), and 16 references on clinical trials.gov are present to support the work of drug repurposing for TNBC.[23]

Screening the PubMed database, preclinical evidence on TNBC models (cell lines and xenograft models of TNBC) for 84 out of 268 old drugs (31.3%) present in the ReDO_DB was found.[24] Various medicines for repurposing are studied, referring to the antiproliferative, proapoptotic, and immune-stimulating effects of metformin; to the cytotoxic and antimetastatic effects of chloroquine; to the antiproliferative and anti-invasive effects of simvastatin; to the anti-inflammatory and antiangiogenic effects of acid acetylsalicylic; and to the antiangiogenic, antiproliferative, and anti-apoptotic effects of zoledronic acid.[24] The research article of Spera et al. analyzes retrospective studies on the efficacy and safety of beta-blockers (BBs) on TNBC.[25] The articles of Hagasewa et al.[26] and Ishikawa et al.[27] studied the same cohort of patients. Clinical evidence on 12 licensed drugs was found; of these drugs, 11 out of 268 (4.1%) were included in ReDO_DB. Several studies are retrospective studies,[25],[28],[29],[30] whereas some are found to be in phase II trials.[26],[27],[31] BBs seem to be the more promising drugs in the repurposing for the treatment of TNBC. Research articles showed significant benefits of these drugs in women with advanced TNBC and early primary TNBC patients treated with the combination of chemotherapy plus BBs.[25],[29],[30] The articles of Shiao et al.[32] and Williams et al.[33] showed conflicting results on aspirin. However, the studies showed a significant survival benefit in women with stage II/ III by the use of aspirin. Despite many studies trying to decipher the use of statins in breast cancer treatment,[34] the literature search on PubMed also retrieved two retrospective studies on their use in the TNBC cohort. The article of Shaitelman et al.[35] reported a nonsignificant improvement of overall survival for patients in the statin group, whereas the second study of Lacerda et al.[36] did not show any results for patients with TNBC. Other authors such as Wang et al. showed significant results on the survival of patients with TNBC treated with esomeprazole.[37]

For those drugs collected in ReDO_DB with favorable preclinical evidence or whose retrospective clinical trials were not so large to provide strong evidence, large retrospective cohort studies are needed to evaluate effectiveness. Further, as for many repurposed drugs such as BBs, they have been proven by retrospective studies to be effective in the treatment of patients with TNBC; randomized clinical trials might be important to confirm the evidence of the repurposing.

The ceiling effect of a drug refers to the dose beyond which there is no additional effect. The ceiling effect of drugs is an important factor to determine its mode of action and how potent a certain drug is for a particular disease. However, there is evidence that there is no ceiling effect seen in the concentration-effect curves, in contrast to the other dynamic effects of lysergic acid diethylamide (LSD) doses.[38] Plasma concentration monitoring of drugs is also valuable but it is often overemphasized in therapeutic decision making. For the maximum value, there must be a reliable, accurate relationship between the plasma drug concentration and drug action. Plasma concentration monitoring of individual drug agents is affected by the presence of active metabolites, optical isomers differing in their activity, and variations in protein binding.[39]

We have seen in this article that RANK-RANKL signaling is involved in cancer development. Binding of TRAF6 to RANK leads to the translocation of transcription factors, including NF-κB, and eventually to the transcription of effector genes involved in cancer development. Hence, blocking the pathway through thiocolchicoside can have a significant effect.


  Conclusion Top


The docking of the drug thiocolchicoside and the protein TRAF6-RANK complex was successfully performed by using bioinformatics tools such as Discovery Studio and AutoDock Tools. The interactions between the drug and the protein suggest that the drug can have a significant effect on the protein TRAF6-RANK, which is involved in RANK-RANKL signaling, leading to cancer development otherwise. The results obtained from the in silico methods were further confirmed by checking the effect of the drug on the TNBC cell line MDA-MB-231. The increasing concentration of the drug had a negative effect on cell growth and proliferation, leading the cells to apoptosis. Based on these results obtained from in silico molecular docking and in vitro MTT assay, it can be anticipated that thiocolchicoside is a good nomination for a drug against TNBC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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