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Systematic Review

A Systematic Review of Molecular Pathway Analysis of Drugs for Potential Use in Liver Cancer Treatment

1
Proteomics and Translational Research Lab, Centre for Medical Biotechnology, Amity Institute of Biotechnology, Amity University, Noida 201301, India
2
Department of Biotechnology, Manipur University, Canchipur, Imphal 795003, India
*
Authors to whom correspondence should be addressed.
Drugs Drug Candidates 2023, 2(2), 210-231; https://doi.org/10.3390/ddc2020013
Submission received: 28 January 2023 / Revised: 16 March 2023 / Accepted: 24 March 2023 / Published: 3 April 2023
(This article belongs to the Section Marketed Drugs)

Abstract

:
Liver cancer is a high mortality cancer, and its increasing prevalence is a concern worldwide. Current treatment modalities for liver cancer include chemotherapy and immunotherapy. These therapies provide symptomatic relief and help prolong the lives of patients but are not an absolute cure. In this paper we have explored an alternative approach, drug repurposing, to identify drugs for treating liver cancer. Databases like PubMed, ScienceDirect, and JSTOR were used for literature mining, and the PRISMA 2020 systemic review guidelines were followed to identify drugs that have been trialed for repurposing in liver cancer. The protein receptors and target protein classes of all the drugs were identified using the Swiss Target Prediction tool. Further, the biological interactions and pathways followed by the drugs were studied via protein interaction networks using Cytoscape. Molecular pathways such as Bile acid receptor activity, Inosine-5′-monophosphate (IMP) dehydrogenase activity, JUN kinase activity, Nitric-oxide synthase activity, and Mitogen-activated protein (MAP) kinase activity were observed to be influenced by these drugs. The fact that the genes targeted by these repurposed drugs are common with the differentially expressed genes in liver cancer is an excellent starting point to verify the current hypothesis.

1. Introduction

Worldwide, liver cancer is the second highest cause of cancer-related death and one of the few neoplasms whose incidence and mortality have been progressively growing, with the United States population experiencing the most significant risk of dying over the preceding two decades [1]. In high-risk countries like the United States, liver cancer can arise before the age of 20 years. From the year 2000, it is indicated that liver cancer remains the fifth most common malignancy in men and the eighth in women worldwide [2].
Liver cancer is a broad collection of malignant tumors that range from hepatocellular carcinoma, i.e., HCC, and intrahepatic cholangiocarcinoma, i.e., iCCA, through mixed hepatocellular-cholangiocarcinoma (HCC-CCA), fibrolamellar HCC, and the paediatric neoplasm hepatoblastoma [3,4]. Primary liver cancer is also the leading cause of cancer-related death worldwide, constituting a serious public health problem. Examples of primary liver cancer are HCC, intrahepatic iCCA, and other rare cancers such as fibrolamellar carcinoma and hepatoblastoma. The most widespread primary liver malignancies are HCC and intrahepatic cholangiocarcinoma, with other neoplasms, including combined HCC-CCA tumors, which account for fewer than 1% of cases. Liver cancer is growing worldwide, with over 1 million cases expected by 2025 [5]. With over 800,000 new cases yearly, HCC alone accounts for 90% of all primary liver cancer cases. Because of the high frequency of hepatitis B virus (HBV) infection, Asia and Sub-Saharan Africa have the greatest incidence [6].
In contrast to other malignancies, the primary risk factors for HCC are known, including viral hepatitis (B or C), alcohol misuse, and non-alcoholic fatty liver disease in individuals with metabolic syndrome and diabetes [7,8,9,10]. iCCA, or intrahepatic cholangiocarcinoma, is the second most frequent kind of liver cancer, with the highest prevalence in Southeast Asia and the lowest incidence in Western nations. The most common kind of liver cancer is HCC, which originates in the primary type of liver cell, i.e., hepatocyte [11,12]. Like many other cancer forms, healthcare providers have more options for treating liver cancer in its early stages. Unlike many other forms of cancer, healthcare professionals understand what increases a person’s risk of developing liver cancer. Healthcare professionals are working hard to identify who is more likely to acquire primary liver cancer so that it may be recognized and treated as early as possible. The distribution of liver cancer cases based on anatomical sites is shown in Figure 1.
In this paper, different drugs with the potential to treat liver cancer were explored. The drug repurposing approach is effective in introducing new drugs to the market by leveraging on the knowledge of toxicity profile, pharmacokinetics, and safety guidelines of already established drugs, thereby minimizing time and cost. Repurposed drugs have the potential to function as chemo-preventive agents and complement the effects of other chemotherapeutic drugs. They may also serve as adjuvant therapy to prevent tumor recurrence and manage the side effects of other medications. Furthermore, they can be combined with other drugs to target various oncogenic pathways or work together to eliminate the tumor completely. Nevertheless, more in-depth research is needed to fully understand their clinical properties.

1.1. Diagnosis, Signs, and Symptoms of Liver Cancer

There may be no apparent signs of HCC. Its symptoms include pain in the right upper abdomen, eating little, bloating, persistent tiredness, abdominal swelling, weight loss, dark urine, or yellow coloring of the eyes and skin (jaundice) [13,14]. Patients who have similar symptoms because of their underlying chronic liver disease may notice an exacerbation of these symptoms. Hepatocellular cancer is usually diagnosed by computed tomography or magnetic resonance imaging [15]. To establish the amount of liver dysfunction, blood tests are employed. A liver biopsy may be needed to confirm the diagnosis [16].

1.2. Treatment of Liver Cancer

1.2.1. Chemotherapy for Treating Liver Cancer

Sorafenib (C21H16ClF3N4O3), an oral multikinase inhibitor, is the first-line therapy for advanced HCC [17,18]. By blocking the MAP kinase cascade and triggering apoptosis in cancer cells, this FDA-approved drug suppresses tumor angiogenesis, proliferation, and cell division. Sorafenib inhibits several proteins, including Raf-1, platelet-derived growth factor receptor, c-KIT, FLT-3, VEGF receptors -2 and -3, and RET. Regardless of the fact that patients’ average survival time increased by just 3 to 5 months compared to the placebo group, the FDA approved sorafenib as a treatment for HCC in 2007 [19]. Cancer cells acquire immunity to sorafenib with repeated medication, making the therapy inefficient [20]. Moreover, when administered to cancer patients, sorafenib causes undesirable reactions. Serum lipase and amylase levels increase; so do hypertension, bleeding, neuropathy, leukopenia, lymphopenia, diarrhea, nausea, vomiting, and dyspnea. Moreover, 10% of those using sorafenib will acquire cutaneous squamous cell carcinomas [21,22]. Although sorafenib improves HCC prognosis only somewhat, recent clinical trials combine it with other drugs to produce more desirable results for patients, such as therapeutic effectiveness and fewer side effects. Vorinostat and sorafenib induce apoptosis in numerous cell lines, including HepG2 cells, by raising the activity of Bax, Bid, Bak, Bim, and Bad while lowering the activity of anti-apoptotic proteins Bcl-xl, Bcl-2, and MCL-1 [23]. Sorafenib and doxorubicin, both well tolerated by HCC, appear to benefit disease treatment. Sorafenib, which inhibits Raf-1, appears to reduce the chance of resistance development in cultured cells [24]. When compared to the two medications’ individual treatments, the combination improved progression-free and overall survival. Overall, only a modest benefit is observed in HCC patients with the use of sorafenib [25]. Some of the other most common chemotherapy drugs used to treat liver cancer are gemcitabine (Gemzar) and oxaliplatin (Eloxatin). Gemcitabine is a pyrimidine analogue which is metabolized internally to its diphosphate and triphosphate forms—both of which have anti-cancer properties—by obstructing ribonucleotide reductase and competing with deoxycytidine triphosphate for DNA incorporation [26]. Cisplatin is known to act synergistically with gemcitabine and may improve disease-free and disease-specific survival in HCC patients [27]. However, cyclic therapy with gemcitabine results in an elevation of serum aminotransferase levels in 30–90% of the patients with pre-existing chronic liver disease or hepatic metastases.

1.2.2. Immunotherapy for Liver Cancer

Cancer can be treated by changing patients’ immune systems so that they recognize specific antigens on cancer cells, boosting immune activity by inhibiting immunological checkpoints necessary for immunosuppressive signaling, cancer vaccines to prevent diseases or inflammatory reactions, and non-specific cancer immunotherapies that strengthen the immune system. Immunotherapy can be combined with drugs to provide a stimulatory effect, which is a benefit of this field of study [28]. For a long time, non-specific T cell activation, cytokines, and vaccination strategies have been tested in HCC, with generally unsatisfactory results [29]. However, with the FDA’s approval of immune checkpoint inhibitors for the treatment of various cancers, the era of immune oncology has undergone a significant change. The Science journal named cancer immunotherapy as the innovation of the year in 2013 [30]. Immune checkpoint inhibitors target proteins that impair the capacity of the human immune system to combat the cancer cells that generate these proteins [31]. The binding of programmed cell death protein 1 and programmed cell death 1 ligand 1 to cells activates these checkpoints. PD-1, i.e., programmed cell death protein 1, is a protein that is articulated on active CD8+ and CD4+ T cells, B cells, Treg cells, natural killer cells, myeloid cells, monocytes, and progenitor cells; and PD-L1, i.e., programmed cell death 1 ligand 1, is displayed on a variety of nonimmune cells including B cells and T cells. The interaction of PD-1 and PD-L1 limits T cell activity and suppresses IFN-, interleukin-2, and other cytokines’ production, resulting in temporary immune-inhibiting signals and a patient’s ability to create antitumor responses that restrict cancer cell survival [32,33,34]. Co-inhibitory molecules are expressed by effector lymphocytes at immune checkpoints to prevent overactivation. Liver tumors and other cancers express the corresponding ligands in the tumor and stromal cells to evade anti-tumor immune responses [35]. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4), which is expressed primarily by Treg cells and activated T cells, is one of the co-inhibitory receptors. It acts as an effector molecule for Treg cells and inhibits the activation of effector T cells [36]. Clinical research in the area of HCC has, thus far, concentrated on the CTLA-4 and PD-1/PD-L1 pathways. Tremelimumab, a fully human IgG2 monoclonal antibody, was the first drug to be clinically tested in HCC among CTLA-4 targeted therapies. Tremelimumab’s encouraging antitumor effects in advanced HCC and its favorable safety profile in cirrhotic patients with viral causes prompted the need to test additional checkpoint inhibitors [37]. An additional mechanism of tumor-induced immune tolerance is provided by the PD-L1/PD-1 pathway. In contrast to cirrhotic patients or healthy controls, HCC patients have higher levels of PD-1 expression on effector phase CD8+T cells [38]. After hepatic resection, HCC patients who had higher levels of tumor-infiltrating and circulating PD-1+CD8+ T cells experienced earlier and more frequent disease progression. Clinical trials are being conducted in combination therapy with chemotherapeutic, immunotherapeutic, or other cancer treatment medications employing the monoclonal antibodies ramucirumab, which targets VEGF receptor-2, and bevacizumab, which inhibits VEGF receptor binding [39,40,41,42]. However, there are some risks involved in taking these medications. Patients may experience an infusion reaction. This can cause symptoms similar to an allergic reaction, such as a fever, chills, face flushing, rash, itchy skin, feeling lightheaded, wheezing, and breathing difficulties. These medications essentially disable one of the body’s immune system’s defenses. The lungs, intestines, liver, hormone-producing glands, kidneys, skin, and other organs can all experience serious or even life-threatening issues when the immune system begins attacking other parts of the body. Ipilimumab seems to be associated with serious side effects more frequently than PD-1 and PD-L1 inhibitors.

1.2.3. Common Risk Factors

Cirrhosis is a liver disease that causes scarring and increases the chance of developing HCC. Chronic hepatitis B or C infections, which are related to the greatest risk of developing HCC; extreme and persistent alcohol consumption; nonalcoholic fatty liver disease, which is predominantly related with diabetes and obesity; and other genetic liver ailments are among these conditions [43]. Because persons with hepatitis B and cirrhosis are at a higher risk of developing carcinoma, it is suggested that they have a liver ultrasound within six months.

1.3. Drug Repurposing

The foundation for drug repositioning is the repurposing of an active pharmacological indication [44]. Developing new therapeutic applications for previously recognized, abandoned, shelved, or experimental medicines is known as drug repurposing (drug reprofiling, indication expansion, or indication shift). Repurposing ‘old’ medications to treat both comparable and different diseases is becoming more appealing because it incorporates the use of derisked molecules, which may decrease total development costs and shorten research timelines [45].
Drug repositioning is based upon two scientific principles: (i) the discovery, via the elucidation of the human genome, that distinct disorders have biological targets that are sometimes shared, and (ii) the concept of pleiotropic medicines.
The approval of medical research and clinical usage takes 12 to 15 years and costs 1.2 billion dollars. Before the FDA may approve a drug for clinical use, it must have good therapeutic potential in the designated target region with low toxicity in both preclinical and clinical studies. Because of growing interest from pharmaceutical companies and observable validation of several cheminformatics and bioinformatics results, drug repurposing has surged in prominence. Regulatory authorities have authorized around 10% of repurposed pharmaceuticals, with the other 70% in different phases of clinical testing.

Drug Repurposing Approaches

The medication repurposing approach consists of three phases before moving the potential therapy forward in the research pipeline:
  • Identifying a promising chemical for a certain indication (hypothesis generation);
  • Conducting a mechanistic examination of the drug’s impact in preclinical models; and
  • Evaluating the efficacy of a Phase II clinical research.
Computational techniques are essentially data-driven; they require a systematic examination of any type of data (such as gene expression, chemical structure, genotyping or proteomic data, or electronic health records) which may lead to the development of repurposing hypotheses. The most often used computational strategies are target-based, knowledge-based, signature-based, pathway- or network-based, and target mechanism-based [46,47]. These strategies have been shown to be both cost-effective and useful in the development of novel therapeutic drugs. Combining cheminformatics, bioinformatics, network biology, and systems biology, computational tools aid in drug development. These strategies, for example, make use of pre-existing targets, drugs, disease biomarkers, or pathways to create novel methodology and accelerate the preparation of key clinical trials.

2. Results and Discussion

Using the PRISMA 2020 guidelines for systematic review, a total of 16,744 entries were acquired from the PubMed, ScienceDirect and JSTOR databases after being reviewed with EndNote 20, and eliminating 223 duplicates. The remaining 16,521 records’ titles and abstracts were then selected further based on their relevance to our topic of inquiry. Only 226 of these were deemed suitable, from which full-text reports were obtained. Finally, 39 papers meeting the qualifying criteria were chosen for our study. The flow diagram of this approach is given in Figure 2.
From these studies, 14 drugs were identified from different disease pathologies which have the potential to be repurposed for liver cancer (Table 1). All of these drugs were originally developed to treat different diseases. Further analysis was carried out to determine their suitability for drug repurposing for liver cancer. The chemical structure of each drug is given in Figure 3.

2.1. Pravastatin

Pravastatin is a statin which is a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and is used as a lipid lowering drug. Statins also have additional effects, other than their intended use as lipid lowering agents. Pravastatin is the bioactive metabolite of mevastatin which is isolated from Penicillium citrinum. Among all the statins, Pravastatin has the most hydrophilic property, and is freely soluble in water and ether [48]. There is an overexpression of Ras protein in the HepG2 cell line derived from the human HCC, which is closely regulated by cholesterol metabolism. Pravastatin decreases the rate of cholesterol biosynthesis in these cell lines.

2.2. Simvastatin

Simvastatin is also a type of statin, like Pravastatin. It is derived from Aspergillus terreus synthetically. Simvastatin competitively inhibits hepatic hydroxymethyl-glutaryl coenzyme A (HMG-CoA) reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate, a key step in cholesterol synthesis. Hydrophilic statins such as Pravastatin require the distinct expression of a transporter peptide, OATP1B1, for transfer into hepatic cells, whereas hydrophobic statins like Simvastatin are easily distributed in the cells. Simvastatin and Pravastatin both effectively slow the growth of hepatocytes that express OATP1B1. Simvastatin is more extensively incorporated into hepatocytes than Pravastatin, which is consistent with their suppression-related actions. Conversely, Simvastatin inhibits the growth of tumor cells lacking OATP1B1 which do not incorporate or respond to Pravastatin [49]. A study by Csomó et al. reported that Simvastatin can increase the oxidizing capability of free cytochrome c which, in turn, raises oxidative stress and thereby encourages apoptosis [62].

2.3. Fluvastatin

Fluvastatin is one of the first fully synthetic HMG-CoA reductase inhibitors. Fluvastatin has unique anti-cancer properties in addition to lowering cholesterol, such as inducing tumor cell death in several cancer cell lines (such as glioma and breast cancer cell lines) [50]. Additionally, Fluvastatin has been suggested as a possible treatment for HCC [63]. The anti-cancer property of Fluvastatin is related to its effect via the SREBP-1 and AMPKa pathway. Fluvastatin activates SIRT6 which is involved in cholesterol homeostasis. After treatment of HepG2 cells in mice, SIRT6 is activated, which leads to the deacetylation of H3K9 and H3K56 and the inhibition of lipid metabolism [64]. Fluvastatin also inhibits cholesterol synthesis via SREBP-1 phosphorylation.

2.4. Metformin

Metformin blocks the mitochondrial respiratory chain at the molecular level in the liver, thereby activating AMPK, improving insulin sensitivity via its effects on fat metabolism, and lowering cAMP, which, in turn, suppresses the production of gluconeogenic enzymes. Furthermore, fructose may be inhibited by AMP in the liver as a result of metformin’s AMPK-independent actions on the liver [51]. Metformin has been demonstrated to reduce ATP concentration—an allosteric inhibitor of pyruvate kinase—in isolated rat hepatocytes, resulting in a reduction in glucose production via boosting pyruvate kinase flux [65]. Patients with type 2 diabetes who take metformin had a 62% lower chance of developing liver cancer according to estimates. Diabetic patients who use metformin over the long term have a decreased chance of developing cancer and a lower overall cancer death rate [66].

2.5. Canagliflozin

Advanced NASH increases the risks of cirrhosis and HCC, which can be countered by reducing the serum ALT baseline. Canagliflozin is a drug from the sodium-glucose cotransporter 2 (SGLT2) inhibitors class [52]. They inhibit the SGLT2 transporter in the S1 segment of the proximal tubule in the kidney and cause glycosuria and natriuresis. Their mechanism of action involves natriuresis, restoration of tubule-glomerular feedback, and amelioration of internal hypoxia. All stages of the development of liver cancer exhibit hypoxia. Hypoxia causes hypoxia-inducible factors (HIFs) to stabilize, and HIFs function as central regulators to reduce the innate immunity [67]. There are possible anti-inflammatory and antifibrotic effects for SGLT2 inhibitors as well. Canagliflozin has been proven to significantly decrease ALT levels from the baseline. It also significantly improved the hepatic fibrosis markers such as the FIB-4 index and the FM-fibro index, suggesting the possibility of improving hepatic fibrosis [68]. Canagliflozin also works on a pathway involving SGLT2 and GLUT1 which leads to the suppression of intracellular glucose uptake in HCC cells [69,70].

2.6. Pimozide

Pimozide, an oral active antipsychotic drug used to treat motor tics, refractory phonic tics, persistent psychosis, and Tourette’s syndrome [71], has received much attention as a possible anticancer drug. This medication affects neurons in the central nervous system by inhibiting dopaminergic, serotonergic, and unknown central nervous system receptors. Due to the HERG channel affinities of pimozide, it exhibits low (10-fold) or no selectivity for D2 or 5 HT2A receptors [53]. This lack of selectivity leads to a number of secondary changes in central dopamine metabolism and function, which have both unpleasant effects as well as therapeutic implications against resistant phonic tics and the symptoms of schizophrenia and psychosis. Inhibiting stem-like cells and carcinogenesis in HCC are additional effects of pimozide (HCC). Pimozide reverses the stem-like cell tumorigenic phenotypes caused by IL-6 treatment in HCC cells and prevents the maintenance and carcinogenesis of HCC stem-like cells (CD133-positive cells). Pimozide’s anticancer effects were also demonstrated in a nude mouse HCC xenograft model [72].

2.7. Valproate

Antineoplastic properties of the well-known anticonvulsive drug valproic acid (VPA) were discovered in 1997. The short chain fatty acids VPA and VPA analogues potently alter the biology of various types of cancer cells by promoting differentiation, reducing proliferation, increasing apoptosis and immunogenicity, and reducing angiogenesis and metastatic potential. Several studies revealed a close relationship between HDAC and the growth of malignant tumor cells and tumor cell differentiation (histone deacetylases). In cancer cells, VPA reduces the activity of the HDAC gene [73]. Multiple exogenous reporter genes, including SV40, p21, and gelsolin, which are linked to HDAC inhibition, were expressed as a result of the use of VPA and its analogues [74]. HCC cells are induced to produce NKG2DL mRNA by sodium valproate. By increasing NKG2DL expression, the HDAC-I VPA may be able to induce NK cell lysis in hepatoma cells [54].

2.8. Bexarotene

Bexarotene has been approved by the FDA for treating cutaneous manifestations of T cell lymphomas in a limited manner. It is a scientifically proven orphan nuclear agonist and is also a member of the retinoid subclass that specifically targets and activates retinoid X receptors (RXRs) [75]. These receptors, after activation, function as transcription factors that are involved in the regulation of expression of genes that directly influence cellular proliferation and differentiation [76]. Retinoids are biologically active vitamin A derivatives that play crucial roles in regulating cell proliferation, differentiation, and apoptosis in both embryonic and adult cell behavior. Two different families of intracellular receptors—retinoid X receptors (RXR)-α, -β and -γ, and retinoid acid receptors (RARs)-α, -β and -γ—mediate the biological effects of retinoids. Bexarotene is a selective RXR agonist that inhibits angiogenesis and metastasis while inhibiting angiogenesis and cell cycle progression, causing apoptosis and differentiation, preventing multidrug resistance, and blocking cell cycle progression [55].

2.9. Chloroquine

Chloroquine-based medications, primarily used to treat malaria, involve autophagy as the target mechanism which affects the inflammatory response and cancer growth. Chloroquine’s pharmaceutical inhibition of autophagic flux causes an increase in apoptosis and a reduction in cell viability in hepatoma cells. When combined with presently used chemotherapy drugs, chloroquine dramatically slows tumor growth and enhances the efficacy of the drugs. Chloroquine has been found to trigger the arrest of cell cycle in the G0/G1 phase and also cause damage to the DNA. It makes the tumor cells more sensitive to the chemotherapy drugs and, hence, can be a potential repurposed therapeutic for HCC.

2.10. Linagliptin

Linagliptin, a hypoglycemic medication, has been shown to reduce cell proliferation by cell cycle arrest and induce apoptosis in HCT116 cells [77]. It has also been shown to inhibit tumor formation in nude mice with HCT116 cells. Linagliptin prevents cell growth in HCT 116 by causing cell cycle arrest at the G2/M and S phase and, by reducing the expression of Ki67, a nuclear protein expressed in all proliferating cells, linagliptin inhibits the growth of tumors [57]. The main mechanism of action of linagliptin to inhibit cell proliferation and promote cell apoptosis is suggested to be via the inhibition of the phosphorylation of Rb and the expression of Bcl2, Pro-caspase3. This is based on the results of molecular docking, the gene regulatory network, and Western blot. Suppression of the CDK1 complex by linagliptin may result in the activation of the p53 signal pathway and the inhibition of the JAK–STAT signal pathway. According to a recent study, linagliptin inhibits hepatocellular cancer cells by inhibiting the protein ADORA3, and causes cell apoptosis at the G2/M phase by raising caspase3 levels.

2.11. Lidocaine

One of the most popular local anaesthetics in medical settings, lidocaine has been found to have a variety of uses, including the potential to treat cancer [78]. As it has been demonstrated, lidocaine exerts its multifunctional effects in analgesia, anti-inflammation, and anti-hyperalgesia through a variety of pathways, including sodium channel inhibitors and the control of G protein-coupled receptors [58]. Lidocaine also has sensitizing effects toward other chemotherapeutics, including mitomycin C and 5-fluorouracil (5-FU). In a study on the SK-MEL-2 melanoma cell line, 5-FU greatly increased the anticancer potency and apoptosis-inducing effects of lidocaine despite its low toxicity [79]. In addition to acting as a chemosensitizer, lidocaine has been shown to have inhibitory effects on a variety of cancer cells and in tumor xenograft models when used only once and at elevated concentrations. Lidocaine prevents the growth of HCC HepG2 cells by triggering apoptosis by enhancing the Bax/Bcl-2 ratio and activating caspase-3 via the ERK1/2 and p38 pathways. This suggested that lidocaine exerted its anticancer effects via cell cycle arrest at the G0/G1 phase [80]. More notably, lidocaine also sensitized cisplatin and decreased tumor development through intraperitoneal administration, indicating a combined therapy in treating HCC without expressing any toxic effects.

2.12. Raloxifene

Raloxifene is a benzothiophene selective estrogen receptor modulator (SERM) [59]. SERMs are a class of compounds that bind and interact with estrogen receptors and act as both agonists and antagonists for estrogen in different tissues [81]. Transcription factors, such as signal transducer and activator of transcription (STAT) proteins, are involved in signal transfer from cytokines and growth factors. Activated STAT3 enters the nucleus and induces multiple oncogene transcription, which causes cell proliferation, metastasis, and evasion from host immune system, and increases the resistance of the cell to apoptosis. Interleukin-6 (IL-6) is a cytokine which is able to induce phosphorylation of STAT3, which leads to its activation [82]. Hepatocyte repair and replication are greatly influenced by IL-6-mediated STAT3 activation, which encourages the development of hepatocarcinogenesis [83]. This process occurs by a complex pathway involving the formation of the IL-6/IL-6Rα/GP130 complex. The dimerization of this complex is the key step involved in the phosphorylation of STAT3. Raloxifene specifically inhibits IL-6 and GP130 binding. It also affects STAT3 downstream genes which induce apoptosis in cells [84].

2.13. Itraconazole

Itraconazole is an antifungal medicine. In recent years, further research has revealed that itraconazole has significant potential as a new anti-tumor drug and to be developed as an anti-liver cancer drug. Itraconazole blocks the abnormally active Wnt/β-catenin signaling pathway, causing cell cycle arrest and inhibiting tumor cell proliferation and metastasis. The AKT/mTOR pathway is known to be crucial in controlling biological functions in cancer cells. In HepG2 cells, itraconazole decreases the expression of p-AKT and p-mTOR and prevents the phosphorylation of the proteins PI3K and S6K, which has an impact on protein synthesis. It can be inferred from this that itraconazole suppresses HepG2 cell growth and proliferation via the PI3K/AKT/mTOR/S6K pathway [60]. The ROS pathway is activated by itraconazole, and apoptosis is induced via activating downstream caspase and PAPR proteins by balancing the ratio of pro- and anti-apoptotic proteins. By promoting the activation of the promoter caspase-8, which, in turn, activates caspase-3 and ultimately results in apoptosis, it upregulates the production of the FAS protein. Itraconazole inhibits the phosphorylation of proteins in the PI3K/AKT/mTOR/S6K signaling pathway, downregulates the Hedgehog and Wnt/-catenin signaling pathways, and downregulates the growth and proliferation of HepG2 cells, thus arresting the progression of liver cancer [85,86].

2.14. Clofazimine

Clofazimine is an antimycobacterial and anti-inflammatory agent which is used in treating diseases caused by mycobacterium such as leprosy, tuberculosis, and discoid lupus erythematosus [87,88]. Clofazimine increases the activity of bacterial phospholipase A2 and increases the amount of lysophospholipids which are toxic to mycobacterium [89]. Clofazimine also works by competing with menaquinone—the only quinone cofactor in mycobacteria—for the electron transported by the flavin adenine dinucleotide (FAD) of reduced NADH2. Therefore, the respiratory system oxidizes clofazimine instead of NADH. As a result, less ATP is produced during respiration [90]. Wnt signaling is a highly evolutionary conserved pathway that is important for regulating cell fate, proliferation, and migration during the development of an organism. However, in healthy adult organs, it is largely inactive. In many tissues, tumorigenesis is linked to the aberrant activation of Wnt signaling [91]. Clofazimine inhibits Wnt signaling transduction, which efficiently suppresses tumor growth. Two HCC cell lines, Hep3b and SNU398, show strong sensitivity to clofazimine, while another two lines, HepG2 and Huh7, show poor sensitivity to clofazimine [61].

2.15. Target Prediction

Further, the Swiss Target Prediction tool [92] was used to identify the targets of each of the repurposed drugs. The chemical SMILES of the drugs were obtained from the PubChem database and entered as input in Swiss Target Prediction, and the species was set as Homo sapiens. The tool predicted the target receptors of the drugs along with the target protein families. The results were obtained in a tabular format along with the UniProt ID, ChEMBL ID, and probability of the target receptor (Table 2).
Later, the proteins targeted by these compounds were used to create protein interaction networks using Cytoscape [93]. The interaction network is useful to understand the molecular pathways targeted by these compounds. We can see a great deal of similarity and commonality in the pathways involved in liver cancer and the pathways targeted by these compounds (Table 3).
Using these protein interaction networks, we studied the molecular function of these networks individually for each drug using the STRING database. These drugs targeted several pathways which are common to those affected in liver cancer. Pathways such as Bile acid receptor activity, IMP dehydrogenase activity, JUN kinase activity, Nitric-oxide synthase activity, and MAP kinase activity were found to be affected by these drugs. The detailed list of molecular functions of each drug affecting liver cancer is given in Table 3.
The liver cancer pathways targeted by these drugs is a promising sign for the repurposing of these drugs to treat liver cancer.
Many of the side effects that have been recorded for all of the medicines are quite harmful for liver cancer patients and must be taken into account again before using them for treatment. The use of repurposed drugs seems to be an appealing approach, but it is necessary to consider the adverse effects associated with the drugs before prescribing them as medications for treating liver cancer. Table 4 lists all the significant side effects of these drugs.

3. Methods

The current review has been conducted in accordance with the PRISMA2020 guidelines. As this study does not involve any clinical or preclinical data, a Systematic Review Registration is not required for this review [94]. Based on the papers published between 1998 and 2022, a thorough analysis of the data revealing the significance of drug repurposing in liver cancer was conducted. The data for our investigation came from PubMed, ScienceDirect, and JSTOR using the following associated keywords in combination: drug repurposing, liver cancer, medication repurposing, diabetes, cancer, statins, anti-alcoholism, chronic psychosis, epilepsy, and bipolar disorder.
The eligibility of the studies was defined based on the following inclusion criteria: (i) studies published in the English language were chosen; (ii) original studies elucidating the effects of previously existing drugs and their interaction with receptors that may be a potential target for treating liver cancer; and (iii) research papers and clinical trial studies were chosen for their authenticity. The exclusion criteria were (i) studies published in languages other than English; (ii) unavailability of the full text of the study; (iii) studies found to be irrelevant once the full text is obtained; (iv) lack of clarity; and (v) lack of rigor.

4. Conclusions

Liver cancer is one of the most common malignancies with a high mortality rate. Identifying treatment options with minimal toxicity is essential for an effective therapeutic outcome; one such approach is drug repurposing. Drug repurposing is a practical approach to finding approved drugs for alternate diseases. The main advantages of this approach include quick processing time, reduced cost for drug development, and a less tedious approval process. The study identifies 14 drugs from different pathologies, targeting different classes of drug receptors in various diseases. The possibility of repurposing these drugs to treat liver cancer has been discussed. Computational techniques such as molecular docking and molecular dynamic simulation can be paired with this approach to study the most potent drug.
These repurposed drugs have great potential for treating liver cancer, but their adverse effects must also be considered. The side effects for each of the repurposed drugs in this study have been mentioned in Table 4. Additionally, despite these drugs being approved by regulatory authorities, they must undergo clinical trials to study their effect on different pathologies. Drug repurposing is an attractive alternative to the slow-paced traditional drug discovery process. It provides an opportunity to utilize previously approved drugs for targeting receptors for various diseases outside the scope of the original medication.

Author Contributions

Conceptualization, R.J.M., D.P.K. and A.M.P.; Data curation, A.T.; Methodology, R.J.M., M.A., K.A., D.P.K. and A.M.P.; Resources, P.N.; Supervision, R.J.M.; Writing—original draft, R.J.M., M.A., K.A., A.T., Q.A.R.H., T.V.S. and P.N.; Writing—review & editing, R.J.M., M.A., K.A., A.T., Q.A.R.H., T.V.S., P.N., D.P.K. and A.M.P. All authors have read and agreed to the published version of the manuscript.

Funding

No funding was received for the current work.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

We acknowledge the NPDF fellowship and support given to Angamba Meetei Potshangbam by DST SERB.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Figure 1. Distribution of Liver Cancer Cases based on Anatomical site.
Figure 1. Distribution of Liver Cancer Cases based on Anatomical site.
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Figure 2. PRISMA 2020 flow diagram for systematic review.
Figure 2. PRISMA 2020 flow diagram for systematic review.
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Figure 3. Two-dimensional chemical structure of the drugs.
Figure 3. Two-dimensional chemical structure of the drugs.
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Table 1. Details of the drugs, originally developed for different disease pathologies, identified as potential candidates for repurposing in the treatment of liver cancer.
Table 1. Details of the drugs, originally developed for different disease pathologies, identified as potential candidates for repurposing in the treatment of liver cancer.
Drug NameIndicationMechanism of ActionReferenceMethod of Prediction
PravastatinLipid Lowering DrugInhibitor of HMG-CoA Reductase Riaño et al. (2020) [48]Target Prediction using Swiss Target tool and Protein Interaction Network analysis using STRING
SimvastatinLipid Lowering DrugInhibitor of HMG-CoA Reductase Menter et al. (2011) [49]
FluvastatinLipid Lowering DrugInhibitor of HMG-CoA Reductase Sławińska-Brych et al. (2014) [50]
MetforminTreat Type 2 DiabetesSuppresses The Production of Gluconeogenic EnzymesRena et al. (2017) [51]
CanagliflozinTreat Type 2 DiabetesSGLT2 InhibitorsLuo et al. (2021) [52]
PimozideAntipsychotic DrugInhibiting Dopaminergic, Serotonergic, And Unknown Central Nervous System ReceptorsKongsamut et al. (2002) [53]
ValproateAnticonvulsive Drug Blockade of Voltage-Gated Sodium Channels And Increased Brain Levels of (GABA)Rithanya and Ezhilarasan (2021) [54]
BexaroteneTreat Cutaneous Manifestations of T Cell Lymphomas Targets And Activates Retinoid X Receptors (RXRs)Qu and Tang (2010) [55]
ChloroquineTreat MalariaInhibition of Autophagic Flux Solomon and Lee (2009)[56]
LinagliptinTreat Type 2 DiabetesInhibitor of DPP-4Li et al. (2020) [57]
LidocaineLocal Anaesthetics Variety of Pathways, Including Sodium Channel Inhibitors And The Control of G Protein-Coupled ReceptorsZhou et al. (2020) [58]
RaloxifeneTo Treat Postmenopausal OsteoporosisBenzothiophene Selective Estrogen Receptor Modulator Hong et al. (2021) [59]
ItraconazoleAntifungal MedicineInhibits Cytochrome P-450-Dependent EnzymesWang et al. (2020) [60]
ClofazimineAntimycobacterial And Anti-Inflammatory Agent Increases The Activity of Bacterial Phospholipase A2 Xu et al. (2020) [61]
Table 2. Potential repurposed drugs, their target, and receptor target class.
Table 2. Potential repurposed drugs, their target, and receptor target class.
Drug NameTarget Common NameReceptor Target Class
PravastatinHMG-CoA reductaseHMGCROxidoreductase
Neurokinin 2 receptorTACR2Family A G protein-coupled receptor
Norepinephrine transporterSLC6A2Electrochemical transporter
Dopamine transporterSLC6A3Electrochemical transporter
Vitamin D receptorVDRNuclear receptor
Thromboxane A2 receptorTBXA2RFamily A G protein-coupled receptor
Inosine-5’-monophosphate dehydrogenase 1IMPDH1Oxidoreductase
Inosine-5’-monophosphate dehydrogenase 2IMPDH2Oxidoreductase
Matrix metalloproteinase 1MMP1Protease
Matrix metalloproteinase 8MMP8Protease
AtorvastatinCytochrome P450 3A4CYP3A4Cytochrome P450
HMG-CoA reductaseHMGCROxidoreductase
Histone deacetylase 6HDAC6Eraser
Histone deacetylase 2HDAC2Eraser
Histone deacetylase 1HDAC1Eraser
Phosphodiesterase 6DPDE6DPhosphodiesterase
Squalene synthetaseFDFT1Enzyme
Glucocorticoid receptorNR3C1Nuclear receptor
Prostanoid EP4 receptor (by homology)PTGER4Family A G protein-coupled receptor
Phosphodiesterase 5APDE5APhosphodiesterase
SimvastatinHMG-CoA reductaseHMGCROxidoreductase
Norepinephrine transporterSLC6A2Electrochemical transporter
Neurokinin 2 receptorTACR2Family A G protein-coupled receptor
Dopamine transporterSLC6A3Electrochemical transporter
Histone deacetylase 6HDAC6Eraser
Corticotropin releasing factor receptor 1 (by homology)CRHR1Family B G protein-coupled receptor
Histone deacetylase 1HDAC1Eraser
Beta amyloid A4 proteinAPPMembrane receptor
Bile acid receptor FXRNR1H4Nuclear receptor
11-beta-hydroxysteroid dehydrogenase 1HSD11B1Enzyme
FluvastatinCytochrome P450 2C9CYP2C9Cytochrome P450
HMG-CoA reductaseHMGCROxidoreductase
Inosine-5’-monophosphate dehydrogenase 1IMPDH1Oxidoreductase
P2X purinoceptor 3P2RX3Ligand-gated ion channel
Prostanoid EP4 receptorPTGER4Family A G protein-coupled receptor
Inosine-5’-monophosphate dehydrogenase 2IMPDH2Oxidoreductase
Prostanoid EP2 receptor (by homology)PTGER2Family A G protein-coupled receptor
p53-binding protein Mdm-2MDM2Other nuclear protein
Type-1 angiotensin II receptor (by homology)AGTR1Family A G protein-coupled receptor
Peroxisome proliferator-activated receptor gammaPPARGNuclear receptor
MetforminThrombinF2Protease
Urokinase-type plasminogen activatorPLAUProtease
Histamine H4 receptorHRH4Family A G protein-coupled receptor
D-amino-acid oxidaseDAOEnzyme
Histamine H3 receptorHRH3Family A G protein-coupled receptor
Xanthine dehydrogenaseXDHOxidoreductase
Dihydrofolate reductase (by homology)DHFROxidoreductase
Integrin alpha-V/beta-3ITGAV ITGB3Membrane receptor
Coagulation factor IXF9Protease
Neuronal acetylcholine receptor; alpha4/beta2CHRNA4 CHRNB2Ligand-gated ion channel
CanagliflozinSodium/glucose cotransporter 2SLC5A2Electrochemical transporter
Sodium/glucose cotransporter 1SLC5A1Electrochemical transporter
Glucose transporter (by homology)SLC2A1Electrochemical transporter
Phosphodiesterase 5APDE5APhosphodiesterase
Adenosine A1 receptor (by homology)ADORA1Family A G protein-coupled receptor
Adenosine A2a receptorADORA2AFamily A G protein-coupled receptor
Adenosine A3 receptorADORA3Family A G protein-coupled receptor
Equilibrative nucleoside transporter 1SLC29A1Electrochemical transporter
Adenosine kinaseADKEnzyme
Coagulation factor VII/tissue factorF3Surface antigen
PimozideUbiquitin carboxyl-terminal hydrolase 1USP1Enzyme
Dopamine D2 receptorDRD2Family A G protein-coupled receptor
Potassium channel subfamily K member 2KCNK2Voltage-gated ion channel
Mu opioid receptorOPRM1Family A G protein-coupled receptor
Delta opioid receptorOPRD1Family A G protein-coupled receptor
Kappa Opioid receptorOPRK1Family A G protein-coupled receptor
HERGKCNH2Voltage-gated ion channel
Serotonin 6 (5-HT6) receptorHTR6Family A G protein-coupled receptor
Voltage-gated T-type calcium channel alpha-1G subunitCACNA1GVoltage-gated ion channel
Glycine receptor subunit alpha-1GLRA1Ligand-gated ion channel
ValproatePeroxisome proliferator-activated receptor deltaPPARDNuclear receptor
Free fatty acid receptor 1FFAR1Family A G protein-coupled receptor
Fatty acid binding protein intestinalFABP2Fatty acid binding protein family
11-beta-hydroxysteroid dehydrogenase 1HSD11B1Enzyme
Fatty acid binding protein adipocyteFABP4Fatty acid binding protein family
Fatty acid binding protein muscleFABP3Fatty acid binding protein family
Aldo-keto reductase family 1 member B10AKR1B10Enzyme
Peroxisome proliferator-activated receptor alphaPPARANuclear receptor
Androgen ReceptorARNuclear receptor
Vitamin D receptorVDRNuclear receptor
BexaroteneRetinoid X receptor betaRXRBNuclear receptor
Retinoic acid receptor gammaRARGNuclear receptor
Retinoid X receptor gammaRXRGNuclear receptor
Retinoic acid receptor betaRARBNuclear receptor
Retinoic acid receptor alphaRARANuclear receptor
Retinoid X receptor alphaRXRANuclear receptor
Cytochrome P450 26B1CYP26B1Cytochrome P450
Cytochrome P450 26A1CYP26A1Cytochrome P450
Nuclear receptor ROR-gammaRORCNuclear receptor
Prostanoid EP4 receptorPTGER4Family A G protein-coupled receptor
ChloroquineHistamine H3 receptorHRH3Family A G protein-coupled receptor
HERGKCNH2Voltage-gated ion channel
Histamine N-methyltransferase (by homology)HNMTEnzyme
Quinone reductase 2NQO2Enzyme
Prion proteinPRNPSurface antigen
Muscarinic acetylcholine receptor M2CHRM2Family A G protein-coupled receptor
Alpha-1d adrenergic receptorADRA1DFamily A G protein-coupled receptor
Norepinephrine transporterSLC6A2Electrochemical transporter
Serotonin 2a (5-HT2a) receptorHTR2AFamily A G protein-coupled receptor
Dopamine D3 receptorDRD3Family A G protein-coupled receptor
LinagliptinMuscarinic acetylcholine receptor M1CHRM1Family A G protein-coupled receptor
Dipeptidyl peptidase IVDPP4Protease
Fibroblast activation protein alphaFAPProtease
Cyclin-dependent kinase 4CDK4Kinase
Dipeptidyl peptidase IXDPP9Protease
MAP kinase p38 alphaMAPK14Kinase
C-C chemokine receptor type 8CCR8Family A G protein-coupled receptor
Tyrosine-protein kinase ABLABL1Kinase
Platelet-derived growth factor receptor betaPDGFRBKinase
Thrombin and coagulation factor XF10Protease
LidocaineSodium channel protein type IV alpha subunitSCN4AVoltage-gated ion channel
Serotonin 1b (5-HT1b) receptor (by homology)HTR1BFamily A G protein-coupled receptor
Dopamine D4 receptorDRD4Family A G protein-coupled receptor
Muscarinic acetylcholine receptor M5CHRM5Family A G protein-coupled receptor
Dopamine D2 receptorDRD2Family A G protein-coupled receptor
Muscarinic acetylcholine receptor M4CHRM4Family A G protein-coupled receptor
Cytochrome P450 2D6CYP2D6Cytochrome P450
Dopamine D1 receptorDRD1Family A G protein-coupled receptor
Alpha-2b adrenergic receptorADRA2BFamily A G protein-coupled receptor
Serotonin 1e (5-HT1e) receptorHTR1EFamily A G protein-coupled receptor
RaloxifeneSerotonin 2b (5-HT2b) receptorHTR2BFamily A G protein-coupled receptor
Tyrosine-protein kinase FYNFYNKinase
Alpha-2a adrenergic receptorADRA2AFamily A G protein-coupled receptor
Serotonin 1b (5-HT1b) receptor (by homology)HTR1BFamily A G protein-coupled receptor
Adrenergic receptor alpha-2ADRA2CFamily A G protein-coupled receptor
Alpha-2b adrenergic receptorADRA2BFamily A G protein-coupled receptor
Dopamine D1 receptorDRD1Family A G protein-coupled receptor
Estrogen receptor alphaESR1Nuclear receptor
Dopamine D2 receptorDRD2Family A G protein-coupled receptor
AcetylcholinesteraseACHEHydrolase
ItraconazoleVasopressin V2 receptorAVPR2Family A G protein-coupled receptor
Tyrosine-protein kinase FYNFYNKinase
C-C chemokine receptor type 4CCR4Family A G protein-coupled receptor
Cytochrome P450 3A4CYP3A4Cytochrome P450
Cytochrome P450 51CYP51A1Cytochrome P450
Interleukin-8 receptor ACXCR1Family A G protein-coupled receptor
Muscarinic acetylcholine receptor M4CHRM4Family A G protein-coupled receptor
Muscarinic acetylcholine receptor M5CHRM5Family A G protein-coupled receptor
Sigma opioid receptorSIGMAR1Membrane receptor
Dopamine D3 receptorDRD3Family A G protein-coupled receptor
ClofazimineCyclophilin A (by homology)PPIAIsomerase
Cannabinoid receptor 1 (by homology)CNR1Family A G protein-coupled receptor
Progesterone receptorPGRNuclear receptor
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3PFKFB3Enzyme
MAP kinase p38 alpha (by homology)MAPK14Kinase
Corticotropin releasing factor receptor 1CRHR1Family B G protein-coupled receptor
Hepatocyte growth factor receptorMETKinase
Glucagon receptorGCGRFamily B G protein-coupled receptor
Translocator protein (by homology)TSPOMembrane receptor
G protein-coupled receptor 39GPR39Family A G protein-coupled receptor
Table 3. Repurposed drugs and their molecular functions affecting liver cancer.
Table 3. Repurposed drugs and their molecular functions affecting liver cancer.
Drug NameMolecular Function (Gene Ontology)
PravastatinBile acid receptor activity
Bradykinin receptor binding
IMP dehydrogenase activity
Dopamine:sodium symporter activity liver cancer
JUN kinase activity
AtorvastatinBile acid receptor activity
Lysophosphatidic acid receptor activity
Prostaglandin receptor activity
3,5-cyclic-AMP phosphodiesterase activity
Cysteine-type endopeptidase activity
SimvastatinOrexin receptor activity
Macrophage colony-stimulating factor receptor activity
Prostaglandin-endoperoxide synthase activity
Neurotrophin receptor activity
PTB domain binding
FluvastatinAMP deaminase activity
Bradykinin receptor binding
Endothelin receptor activity
IMP dehydrogenase activity
Prostaglandin receptor activity
Metformin Nitric-oxide synthase activity
Histamine receptor activity
Arginine binding
G protein-coupled acetylcholine receptor activity
Folic acid binding
CanagliflozinJUN kinase activity
Glucosylceramidase activity
Ubiquitin activating enzyme activity
MAP kinase activity
MAP activity
PimozideTachykinin receptor activity
alpha2-adrenergic receptor activity
alpha1-adrenergic receptor activity
Histone kinase activity
Nitric-oxide synthase activity
ValproateBile acid receptor activity
Geranylgeranyl reductase activity
Prostaglandin f receptor activity
Prostaglandin j receptor activity
Prostaglandin receptor activity
BexaroteneBradykinin receptor binding
Prostaglandin d receptor activity
Prostaglandin receptor activity
Arachidonate 15-lipoxygenase activity
DNA binding domain binding
ChloroquineAlpha-adrenergic receptor activity
Tachykinin receptor activity
alpha1-adrenergic receptor activity
G protein-coupled acetylcholine receptor activity
Adrenergic receptor activity
LinagliptinFBXO family protein binding
Bradykinin receptor activity
Insulin-activated receptor activity
Platelet activating factor receptor activity
Somatostatin receptor activity
LicodaineDopamine neurotransmitter receptor activity
Serotonin binding
Dopamine binding
Adrenergic receptor activity
Catecholamine binding
RaloxifeneRho-dependent protein serine/threonine kinase activity
Acetylcholinesterase activity
Alpha-adrenergic receptor activity
Serotonin binding
Dopamine neurotransmitter receptor activity
ItraconazoleAlpha-adrenergic receptor activity
G protein-coupled acetylcholine receptor activity
JUN kinase activity
Serotonin binding
MAP kinase activity
ClofazimineJUN kinase activity
Cannabinoid receptor activity
Orexin receptor activity
Somatostatin receptor activity
G protein-coupled acetylcholine receptor activity
Table 4. Side effects of repurposed drugs.
Table 4. Side effects of repurposed drugs.
Name of the DrugChemical NameMechanism of ActionSide Effect
Pravastatin(3R,5R)-3,5-dihydroxy-7-((1R,2S,6S,8R,8aR)-6-hydroxy-2-methyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8a-hexahydronaphthalen-1-yl)-heptanoic acidCompetitive inhibition of HMG-CoA reductase to reduce cholesterol metabolismHeadache, nausea, muscle pain, rashes
Simvastatin[(1S,3R,7S,8S,8aR)-8-[2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoateCompetitive inhibition of HMG-CoA reductase to reduce cholesterol metabolismNausea, headache, memory loss, stomach pain
Fluvastatin (E,3R,5S)-7-[3-(4-fluorophenyl)-1-propan-2-ylindol-2-yl]-3,5-dihydroxyhept-6-enoic acidCompetitive inhibition of HMG-CoA reductase, effect on SREBP1 pathway to reduce cholesterol metabolismChills, loss of appetite, muscle ache, joint pain
DisulfiramN,N-diethyl[(diethylcarbamothioyl)disulfanyl]carbothioamideCombination with Copper has cytotoxic eventsBlurred vision, chest pain, confusion, nausea
Metformin3-(diaminomethylidene)-1,1-dimethylguanidineBlocks mitochondrial respiratory chain, reducing ATP concentrationNausea, stomach ache, loss of appetite, metallic taste in mouth
Canagliflozin(2S,3R,4R,5S,6R)-2-[3-[[5-(4-fluorophenyl)thiophen-2-yl]methyl]-4-methylphenyl]-6-(hydroxymethyl)oxane-3,4,5-triolSuppression of intracellular glucose uptake by HCC cells by interfering with SGLT2 and GLUT1 pathwayIndigestion, nausea, loss of appetite, trouble in breathing
Pimozide3-[1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl]-1H-benzimidazol-2-oneInhibits stem-like cells and carcinogenesis in HCC cellsWeakness, constipation, changes in posture, dry mouth
Valproate2-propylpentanoic acidReduces the activity of the HDAC (histone deacetylases) gene and tumor cell differentiationStomach ache, tremors, headache, weight gain
Bexarotene4-[1-(3,5,5,8,8-pentamethyl-6,7-dihydronaphthalen-2-yl)ethenyl]benzoic acidSelective inhibition of RXR that reduces angiogenesis and metastasisWeakness, chills, weight gain, skin rash
Chloroquine 4-N-(7-chloroquinolin-4-yl)-1-N,1-N-diethylpentane-1,4-diamineInhibition of receptor tyrosine kinases and mTORC1 pathwayBleeding gums, difficulty in breathing, paralysis, nausea
Linagliptin8-[(3R)-3-aminopiperidin-1-yl]-7-but-2-ynyl-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]purine-2,6-dioneCauses cell cycle arrest at G2/M and S phase Trembling, sweating, confusion, difficulty concentrating
Lidocaine2-(diethylamino)-N-(2,6-dimethylphenyl)acetamideChemosensitizing effect with 5-fluorouracil increases its anticancer potency and apoptosis inducing effectsHeadache, drowsiness, feeling fear, blistering at site of application
Raloxifene[6-hydroxy-2-(4-hydroxyphenyl)-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanoneInhibition of IL-6 and GP130 binding, and STAT3 genesHot flashes, trouble in sleeping, swollen joints, depression
Itraconazole2-butan-2-yl-4-[4-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-oneInhibition of Wnt/β-catenin signaling pathway, causing cell cycle arrestTrouble breathing, mood changes, irregular heartbeat, increased thirst
ClofazimineN,5-bis(4-chlorophenyl)-3-propan-2-yliminophenazin-2-amineBlocks menaquinone, leading to reduction in ATP productionDecreased vision, bone pain, irregular heartbeat, depression
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Mani, R.J.; Anand, M.; Agarwal, K.; Tiwari, A.; Amanur Rahman Hashmi, Q.; Vikram Singh, T.; Nongdam, P.; Katare, D.P.; Potshangabam, A.M. A Systematic Review of Molecular Pathway Analysis of Drugs for Potential Use in Liver Cancer Treatment. Drugs Drug Candidates 2023, 2, 210-231. https://doi.org/10.3390/ddc2020013

AMA Style

Mani RJ, Anand M, Agarwal K, Tiwari A, Amanur Rahman Hashmi Q, Vikram Singh T, Nongdam P, Katare DP, Potshangabam AM. A Systematic Review of Molecular Pathway Analysis of Drugs for Potential Use in Liver Cancer Treatment. Drugs and Drug Candidates. 2023; 2(2):210-231. https://doi.org/10.3390/ddc2020013

Chicago/Turabian Style

Mani, Ruchi Jakhmola, Mridul Anand, Kritie Agarwal, Avi Tiwari, Qazi Amanur Rahman Hashmi, Tumul Vikram Singh, Potshangbam Nongdam, Deepshikha Pande Katare, and Angamba Meetei Potshangabam. 2023. "A Systematic Review of Molecular Pathway Analysis of Drugs for Potential Use in Liver Cancer Treatment" Drugs and Drug Candidates 2, no. 2: 210-231. https://doi.org/10.3390/ddc2020013

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