Summary of the repurposed drugs for BC discussed in the chapter.
Abstract
Drug repurposing is one of the best strategy for drug discovery. There are several examples where drug repurposing has revolutionized the drug development process, such as metformin developed for diabetes and is now employed in polycystic ovarian syndrome. Drug repurposing against breast cancer is currently a hot topic to look upon. With the continued rise in breast cancer cases, there is a dire need for new therapies that can tackle it in a better way. There is a rise of resistance to current therapies, so drug repurposing might produce some lead candidates that may be promising to treat breast cancer. We will highlight the breast cancer molecular targets, currently available drugs, problems with current therapy, and some examples that might be promising to treat it.
Keywords
- drug repurposing
- breast cancer
- mechanism
- non-oncology drugs
- resistance
1. Introduction
Drug discovery is a multifaceted process that aims at identifying a therapeutic agent that can be useful in treating and managing certain medical conditions. This process includes identification of candidates, characterization, validation, optimization, screening, and assays for therapeutic effectiveness. If a molecule achieves acceptable results in these studies, then the molecule has to go through drug development processes and be recruited to clinical trials [1]. Several drug candidates (about 90%) have collapsed in early clinical trials due to unexpected results such as adverse effects or inadequate effectiveness [2, 3]. Drug development is probably among the most complicated and challenging processes in biomedical research. Apart from the already enormous complexities underlying pharmacological drug designs, additional significant challenges arise from clinical, regulatory, intellectual property, and commercial constraints. Such as challenging atmosphere has made the drug development process very sluggish and unpredictable [4]. The process of discovering and developing a new drug is a lengthy and expensive process taking somewhere from 10 to 15 years and costs about US$2–3 billion [1]. Despite massive sums of money being spent on drug development, no substantial rise in the new therapeutic drug agents in a clinical setting has been observed over several decades. Although overall global R&D spending for drug discovery has risen 10-fold from 1975 (the US $4 billion) to 2009 ($40 billion), the number of novel molecular entities (NMEs) approved has stayed essentially constant since 1975 (26 new drugs approved in 1976 and 27 new drugs approved in 2013) [5].
The essential step in discovering new drugs involves the evaluation of the safety and effectiveness of new drug candidates in human subjects, and it consists of four phases. In Phase I clinical trial, the candidate drug’s safety is assessed in a small population (20–80 individuals) to establish safe dose range and uncover adverse effects. Phase II involves the examination of intervention for its effectiveness and safety in large populations (a few hundred people). Phase III further involves the assessment of drug efficacy in a large population (several thousand) and compares new drug candidates with standard or experimental treatments. Phase IV is conducted when the intervention is marketed. This study aims to track how well the approved treatment is performing in the general population and gather data on side effects that may arise from broad usage over time. Phase III studies determine whether or not a medication is effective, and if so, FDA clearance is granted. The FDA approves one anticancer treatment out of every 5000–10,000 applicants, and just 5% of oncology medicines entering Phase I clinical trials are approved in the end. Because of the increased cost and time frame for new medication development in recent years, patients with severe illness may die until alternative therapies are available if they develop resistance to current therapy [6]. In searching for an alternative treatment option for managing various diseases, including cancer, the researchers have shifted their focus to drug repurposing strategies.
The drug purposing or drug reprofiling or drug redesigning process explores the therapeutic use of existing clinically approved, off patent drugs with known targets for another indication to minimize the cost of therapy, time, and risk [7]. The huge benefit of drug repurposing is that the efficacy, pharmacokinetics, pharmacodynamics, and toxicity characteristics have previously been explored in preclinical and Phase I investigation. These drug moieties may thus be quickly made to proceed to Phase II and Phase III clinical trials, and hence related developmental costs might be substantially lowered [6, 8]. The failure risk in drug development is low because
The development of new drugs for breast cancer like any other cancer is a multistep process that includes drug designing, synthesis, characterization, safety and efficacy assessment, and finally, regulatory approval (Figure 2). The overall process is very lengthy and involves significant financial expenditure [11]. Further, the sky-high cost of the therapies and associated side effects make it desirable to look for other approaches to manage cancer effectively. Therefore, concurrently with the synthesis and design of new therapeutic modalities, various strategies should be considered for repurposing various already approved drugs that may target this deadly disease.
2. Non-oncology drugs repurposed for breast cancer (preclinical data)
2.1 Aspirin
Aspirin was originally discovered in 1897 and was first commercialized as an analgesic. It has been utilized as an anti-inflammatory medication and for managing arterial and venous thrombosis [12]. Recent research has sparked interest in the usage of Aspirin for the prevention of various cancers. There are compelling evidences authenticating that regular use of low doses of aspirin results in a significant reduction in the occurrences and mortality of various cancers [13, 14, 15, 16, 17]. The possibility that Aspirin has an anticancer benefit has received considerable interest nowadays, with a lot of research being done to figure out how successful it is in the prevention of colorectal cancer [18], lung cancer [19], gastric cancer [20], prostate cancer [21], and many other cancers including breast cancer. Because of the effect of Aspirin in several biological processes such as inhibitory effect on angiogenesis [22], cancer cell metastasis [23], causing cell apoptosis [24], etc., it is reasonable to predict that Aspirin will be beneficial when employed as an additional alternative treatment option for cancer patients. Aspirin directly inhibits the activity of the enzyme cyclooxygenase (COX-2) and thereby impedes the synthesis of prostaglandin E2 (PGE-2), which leads to cancer cell death [25]. Recent research also suggests that Aspirin may mediate anticancer potential through COX-independent pathways such as inhibition of NFκB [26], downregulation of survivin [20], targeting AMPK-mTOR signaling [27], Wnt signaling cascade [28], etc.
A study was conducted by Dai et al. reported that Aspirin possesses antiangiogenic and anti-metastatic potential in MDA MB 23 cell line by directly binding to the enzyme heparinase. The results were further confirmed
Further inhibitory effect of TGF-β/SMAD4 signaling, as evident from decreasing the production of SMAD proteins, also contributes to the anti-metastatic potential of Aspirin [30]. In another study, Choi et al. demonstrated the effect of Aspirin in the MCF-7 cell line. It was observed that Aspirin alters the complex formation between Bcl-2 and FKBP38 and leads to the nuclear translocation of Bcl-2 and phosphorylation that causes its activation, contributing to its inhibitory effect on MCF-7 cell proliferation and also triggers apoptosis in cell lines [31]. In combination with exemestane, Aspirin showed synergy in inhibition of cell proliferation. Significant arrest in the G0/G1 phase was observed along with a more detrimental effect on COX-1 and Bcl-2 expression than individual therapy [32]. In addition, when combined with tamoxifen (which is used as a drug of choice for the estrogen receptor positive BC), it downregulates the level of cyclinD1. Subsequently, it arrests the cell cycle in phase G0/G1. In the same study, authors also reported that Aspirin inhibits the ER + ve BC cells growth and overcomes the resistance to tamoxifen in MCF-7/TAM cell line. Study demonstrated a new way to treat ER + ve BC in combination therapy of Aspirin and tamoxifen [33].
2.2 Metformin
Metformin (1,1-dimethyl biguanide hydrochloride) is a well-recognized biguanide derivative and has a long history of usage in managing type 2 diabetes (T2D). Because of the outstanding ability to lower plasma glucose levels, metformin has become the primary drug for managing T2D [34]. The drug was firstly approved in 1958 in the United Kingdom, and this decade-old drug is in the WHO’s list of essential medicines [35]. Metformin belongs to the category of successful repurposed drugs and advanced into the clinical trials Phase 3/4 for its use in the prostate, oral, breast, pancreatic, and endometrial cancers [6]. Various preclinical and clinical examinations have demonstrated the effectiveness of metformin in the treatment of various malignancies such as pancreatic cancer [36], gastric cancer [37], blood cancer [38], etc. A meta-analysis study on diabetic patients with breast cancer concluded that patients who were treated with metformin and neoadjuvant therapy had a higher pathological complete response rate (24%) compared with patients not undergoing metformin treatment (8%) [39]. Another meta-analysis study demonstrated 65% survival improvement when compared with control [40]. Metformin has increased the survival opportunity in type 2 diabetic patients suffering from invasive breast cancer [41]. Study also suggested that patients on metformin demonstrate improved in the survival and response to treatment [40]. The metformin uptake is mediated by the OCT1 in BC cells [42], which is reported to play important role in the BC cells as an anticancer activity [43]. Upon entry into the cells, it leads to increase apoptosis, anti-proliferative, anti-angiogenic, which seems to be mediated by the mTOR, Akt/MAPK pathway [44]. Study conducted by Shi et al., established that metformin can also inhibit the expression of the COX-2, suggested the potential of metformin in combination with others COX-2 inhibitor [45]. Low cost and stability of metformin make it a good candidate for the treatment of cancers when compared with available treatment options [46].
2.3 Itraconazole (ITC)
Itraconazole, a triazole antifungal drug, is a well-tolerable agent that is extremely effective against a wide range of fungal infections. Itraconazole is a highly potent and effective antifungal agent due to its active metabolite, hydroxy-itraconazole, which also has significant antifungal action [47]. Itraconazole blocks ergosterol synthesis in the fungal cell membrane by inhibiting the enzyme 14α-demethylase and suppressing their growth [48]. It has emerged as a potent anticancer agent because of its ability to overcome chemoresistance prompted by P glycoproteins, altering various signaling pathways such as hedgehog (Hh) signaling cascade, Wnt/β-catenin pathway in cancer cells, and also preventing angiogenesis and lymphangiogenesis [49]. Itraconazole has been shown to have the ability to eliminate cancer cells by disrupting Hh signaling [50]. In invertebrates, the Hh signaling cascade is responsible for the regulation of complicated developmental processes. However, aberrant activation of this pathway plays a crucial role in carcinogenesis and cancer maintenance and contributes to chemoresistance, thus, targeting this pathway offers the potential therapeutic possibility [51]. Itraconazole was able to exhibit cytotoxicity in breast cancer cell lines by influencing mitochondrial membrane potential through induction of apoptosis, decreasing expression of Bcl-2, and enhancing the caspase activity. Itraconazole also promoted autophagic cell death via elevation of LC3-II expression, degradation of P62/SQSTM1, formation of autophagosomes. Hedgehog signaling is an important regulator of apoptosis and autophagy. Hence, inhibition of this signaling by Itraconazole results in cytotoxicity, tumor shrinkage, apoptosis, and autophagy in breast cancer both in
Additionally, the level of other growth factors such as fibroblast growth factor (FGF) and placenta-derived growth factor also decreased without any direct association with the Itraconazole [54]. When administered in combination with other cytotoxic agents, Itraconazole increased the response rate [55]. Researchers are trying various ways to enhance the anti-neoplastic activity of itraconazole. One such example is the development of the modified lipid nanoparticles having Miltefosine (subtherapeutic dose), called M-ITC-LNC (Membrane additive itraconazole with lipid nanoparticles (Miltefosine). The results from the cytotoxicity studies demonstrated that the anticancer activity and selectivity significantly increased in MCF-7 BC cells compared with the ITC-solution and ITC-LNC without modification [56]. In another study, itraconazole was co-delivered with the doxorubicin by liposome (coated with the Pluronic P123), resulting in the increased anti-neoplastic activity in BC [57]. The combination of the verapamil and ITC with 5-FU decreased cell survival and proliferation.
Moreover, ITC and 5-FU are more effective in the treatment of BC [58]. Administration of the Itraconazole with erlotinib (tyrosine kinase inhibitor) increased the AUC and Cmax by 10.8 and 2.78-fold, respectively, without any SAE [59]. Abovementioned all the studies reveal the potential of Itraconazole alone or in combination with other anticancer agents to treat BC.
2.4 Simvastatin
Simvastatin belongs to the class of statins and is a well-explored hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that reduces cholesterol biosynthesis initially used to reduce cholesterol biosynthesis marketed in 1988 [60]. Clinical data suggest that statins are effective in BC management. Statins amplify tumor cell death and radiosensitivity in various cell lines, inhibit invasion and proliferation, and show anti-metastatic activity. Clinical trials conducted on breast cancer (inflammatory and TNBC) patients also favored these observations by representing improved mortality benefits for patients on statins [61, 62]. In the same context, Simvastatin is the most explored statin to explore the role of statins in cancer. Simvastatin targets the transcription factor NFκB that reduces the expression level of anti-apoptotic protein Bcl-xL, concomitantly inhibits the expression of anti-proliferative and proapoptotic tumor suppressor PTEN and hence inhibiting the growth of breast cancer cells. The elevation of PTEN expression results in the suppression of Akt phosphorylation. Akt activity is upregulated in many cancers by increasing cancer cell survival, inhibiting apoptosis, and increasing proliferation. Therefore, Simvastatin substantially decreased Akt phosphorylation concurrently with the reduction in expression of anti-apoptotic protein by dysregulation of NFκB, thus showing the anticancer activity against BC [63]. On administration of Simvastatin, the expression of PTTG1 (pituitary tumor-transforming gene 1) was also reduced in a dose-dependent manner in the MDA-MB-231 cell line. PTTG1 is the important gene involved in the invasion and metastasis of BC [64]. In the same cell line (MDA-MB-231), Simvastatin leads to fragmentation of the cell’s nuclei, subsequently inducing apoptosis. It also enhanced the level of ROS in a dose-dependent manner, which causes oxidative stress and further DNA damage [65]. Apoptotic effects were due to the increased expression of miR-140-5p in a dose-dependent manner mediated by the activating transcription factor NRF1 [65]. Apart from the MDA-MB-231 cell line, Simvastatin effects were also explored in other breast cancer cell lines such as T47D, BT-549, and MCF-7, showing apoptotic inducer anti-proliferative activity [66, 67]. In
In the same series, Sed et al. used nanoparticles made of superparamagnetic iron oxide to Simvastatin delivery with enhanced anticancer activity in the PC-3 cell line. This action is mediated by inducing apoptosis and cell cycle arrest in the G2 phase [70]. Researchers from another lab developed poly D, L-lactide-co-glycolide (PLGA) with cholic-acid-based nanoparticles for Simvastatin release in a sustained and controlled manner for breast adenocarcinoma treatment. These nanoparticles showed maintainable and more efficiently inhibit tumor growth than normal Simvastatin [71]. Other formulations such as nanocapsule [72], nanoemulsions [73], liposomes [74], and immunoliposome [75] for Simvastatin were developed with increased anticancer activity in breast cancer cells. In a randomized placebo-controlled study, Simvastatin shows a better anticancer profile with the carboplatin and vinorelbine in metastatic breast cancer [76]. Consistency in the results from both clinical and preclinical studies suggests the vast potential of Simvastatin in treating breast cancer either alone or in combination. Moreover, the development of nanoformulations also provided advantages such as enhanced cytotoxicity, lower side effects, targeted delivery over the conventional available treatment options for BC.
2.5 Niclosamide
Niclosamide, an FDA-approved anthelminthic drug used to manage tapeworm infection, has been used almost from the last half of the century and included in the WHO’s list of essential medicines. Recent research suggests that niclosamide has a wide range of therapeutic uses other than treating parasitic infection. Niclosamide’s clinical application diseases include type 2 diabetes, endometriosis, neuropathic pain, bacterial and viral infections, including cancer [77]. The anticancer benefits of niclosamide have been shown in many malignancies such as colon cancer, lung cancer, prostate cancer in humans, as well as breast cancer by suppressing various cancer related pathways such as Wnt Notch, mTOR, STAT, and NFκB [78, 79]. The combinational treatment of niclosamide with cisplatin overcomes the resistance to cisplatin and induces an inhibitory effect on proliferation
Further, niclosamide prevented the epithelial-mesenchymal transition (EMT) by suppressing mesenchymal markers such as snail and vimentin. The inhibitory effect on EMT and prevention of stem-like phenotype of TNBC by Niclosamide operate by disabling various abnormal signaling pathways such as Akt, ERK, and Src [80]. The niclosamide acts as a potent inhibitor of STAT signaling by preventing cancer cell proliferation, invasion, and metastasis by decreasing the phosphorylation of STAT3 that otherwise was found in 35% of breast cancer tissues. Furthermore, STAT3 promotes the expression of several key downstream genes involved in proliferation, cell survival, and angiogenesis in breast cancer [81]. Human monocyte cells were reduced to HUVECs in the presence of niclosamide. Niclosamide also inhibited VCAM-1 and ICAM1 protein expression in HUVECs. Niclosamide decreased HUVEC proliferation, migration, and development of cord-like structures.
Drug | Experimental model | Mechanism of action | Observation | Original indication | References |
---|---|---|---|---|---|
Aspirin | B16F10, MDA-MB-231, MDA-MB-435 xenograft mode MCF-7, MDA-MB-231 MCF-7, MDA-MB231 | Inhibition of heparinase Inhibition of TGF-β/SMAD4 signaling pathway ↓EMT Apoptosis | ↓Metastasis, ↓angiogenesis ↓Mesenchymal markers (vimentin, Snail, TWIST) | NSIAD | [23, 30, 31] |
Itraconazole | MCF-7 and SKBR-3 breast cancer cell | Antiproliferative effect via inhibition of hedgehog signaling cascade ↑Apoptosis ↑Autophagy ↑Cell cycle arrest | ↓Tumor size ↑Caspase 3 ↓Bcl-2 | Antifungal drug | [50] |
Niclosamide | ↓EM T ↑Apoptosis Inhibition of stat signaling | ↓Snail ↓Vimentin ↓Tumor growth ↑Caspase 3, ↓Bcl-2, ↓surviving, ↓Mcl-1 expression | Anthelminthic drug | [80, 81] | |
Simvastatin | MDA-MB-231, T47D, BT-549 and MCF-7 ( DMBA model ( | ↓PTTG1, ↓Bcl-xL ↑ROS ↑miR-140-5p Inhibition of Akt and DNA damage | Anti-proliferative, induce apoptosis, and increased survival | Anti-hypercholesterolemic drug | [63, 64, 65, 66, 67] |
Metformin | MDA-MB-231, MCF-7 | Via mTOR, Akt/MAPK pathway COX-2 inhibition | Apoptosis, anti-proliferative, anti-angiogenic | Anti-diabetic drug | [44, 45] |
3. Conclusion
Drug discovery is a multifaceted process that aims at identifying a therapeutic agent that can be useful in treating and managing various ailments. This process includes identification of candidates, characterization, validation, optimization, screening, and assays for therapeutic effectiveness. As the mortality due to cancer is progressively increasing, we need effective therapy to treat breast cancer patients or improve survival. When any pharmaceutical organization starts developing a novel chemical entity for the BC, its cost and attrition rate are very high. Drugs repurposing is how we can minimize the cost and attrition rate by using the already marketed drugs for a new use. Drug repurposing against breast cancer is one of the best alternatives to treat progressive ailments. In the above discussion, we have discussed various drugs that can be repurposed against breast cancer. It will be a game-changing scenario in the treatment of breast cancer. Certain challenges need to be rectified. However, there is a need for optimization of models and more screening of drugs at preclinical stages.
4. Future prospective
To tackle all the challenges associated with the drug development process for breast cancer, scientists need to shift their interest to the alternative drug development, that is, drug repurposing. All the BC repurposed drugs discussed in the book chapter show impressive results that suggest exploring more new non-cancerous drugs for cancerous use [92]. Using the drugs repurposing approaches alone and in combination with other drugs will also reduce the side effects associated with high doses. It will also reduce the cost of the drug development process, ultimately patient compliances and burden. Patients who could not afford the treatment due to the high cost can take treatment and improve survival. As the safety is already studied of drugs that seem a novel interest in the repurposing for BC, the chances of failure at the clinical level will also be less. With the advancement in drug repurposing, there is still a need to develop a valuable model of different types of cancers that mimic cancer. The development of such a model provides the actual clue for drug repurposing. So far, the advantages we discussed, there are some challenges associated with the drugs repurposing such as patent issue, regulatory consideration, inequitable prescription that need to be overcome so, more and more pharma companies show their interest in drug repurposing. It is expected that drug repurposing will achieve the milestone that is currently not possible with the conventional available treatment for cancers in the future. Furthermore, new nanoformulations need to be developed for the targeted and specific delivery of repurposed anticancer drug to avoid the off-target side effects.
References
- 1.
Deore A, Dhumane J, Wagh R, Sonawane R. The stages of drug discovery and development process. Asian Journal of Pharmaceutical Research & Development. 2019; 7 :62-67 - 2.
Arrowsmith J. Trial watch: Phase II failures: 2008-2010. Nature Reviews Drug Discovery. 2011; 10 (5):328-329 - 3.
Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemporary Clinical Trials Communications. 2018; 11 :156-164 - 4.
Hernández-Lemus E, Martínez-García M. Pathway-based drug-repurposing schemes in cancer: The role of translational bioinformatics. Frontiers in Oncology. 2020; 10 :605680 - 5.
Shim JS, Liu JO. Recent advances in drug repositioning for the discovery of new anticancer drugs. International Journal of Biological Sciences. 2014; 10 (7):654-663 - 6.
Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui Y, et al. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduction and Targeted Therapy. 2020; 5 (1):113 - 7.
Pushpakom S, Iorio F, Eyers PA, Escott KJ, Hopper S, Wells A, et al. Drug repurposing: Progress, challenges and recommendations. Nature Reviews Drug Discovery. 2019; 18 (1):41-58 - 8.
Armando RG, Mengual Gómez DL, Gomez DE. New drugs are not enough-drug repositioning in oncology: An update. International Journal of Oncology. 2020; 56 (3):651-684 - 9.
Ko Y. Computational drug repositioning: Current progress and challenges. Applied Sciences. 2020; 10 (15):5076 - 10.
Ávalos-Moreno M, López-Tejada A, Blaya-Cánovas JL, Cara-Lupiañez FE, González-González A, Lorente JA, et al. Drug repurposing for triple-negative breast cancer. Journal of. Personalized Medicine. 2020; 10 (4):200 - 11.
Aggarwal S, Verma SS, Aggarwal S, Gupta SC. Drug repurposing for breast cancer therapy: Old weapon for new battle. Seminars in Cancer Biology. 2021; 68 :8-20 - 12.
Rose PW, Watson EK, Jenkins LSC. Aspirin for prevention of cancer and cardiovascular disease. The British Journal of General Practice. 2011; 61 (587):412-415 - 13.
Tsoi KKF, Ho JMW, Chan FCH, Sung JJY. Long-term use of low-dose Aspirin for cancer prevention: A 10-year population cohort study in Hong Kong. International Journal of Cancer. 2019; 145 (1):267-273 - 14.
Algra AM, Rothwell PM. Effects of regular Aspirin on long-term cancer incidence and metastasis: A systematic comparison of Evidence from observational studies versus randomised trials. The Lancet Oncology. 2012; 13 (5):518-527 - 15.
Qiao Y, Yang T, Gan Y, Li W, Wang C, Gong Y, et al. Associations between aspirin use and the risk of cancers: A meta-analysis of observational studies. BMC Cancer. 2018; 18 (1):288 - 16.
Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, et al. Short-term effects of daily Aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. The Lancet. 2012; 379 (9826):1602-1612 - 17.
Mills EJ, Wu P, Alberton M, Kanters S, Lanas A, Lester R. Low-dose aspirin and cancer mortality: A meta-analysis of randomized trials. The American Journal of Medicine. 2012; 125 (6):560-567 - 18.
Garcia-Albeniz X, Chan AT. Aspirin for the prevention of colorectal cancer. Best Practice & Research. Clinical Gastroenterology. 2011; 25 (4-5):461-472 - 19.
Shi T, Fujita K, Gong J, Nakahara M, Iwama H, Liu S, et al. Aspirin inhibits hepatocellular carcinoma cell proliferation in vitro and in vivo via inducing cell cycle arrest and apoptosis. Oncology Reports. 2020; 44 (2):457-468 - 20.
Yang L, Zhu H, Liu D, Liang S, Xu H, Chen J, et al. Aspirin suppresses growth of human gastric carcinoma cell by inhibiting survivin expression. Journal of Biomedical Research. 2011; 25 (4):246-253 - 21.
Lloyd FP Jr, Slivova V, Valachovicova T, Sliva D. Aspirin inhibits highly invasive prostate cancer cells. International Journal of Oncology. 2003; 23 (5):1277-1283 - 22.
Zhang X, Wang Z, Wang Z, Zhang Y, Jia Q, Wu L, et al. Impact of acetylsalicylic acid on tumor angiogenesis and lymphangiogenesis through inhibition of VEGF signaling in a murine sarcoma model. Oncology Reports. 2013; 29 (5):1907-1913 - 23.
Dai X, Yan J, Fu X, Pan Q, Sun D, Xu Y, et al. Aspirin inhibits cancer metastasis and angiogenesis via targeting heparanase. Clinical Cancer Research. 2017; 23 (20):6267 - 24.
Zimmermann KC, Waterhouse NJ, Goldstein JC, Schuler M, Green DR. Aspirin induces apoptosis through release of cytochrome C from mitochondria. Neoplasia. 2000; 2 (6):505-513 - 25.
Sostres C, Gargallo CJ, Lanas A. Aspirin, cyclooxygenase inhibition and colorectal cancer. World Journal of Gastrointestinal Pharmacology and Therapeutics. 2014; 5 (1):40-49 - 26.
Chen J, Stark LA. Aspirin prevention of colorectal cancer: Focus on NF-κB signalling and the nucleolus. Biomedicine. 2017; 5 (3):43 - 27.
Yue W, Yang CS, DiPaola RS, Tan X-L. Repurposing of metformin and aspirin by targeting AMPK-mTOR and inflammation for pancreatic cancer prevention and treatment. Cancer Prevention Research. 2014; 7 (4):388 - 28.
Gala MK, Chan AT. Molecular pathways: Aspirin and Wnt signaling-a molecularly targeted approach to cancer prevention and treatment. Clinical Cancer Research. 2015; 21 (7):1543-1548 - 29.
Coombe DR, Gandhi NS. Heparanase: A challenging cancer drug target. Frontiers in Oncology. 2019; 9 (1316):1316 - 30.
Maity G, De A, Das A, Banerjee S, Sarkar S, Banerjee SK. Aspirin blocks growth of breast tumor cells and tumor-initiating cells and induces reprogramming factors of mesenchymal to epithelial transition. Laboratory Investigation. 2015; 95 (7):702-717 - 31.
Choi B-H, Chakraborty G, Baek K, Yoon HS. Aspirin-induced Bcl-2 translocation and its phosphorylation in the nucleus trigger apoptosis in breast cancer cells. Experimental and Molecular Medicine. 2013; 45 (10):e47-e - 32.
Hu LX, Du YY, Zhang Y, Pan YY. Synergistic effects of exemestane and Aspirin on MCF-7 human breast cancer cells. Asian Pacific Journal of Cancer Prevention : APJCP. 2012; 13 (11):5903-5908 - 33.
Cheng R, Liu YJ, Cui JW, Yang M, Liu XL, Li P, et al. Aspirin regulation of c-myc and cyclinD1 proteins to overcome tamoxifen resistance in estrogen receptor-positive breast cancer cells. Oncotarget. 2017; 8 (18):30252-30264 - 34.
Lv Z, Guo Y. Metformin and its benefits for various diseases. Frontiers in Endocrinology. 2020; 11 :191 - 35.
Bailey CJ. Metformin: Historical overview. Diabetologia. 2017; 60 (9):1566-1576 - 36.
Li X, Li T, Liu Z, Gou S, Wang C. The effect of metformin on survival of patients with pancreatic cancer: A meta-analysis. Scientific Reports. 2017; 7 (1):5825 - 37.
Sekino N, Kano M, Matsumoto Y, Sakata H, Murakami K, Toyozumi T, et al. The antitumor effects of metformin on gastric cancer in vitro and on peritoneal metastasis. Anticancer Research. 2018; 38 (11):6263 - 38.
Cunha Júnior AD, Pericole FV, Carvalheira JBC. Metformin and blood cancers. Clinics (São Paulo, Brazil). 2018; 73 (suppl 1):e412s-es - 39.
Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology. 2009; 27 (20):3297-3302 - 40.
Xu H, Chen K, Jia X, Tian Y, Dai Y, Li D, et al. Metformin use is associated with better survival of breast cancer patients with diabetes: A meta-analysis. The Oncologist. 2015; 20 (11):1236-1244 - 41.
Hui T, Shang C, Yang L, Wang M, Li R, Song Z. Metformin improves the outcomes in Chinese invasive breast cancer patients with type 2 diabetes mellitus. Scientific Reports. 2021; 11 (1):10034 - 42.
Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. The Journal of Clinical Investigation. 2007; 117 (5):1422-1431 - 43.
Hadad S, Iwamoto T, Jordan L, Purdie C, Bray S, Baker L, et al. Evidence for biological effects of metformin in operable breast cancer: A pre-operative, window-of-opportunity, randomized trial. Breast Cancer Research and Treatment. 2011; 128 (3):783-794 - 44.
Zhu P, Davis M, Blackwelder AJ, Bachman N, Liu B, Edgerton S, et al. Metformin selectively targets tumor-initiating cells in ErbB2-overexpressing breast cancer models. Cancer Prevention Research (Philadelphia, Pa.). 2014; 7 (2):199-210 - 45.
Shi B, Hu X, He H, Fang W. Metformin suppresses breast cancer growth via inhibition of cyclooxygenase-2. Oncology Letters. 2021; 22 (2):615 - 46.
Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: A comprehensive review of recent advances. Cancer Management and Research. 2019; 11 :3295-3313 - 47.
De Beule K, Van Gestel J. Pharmacology of itraconazole. Drugs. 2001; 61 (1):27-37 - 48.
Ghelardi E, Celandroni F, Gueye SA, Salvetti S, Senesi S, Bulgheroni A, et al. Potential of ergosterol synthesis inhibitors to cause resistance or cross-resistance in Trichophyton rubrum . Antimicrobial Agents and Chemotherapy. 2014;58 (5):2825-2829 - 49.
Tsubamoto H, Ueda T, Inoue K, Sakata K, Shibahara H, Sonoda T. Repurposing itraconazole as an anticancer agent. Oncology Letters. 2017; 14 (2):1240-1246 - 50.
Wang X, Wei S, Zhao Y, Shi C, Liu P, Zhang C, et al. Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death. Cancer Letters. 2017; 385 :128-136 - 51.
Briscoe J, Thérond PP. The mechanisms of hedgehog signalling and its roles in development and disease. Nature Reviews Molecular Cell Biology. 2013; 14 (7):416-429 - 52.
Liang G, Liu M, Wang Q, Shen Y, Mei H, Li D, et al. Itraconazole exerts its anti-melanoma effect by suppressing hedgehog, Wnt, and PI3K/mTOR signaling pathways. Oncotarget. 2017; 8 (17):28510-28525 - 53.
Zhang W, Bhagwath AS, Ramzan Z, Williams TA, Subramaniyan I, Edpuganti V, et al. Itraconazole exerts its antitumor effect in esophageal cancer by suppressing the HER2/AKT signaling pathway. Molecular Cancer Therapeutics. 2021; 20 (10):1904-1915 - 54.
Ademuyiwa FO, Zhao Q, Perkins SM, Gebregziabher N, Jones DR, Vaughn LG, et al. A pilot trial of itraconazole pharmacokinetics in patients with metastatic breast cancer. Journal of Clinical Oncology. 2011; 29 (15_suppl):e13565-e - 55.
Tsubamoto H, Sonoda T, Inoue K. Impact of itraconazole on the survival of heavily pre-treated patients with triple-negative breast cancer. Anticancer Research. 2014; 34 (7):3839-3844 - 56.
El-Sheridy NA, El-Moslemany RM, Ramadan AA, Helmy MW, El-Khordagui LK. Enhancing the in vitro and in vivo activity of itraconazole against breast cancer using miltefosine-modified lipid nanocapsules. Drug Delivery. 2021; 28 (1):906-919 - 57.
Lin Y, He X, Zhou D, Li L, Sun J, Jiang X. Co-delivery of doxorubicin and itraconazole by Pluronic® P123 coated liposomes to enhance the anticancer effect in breast cancers. RSC Advances. 2018; 8 (42):23768-23779 - 58.
Correia A, Silva D, Correia A, Vilanova M, Gärtner F, Vale N. Study of new therapeutic strategies to combat breast cancer using drug combinations. Biomolecules. 2018; 8 (4):175 - 59.
Liu Y, Zhang Q, Lu C, Hu W. Multiple administrations of itraconazole increase plasma exposure to pyrotinib in Chinese healthy adults. Drug Design, Development and Therapy. 2021; 15 :2485-2493 - 60.
Pedersen TR, Tobert JA. Simvastatin: A review. Expert Opinion on Pharmacotherapy. 2004; 5 (12):2583-2596 - 61.
Van Wyhe RD, Rahal OM, Woodward WA. Effect of statins on breast cancer recurrence and mortality: A review. Breast Cancer (Dove Medical Press). 2017; 9 :559-565 - 62.
Tilija Pun N, Jeong C-H. Statin as a potential chemotherapeutic agent: Current updates as a monotherapy, combination therapy, and treatment for anti-cancer drug resistance. Pharmaceuticals. 2021; 14 (5):470 - 63.
Beckwitt CH, Brufsky A, Oltvai ZN, Wells A. Statin drugs to reduce breast cancer recurrence and mortality. Breast Cancer Research. 2018; 20 (1):144 - 64.
Yin L, He Z, Yi B, Xue L, Sun J. Simvastatin suppresses human breast cancer cell invasion by decreasing the expression of pituitary tumor-transforming gene 1. Frontiers in Pharmacology. 2020; 11 (1698):574068 - 65.
Bai F, Yu Z, Gao X, Gong J, Fan L, Liu F. Simvastatin induces breast cancer cell death through oxidative stress upregulating miR-140-5p. Aging. 2019; 11 (10):3198-3219 - 66.
Li G, Zheng J, Xu B, Ling J, Qiu W, Wang Y. Simvastatin inhibits tumor angiogenesis in HER2-overexpressing human colorectal cancer. Biomedicine & Pharmacotherapy. 2017; 85 :418-424 - 67.
Rezano A, Ridhayanti F, Rangkuti AR, Gunawan T, Winarno GNA, Wijaya I. Cytotoxicity of Simvastatin in human breast cancer MCF-7 and MDA-MB-231 cell lines. Asian Pacific Journal of Cancer Prevention. 2021; 22 (S1):33-42 - 68.
Rennó AL, Alves-Júnior MJ, Rocha RM, De Souza PC, de Souza VB, Jampietro J, et al. Decreased expression of stem cell markers by Simvastatin in 7,12-dimethylbenz(a)anthracene (DMBA)-induced breast cancer. Toxicologic Pathology. 2015; 43 (3):400-410 - 69.
Karimi B, Ashrafi M, Shomali T, Yektaseresht A. Therapeutic effect of Simvastatin on DMBA-induced breast cancer in mice. Fundamental and Clinical Pharmacology. 2019; 33 (1):84-93 - 70.
Sedki M, Khalil IA, El-Sherbiny IM. Hybrid nanocarrier system for guiding and augmenting Simvastatin cytotoxic activity against prostate cancer. Artificial Cells, Nanomedicine, and Biotechnology. 2018; 46 (sup3):S641-SS50 - 71.
Duarte JA, de Barros ALB, Leite EA. The potential use of Simvastatin for cancer treatment: A review. Biomedicine and Pharmacotherapy. 2021; 141 :111858 - 72.
Matusewicz L, Czogalla A, Sikorski AF. Attempts to use statins in cancer therapy: An update. Tumor Biology. 2020; 42 (7):1010428320941760 - 73.
Alkreathy HM, Alkhatib MH, Al Musaddi SA, Balamash KSA, Osman NN, Ahmad A. Enhanced antitumour activity of doxorubicin and Simvastatin combination loaded nanoemulsion treatment against a Swiss albino mouse model of Ehrlich ascites carcinoma. Clinical and Experimental Pharmacology and Physiology. 2019; 46 (5):496-505 - 74.
Li N, Xie X, Hu Y, He H, Fu X, Fang T, et al. Herceptin-conjugated liposomes co-loaded with doxorubicin and Simvastatin in targeted prostate cancer therapy. American Journal of Translational Research. 2019; 11 (3):1255-1269 - 75.
Matusewicz L, Podkalicka J, Sikorski AF. Immunoliposomes with Simvastatin as a potential therapeutic in treatment of breast cancer cells overexpressing her2—An in vitro study. Cancers. 2018; 10 (11):418 - 76.
Alarfi H, Youssef LA, Salamoon M. A prospective, randomized, placebo-controlled study of a combination of Simvastatin and chemotherapy in metastatic breast cancer. Journal of Oncology. 2020; 2020 :4174395 - 77.
Chen W, Mook RA Jr, Premont RT, Wang J. Niclosamide: Beyond an antihelminthic drug. Cellular Signalling. 2018; 41 :89-96 - 78.
Oh H-C, Shim J-K, Park J, Lee J-H, Choi RJ, Kim NH, et al. Combined effects of niclosamide and temozolomide against human glioblastoma tumorspheres. Journal of Cancer Research and Clinical Oncology. 2020; 146 (11):2817-2828 - 79.
World Health Organization. The Selection and Use of Essential Medicines. Geneva: World Health Organization; 2008 - 80.
Liu J, Chen X, Ward T, Pegram M, Shen K. Combined niclosamide with cisplatin inhibits epithelial-mesenchymal transition and tumor growth in cisplatin-resistant triple-negative breast cancer. Tumor Biology. 2016; 37 (7):9825-9835 - 81.
Ye T, Xiong Y, Yan Y, Xia Y, Song X, Liu L, et al. The anthelmintic drug niclosamide induces apoptosis, impairs metastasis and reduces immunosuppressive cells in breast cancer model. PLoS One. 2014; 9 (1):e85887 - 82.
Chen M, Wang J, Lu J, Bond MC, Ren XR, Lyerly HK, et al. The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry. 2009; 48 (43):10267-10274 - 83.
Chen W, Chen M, Barak LS. Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: A high-throughput screening approach. American Journal of Physiology. Gastrointestinal and Liver Physiology. 2010; 299 (2):G293-G300 - 84.
Yin L, Gao Y, Zhang X, Wang J, Ding D, Zhang Y, et al. Niclosamide sensitizes triple-negative breast cancer cells to ionizing radiation in association with the inhibition of Wnt/β-catenin signaling. Oncotarget. 2016; 7 (27):42126-42138 - 85.
Osada T, Chen M, Yang XY, Spasojevic I, Vandeusen JB, Hsu D, et al. Antihelminth compound niclosamide downregulates Wnt signaling and elicits antitumor responses in tumors with activating APC mutations. Cancer Research. 2011; 71 (12):4172-4182 - 86.
Londoño-Joshi AI, Arend RC, Aristizabal L, Lu W, Samant RS, Metge BJ, et al. Effect of niclosamide on basal-like breast cancers. Molecular Cancer Therapeutics. 2014; 13 (4):800-811 - 87.
Lohiya G, Katti DS. A synergistic combination of niclosamide and doxorubicin as an efficacious therapy for all clinical subtypes of breast cancer. Cancers (Basel). 2021; 13 (13):3299 - 88.
Han Z, Li Q, Wang Y, Wang L, Li X, Ge N, et al. Niclosamide induces cell cycle arrest in G1 phase in head and neck squamous cell carcinoma through Let-7d/CDC34 axis. Frontiers in Pharmacology. 2019; 9 (1544):1544 - 89.
Cámara-Sánchez Vall P, García-Aranda Vall N, Gener Vall D’ P, Seras J, Vall F, Giani M, et al. Selectively Targeting Breast Cancer Stem Cells By 8-Quinolinol and Niclosamide. Research Square; 2021. DOI: 10.21203/RS.3.RS-686641/V - 90.
Liu D, Quan H. Anthelminthic niclosamide inhibits tumor growth and invasion in cisplatinresistant human epidermal growth factor receptor 2-positive breast cancer. Oncology Letters. 2021; 22 (3):1-9 - 91.
Ari F, Erkisa M, Pekel G, Erturk E, Buyukkoroglu G, Ulukaya E. Anticancer potential of albumin bound Wnt/β-catenin pathway inhibitor niclosamide in breast cancer cells. ChemistrySelect. 2021; 6 (29):7463-7475 - 92.
Malik JA, Ahmed S, Jan B, Bender O, al Hagbani T, Alqarni A, Anwar S. Drugs repurposed: An advanced step towards the treatment of breast cancer and associated challenges. Biomedicine & Pharmacotherapy; 2022; 145 :112375. DOI: 10.1016/J.BIOPHA.2021.112375