Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials.

1. Introduction

Drug repurposing, also called drug repositioning, is the process of discovering new uses outside the scope of the original medical indication for existing drugs [ 1 ]. It offers important advantages in comparison with traditional drug development procedures. While de novo drug discovery and development may require a 10- to 17-year procedure with a low overall probability of success, drug repurposing may reduce time and risk, as several questions and issues regarding drug discovery and development have been previously addressed [ 1 , 2 , 3 ]. In addition, pharmacovigilance systems continuously collect data regarding the safety profile of the marketed drugs in the real-world setting; this is vital considering multimorbidity (i.e., the coexistence of multiple chronic conditions) and polypharmacy in an aging population with, consequently, well-established and yet-to-discover drug-drug, drug-disease, and disease-disease interactions and relationships.

After the identification of a potential new indication and compound identification and acquisition, drug development may start in preclinical Phase I or Phase II stages, saving time, risk, and costs. In drug repurposing, one of the major objectives during drug development is to study the efficacy of the drug in the new indication under investigation [ 1 ]. Randomized, controlled clinical trials can offer high-quality evidence in this regard. Placebo-controlled or no intervention-controlled studies can generate evidence on the efficacy of the drug in the new indication, assess risk/benefit, and compare with well-established standards of care. Dose-escalation studies help identify the optimal dose for treatment.

Chronic diseases and multimorbidity challenge public health systems worldwide and constitute a global health research priority [ 4 ]. Approximately seven in ten deaths are attributed to chronic conditions; cardiovascular diseases, cancers, chronic respiratory diseases, and diabetes account for over 80% of all premature deaths related to chronic diseases [ 5 , 6 ]. The World Health Organization’s global action plan for the prevention and control of noncommunicable diseases 2013–2020, extended till 2030, includes an important reduction in the risk of premature death and an 80% availability of the affordable basic technologies and essential medicines required to treat these major chronic diseases [ 7 , 8 ]. In this systematic review, we focus on cancer, the second leading cause of death globally, accounting for one in six deaths [ 9 ].

Cancer is one of the most lethal diseases, with a significantly high mortality rate. Prevention mechanisms and research on the human genome offer the possibility of improving cancer diagnosis and treatment [ 10 , 11 ]. Since the 1950s, 5-fluorouracil has been increasingly used and has remained the backbone of most chemotherapy regimens. Several methods related to the function of non-coding transcripts in the modulation of cells can help in the therapeutic effect of 5-fluorouracil [ 12 ]. Currently, there are many therapeutic options, including surgery, chemotherapy, radiation therapy, immunotherapy, and biologic agents [ 13 ]. In recent years, many studies have been carried out to find new therapeutic alternatives, including repositioning [ 13 ].

Accessible early detection and quality treatment can improve survival for many types of cancer [ 9 ]. Significant work is in progress for novel, efficient strategies in cancer treatment; a promising approach is drug repurposing [ 14 ]. We aimed to perform a systematic review in MEDLINE to identify randomized placebo- or no intervention-controlled clinical trials that evaluate drug repurposing possibilities in cancer for marketed drugs that are currently authorized for non-oncological indications. A secondary objective is to identify trials that aim to study the potential use of antineoplastic agents in other non-oncological conditions.

2. Materials and Methods

We conducted a systematic review of the peer-reviewed literature in MEDLINE, following the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement guidelines (see Supplementary Material File S1 ) [ 15 ]. The search strategy combined algorithms for drug repurposing and neoplasms, as shown in Table 1 . MEDLINE was selected as a data source as it comprises more than 35 million citations for biomedical literature, covering most of the research literature in the field.

In this study, we included articles that met all the following criteria: (i) the study was a randomized controlled clinical trial (RCT); (ii) the full text is available; (iii) the paper is in English or Spanish; and (iv) it answers the research question. To properly address this last criterion, we applied the Patient/Population, Intervention, Comparison, and Outcomes (PICO) model [ 16 ], as shown in Figure 1 .

Information from study protocols was also recorded to include RCTs that are in progress. We performed the literature review on 20 November 2022. Three researchers (I.I.-S., N.T.-R., and J.V.-R.) screened titles, abstracts, and full text when considered necessary in pairs, following a double-blind method, to exclude irrelevant articles. When there was disagreement, a final decision was made by consensus. Relevant articles that were cited in the reference list of the included studies and met all the inclusion criteria were also screened for inclusion in the systematic review.

We extracted data regarding the year of publication, country, study period, clinical trial phase, masking, potential new indication in investigation, drug, route of administration, the aim of the study, time frame, target population, age of patients, number of enrolled individuals, intervention group, control group, loss to follow-up, mortality, outcome, main findings, serious adverse drug reactions, authors’ conclusions, limitations, and funding, amongst others. We recorded if multimorbidity was considered. The quality of evidence was assessed following the grading of recommendations assessment, development, and evaluation (GRADE) system [ 17 , 18 ]; a detailed report of the assessment is presented in the Supplementary Material Table S1 .

3. Results

3.1. Literature Search Results

The literature search in MEDLINE gave 55 potentially relevant publications ( Figure 2 ). After the screening, we excluded 13 publications that were not investigating the repurposing of an approved antineoplastic agent for a new non-oncological indication or the repurposing of a drug used in non-oncological conditions for the pharmacological treatment of cancer. We assessed for eligibility the remaining 42 articles plus eight new articles identified as potentially relevant records via citation searching. Finally, 16 articles were included in the review; eight of them were study protocols.

3.2. Excluded Articles

Many of the clinical trials excluded were not randomized controlled trials. Most of them were dose-escalation studies without a placebo- or standard-of-care-alone-control group. Examples were trials that studied the potential use of the antiparasitic agent mebendazole [ 19 , 20 , 21 ], various renin-angiotensin system modulators [ 22 ], or disulfiram [ 23 ], for gliomas; the antiprotozoal pyrimethamine [ 24 ], or the immunosuppressant leflunomide [ 25 ], for hematological cancers; and various other drugs for gynecological cancer [ 26 ], non-small cell lung cancer [ 27 ], prostate cancer [ 28 , 29 ], and head and neck cancers [ 30 ]. Some trials used historical data to compare, for example, a trial that studied the potential to use metformin for non-small cell lung cancer [ 31 ]. One clinical trial studied the potential to use valproic acid for various types of cancer in the pediatric population [ 32 ]. There were also trials aiming to study the potential repurposing of antineoplastic agents for other non-oncological conditions, for example, aldesleukin for type 1 diabetes mellitus [ 33 ] and the study protocol for the potential use of bosutinib in amyotrophic lateral sclerosis [ 34 ]. In general, most of these studies reported a good safety profile for the drug under investigation. Results regarding efficacy are very heterogeneous among the studies, and further research is needed in most of the cases.

3.3. Drugs in Investigation for Repurposing and Use in Oncological Conditions

Our study identified seven randomized clinical trials that evaluated the potential use of drugs currently used in non-neoplastic diseases for the pharmacological treatment of various types of cancer ( Table 2 ). These trials studied the use of mebendazole for metastatic colorectal cancer [ 35 ], metformin for locally advanced and metastatic hormone-sensitive prostate cancer [ 36 ], metformin for advanced or metastatic non-squamous non-small cell lung cancer [ 37 ], propranolol in autologous hematopoietic stem cell transplantation for multiple myeloma [ 38 ], low-weight heparin for esophageal squamous cell carcinoma [ 39 ], propranolol and etodolac for breast cancer stages I–III [ 40 ], and metformin for metastatic or unresectable locally advanced pancreatic adenocarcinoma [ 41 ]. Most of the clinical trials aimed to study safety, efficacy, and feasibility. The most common main outcomes were overall survival (OS), progression-free survival (PFS), and the occurrence of adverse drug reactions (ADRs). All these trials enrolled only adults. Common limitations were the small sample size (most of them had less than 100 participants) and the high clinical heterogeneity of the study population. None of the trials considered multimorbidity. In general, overall survival was not significantly improved in the intervention group compared to the control group. Some studies reported higher progression-free survival in the intervention group. A detailed description of all randomized clinical trials, including information regarding safety and efficacy, is presented in Supplementary Table S1 .

Our literature search identified five study protocols ( Table 3 ) [ 42 , 43 , 44 , 45 , 46 ]. These trials aim to study safety, efficacy, feasibility, medication adherence, and health-related quality of life. Drugs under investigation include meclofenamate, sodium valproate, propranolol, etodolac, atorvastatin, and disulfiram.

3.4. Antineoplastics in Investigation for Repurposing and Use in Non-Oncological Conditions

We identified one randomized placebo-controlled clinical trial studying the potential repurposing of an antineoplastic agent for use in a non-oncological condition ( Table 2 ). The drug under investigation was imatinib, a BCR-ABL tyrosine kinase inhibitor, and the potential new indication was the treatment of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and hypoxic respiratory failure [ 47 ]. Multimorbidity was taken into consideration in this clinical trial. The main outcome of the study was the time to discontinue ventilation and supplemental oxygen for more than 48 consecutive hours while alive; the study reported no significant differences between the intervention and the control group.

We identified three study protocols ( Table 3 ) [ 48 , 49 , 50 ]. Two trials aim to study the potential use of imatinib in coronavirus disease 2019 (COVID-19) [ 48 , 50 ]. The other clinical trial investigates the possible repurposing of leuprolide, a gonadotropin-releasing hormone analogue, for the treatment of patients with Alzheimer’s disease [ 49 ].

4. Discussion

Our study revealed that few clinical studies on drug repurposing in oncology were randomized placebo-controlled or standard-of-care-alone-controlled trials. These studies mainly assess the efficacy and safety of the drug in conditions outside the scope of the authorized indications. This objective was commonly assessed through the overall response rate, overall survival, progression-free survival, disease-free survival, and the notification of drug-related side effects and adverse reactions. Among the most common limitations of the identified studies were the small sample size (most of them had less than 100 participants), the high clinical heterogeneity of the participants, and the lack of accounting for multimorbidity and other baseline characteristics.

Metformin has been studied for potential use in some types of cancer in combination with standard treatment. A blinded RCT with 124 enrolled patients with locally advanced and metastatic hormone-sensitive prostate cancer showed that metformin, in combination with standard of care, prolonged castration-resistant prostate cancer-free survival by nine months in comparison with the group treated with standard of care alone (29 vs. 20 months; p = 0.01) [ 36 ]. The difference was particularly observed in localized disease, whereas in advanced or metastatic cases it was found to be not statistically significant. There were no differences regarding PSA levels or overall survival between the two groups. Concurrent diabetes mellitus (approximately present in 20% of the study population; both metformin- and control-group) was not identified as a predictor of shorter castration-resistant prostate cancer-free survival. Another open-label clinical trial with 25 enrolled non-diabetic patients with chemotherapy-naive advanced or metastatic non-squamous non-small-cell lung cancer (NSCLC) showed that metformin has the potential to improve progression-free survival within three months when combined with chemotherapy compared with chemotherapy alone (9.6 vs. 6.7 months, p = 0.024), without significant difference regarding overall survival [ 37 ]. However, an open-label RCT with 121 patients with metastatic or unresectable locally advanced pancreatic adenocarcinoma reported lower overall survival when metformin was added compared with placebo to gemcitabine and erlotinib, although the difference was not statistically significant (6.8 vs. 7.6 months, p = 0.78) [ 41 ]. The authors reported similar findings regarding progression-free survival in favor of the placebo group, although differences were not statistically significant (4.1 vs. 5.4 months, p = 0.44). The small sample size and the high clinical heterogeneity of the enrolled patients were among the most important limitations of the clinical trials.

Epidemiologic studies have suggested that type 2 diabetes mellitus, insulin resistance, and hyperinsulinemia might be associated with a higher risk of cancer [ 51 ]. Many retrospective observational studies reported findings that call for an in-depth study of the possible beneficial use of metformin in some types of cancer [ 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ], boosting interest in studying the interlinking metabolic pathways between diabetes and cancer and the role, if any, of metformin. However, there are discrepancies in the literature and various limitations and questions that should be properly addressed, mostly regarding several confounding factors. For example, comorbid diabetes (considering year of onset, treatment, and complications), other comorbidities, clinical status, and concomitant medication, medication adherence, potentially drug-drug and drug-disease interactions, current clinical management, patient’s preferences and socioeconomic status, lifestyle factors, and many other variables could influence prognosis. A recent meta-analysis showed that metformin was found to improve patient outcomes in patients with head and neck cancer in studies that did not adjust for comorbidities; in studies that adjusted for comorbidities, no significant improvement was found [ 63 ]. The potential of repurposing a widely used and safe drug, a drug that is included in the World Health Organization’s model List of Essential Medicines [ 64 ], must be carefully examined with well-designed RCTs. It is also essential to evaluate the posology and administration regimens in order to achieve optimal delivery to the tumor with acceptable tolerability and antineoplastic activity [ 65 ]. It is important to keep in mind other potential uses of metformin for many other indications, currently, in clinical research—highlighting even more the necessity to consider comorbidity in the clinical trials on drug repurposing—describing metformin as the drug of the future fighting a multitude of diseases [ 66 ]; although the exact mechanism is unknown, some of these findings may be attributed to its insulin-sensitizing and anti-hyperglycemic effects [ 67 ].

Mebendazole is a broad-spectrum antihelminthic that has been in use for more than five decades [ 68 ]. The first observations of a potential anticancer effect of mebendazole were reported in 2002 [ 69 , 70 ]; they were preclinical studies in lung cancer. Among the antitumoral effects suggested were angiogenesis inhibition [ 69 ] and tubulin depolymerization [ 70 ]. Since then, other anticancer effects have been attributed to mebendazole [ 71 , 72 , 73 , 74 ], including inhibition of the Hedgehog signaling pathway [ 75 ], induction of apoptosis and cytotoxicity [ 76 ], inhibition of kinases [ 77 ], induction of a pro-inflammatory (M1) phenotype of monocytoid cells [ 78 ], and sensitization to chemotherapy and radiotherapy [ 79 ]. Various preclinical studies, in vitro and in vivo, reported anticancer activity [ 72 ] in a wide range of cancer types, such as non-small cell lung cancer [ 69 , 70 ], glioblastoma [ 80 , 81 ], melanoma [ 82 , 83 ], acute myeloid leukemia [ 84 ], ovarian cancer [ 85 ], and colorectal cancer [ 86 ]. Two case reports reported favorable outcomes: long-term tumor control in a patient with metastatic adrenocortical carcinoma [ 87 ] and nearly complete remission of the metastases in the lungs and lymph nodes in a patient with metastatic colon cancer [ 88 ]. At the moment, information from clinical trials is limited. We identified one randomized controlled clinical trial with 64 patients with metastatic colorectal cancer (stage 4) in treatment with bevacizumab and FOLFOX4 [ 35 ]. Twelve weeks after treatment with mebendazole (in addition to standard baseline therapy), it was observed that the overall response rate improved and vascular endothelial growth factor declined in comparison with the control group (only baseline treatment); however, after one year, differences were not significant. Among the most common adverse events and drug reactions were gastrointestinal (abdominal pain and diarrhea) and biochemical alterations (aspartate transaminase, alanine transaminase, serum creatinine, and estimated creatinine clearance). A phase 1 study in 11 patients with relapsed or recurrent high-grade gliomas aimed to identify the maximum tolerable dose of mebendazole in combination with other therapeutic approaches (lomustine, temozolomide, or re-radiation plus temozolomide) [ 19 ]. This escalation study (dose range 100–1600 mg three times daily) suggested that the recommended phase 2 dose of mebendazole is 1600 mg three times daily when combined with temozolomide or re-radiation plus temozolomide and 800 mg when combined with lomustine. In a phase 2 study, the authors reported that using these recommended doses, these combinations of mebendazole did not reach the pre-defined benchmark of 55% overall survival at nine months [ 20 ]. Regarding safety profile, another dose-escalation phase 1 study reported long-term safety and acceptable toxicity with doses up to 200 mg/kg [ 21 ].

Propranolol is the first successfully developed beta-blocker [ 89 , 90 ]. It is mainly used in hypertension, cardiac disease, and other conditions, including infantile hemangiomas [ 91 , 92 , 93 ]. Various studies during the last 25 years showed that beta-blockers may have anti-proliferative properties and inhibit metastasis in a variety of cancers [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 ], such as lung [ 94 ], colorectal [ 100 ], prostate [ 99 ], and ovarian cancer [ 101 ]. Other studies reported better clinical outcomes in multiple myeloma [ 98 , 102 , 103 , 104 ]. Better prognosis in multiple myeloma, especially when treated with hemopoietic stem cell transplantation, may be partly attributed to the blockade of the sympathetic nervous system in the bone marrow niche induced by b-blockers [ 102 , 104 , 105 , 106 ]. A clinical trial reported that, although challenging, it is feasible to recruit and treat multiple myeloma patients with propranolol during hemopoietic stem cell transplantation [ 38 ]. The same study reported a good safety profile with the use of propranolol, with the most common adverse reactions being hypotension, dizziness, maculopapular rash, hypokalemia, hypertension, and chest pain. There is a need for further clinical studies, primarily randomized controlled clinical trials, that also consider molecular tumor characteristics and the baseline clinical profile of the patients.

Various studies suggest that combining b-blockers and cyclooxygenase-2 (COX-2) inhibitors may be beneficial in some types of cancer, suppressing cancer progression [ 107 , 108 ]. The effect of COX-2 inhibitors may be attributed to different mechanisms of action [ 107 ], including apoptosis [ 109 ] and an anti-angiogenic action [ 110 ]. Furthermore, it has been reported that some cancers secrete prostaglandins to escape destruction, such as renal cell carcinoma [ 111 ]. Perioperative b-blockers in combination with COX-2 inhibitors may improve immune competence and reduce the risk of metastasis [ 107 , 108 ]. A randomized clinical trial in patients with primary operable breast cancer reported a decreased epithelial-to-mesenchymal transition, reduced activity of prometastatic/proinflammatory transcription factors, and decreased tumor-infiltrating monocytes while increasing tumor-infiltrating B cells in patients who received propranolol and etodolac [ 40 ]. Regarding the safety profile, no severe or moderate adverse events were observed, with nausea among the most common. Another clinical trial is in progress in patients with resectable carcinoma of the pancreatic head planned for pancreatoduodenectomy, aiming to study serious adverse drug reactions, post-operative mortality, pancreas-associated morbidity, medication adherence, overall and disease-free survival, and rates of local and distant recurrence [ 44 ].

There is a lot of discussion regarding interactions and relations, especially common etiopathogenic mechanisms, between cardiovascular and oncological conditions [ 112 ]. Revealing common pathophysiological factors generates hypotheses for repurposing well-known cardiovascular drugs for potential use in oncological diseases, amongst them b-blockers (as previously discussed), angiotensin receptor antagonists, statins, and low molecular weight heparins. Our review identified a protocol for a randomized controlled clinical trial studying the efficacy and potential use of atorvastatin in patients with cavernous angiomas [ 45 ]. Many studies reported a potential benefit of heparin in cancer patients, suggesting that low-weight heparins may have direct anti-metastatic effects above their anticoagulation properties [ 113 , 114 , 115 , 116 , 117 ]. Studies include various types of cancer, such as multiple myeloma, pancreatic cancer, prostate cancer, and hepatocellular carcinoma [ 118 , 119 ]. A randomized controlled clinical trial in patients with esophageal squamous cell carcinoma reported that integration of enoxaparin into the chemoradiation protocol is safe and tolerable; however, a higher probability of neutropenia was observed in patients treated with enoxaparin [ 39 ]. There are conflicting results in the literature regarding the overall benefit of heparin in oncology [ 118 ]. It is crucial to conduct further research to fully understand the biological mechanisms, the clear benefit, and the risks of using heparin in patients with cancer [ 113 , 118 ].

In this systematic review, we also identified study protocols for upcoming/ongoing RCTs addressing various types of cancer. Moreover, assessing efficacy and safety, two of these protocols also aim to assess health-related quality of life [ 42 , 46 ]. On the other hand, we identified RCTs that aim to study the potential use of known antineoplastic agents against other non-oncological conditions. One finished study and two protocols investigate the potential use of imatinib, a BCR-ABL tyrosine kinase inhibitor, in patients with severe coronavirus disease 2019 (COVID-19) [ 47 , 48 , 50 ], as various authors reported findings that the use of imatinib may be beneficial in hospitalized patients with COVID-19 [ 120 , 121 ]. However, an RCT identified in this systematic review showed that imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen in hospitalized COVID-19 patients who required supplemental oxygen [ 47 ]; this RCT was considered multimorbidity. We also identified an RCT protocol aiming to investigate the potential use of leuprolide, a gonadotropin-releasing hormone analogue, in women with Alzheimer’s disease [ 49 ].

This systematic review aimed to identify the most recent RCTs that focused on drug repurposing in oncology. A limitation of this study, commonly found in literature reviews, regards the identification of potentially eligible studies. For example, we used only MEDLINE and not other databases. However, MEDLINE covers most of the studies worldwide and assures a collection of high-quality papers. In addition, the search algorithm is available and published in this article to enhance transparency—an algorithm that exhaustively searches for all potential uses in oncology. This algorithm allowed us to also identify the repurposing of antineoplastic agents for other non-oncological conditions. Furthermore, we chose to include study protocols separately in order to study ongoing/upcoming studies. The aim of this systematic review was to publish the “state of the art”; the high heterogeneity in methodologies, outcomes, indications, etc. did not make it possible to apply meta-analysis. Another limitation is the low number of RCTs that were included in the systematic review. A detailed description of all included studies (including a GRADE assessment regarding the quality of evidence) is available in the Supplementary Material .

5. Conclusions

This systematic review revealed that only a few clinical trials in drug repurposing in oncology were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. Overall response rate, overall survival, progression-free survival, disease-free survival, and the notification of drug-related side effects and adverse reactions were the most commonly used variables/outcomes. Among the most common limitations of the identified studies were the small sample size, the high clinical heterogeneity of the participants, and the baseline clinical characteristics. It is essential to conduct further trials with a higher number of participants and a more homogeneous study population considering the stage of the neoplastic disease and the baseline clinical profile, especially multimorbidity, concurrent medication, mental health, and functional status. The age of the participants is an important factor, but it may also depend on the length of time a concurrent disease has been present and whether it is well controlled or means a high morbidity burden for the patient. It is also vital to consider other factors, such as socio-economics and lifestyle, as they are key to an optimal person-centered approach and to obtaining the best results. By addressing all these aspects, data from randomized controlled clinical trials may have the potential to answer important clinical questions, and by using common protocols, we will be able to make plausible comparisons and conduct useful meta-analyses.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/cancers15112972/s1 . Table S1: A general overview of the randomized controlled clinical trials included in the systematic review and GRADE assessment; File S1. PRISMA checklist: PRISMA 2020 main checklist and abstract checklist.

Click here for additional data file.

Author Contributions

Conceptualization, I.I.-S.; methodology, I.I.-S. and J.V.-R.; software, I.I.-S.; formal analysis, I.I.-S., N.T.-R. and J.V.-R.; investigation, I.I.-S., N.T.-R., E.O. and J.V.-R.; resources, I.I.-S. and J.V.-R.; data curation, I.I.-S., N.T.-R. and J.V.-R.; writing—original draft preparation, I.I.-S.; writing—review and editing, N.T.-R., E.M., M.A.-P.-S., A.G.-M., V.O., F.G.-R., A.F.-V., C.L.-A., E.O. and J.V.-R.; visualization, I.I.-S. and J.V.-R.; supervision, I.I.-S. and J.V.-R. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Ashburn T.T. Thor K.B. Drug repositioning: Identifying and developing new uses for existing drugs Nat. Rev. Drug Discov. 2004 3 673 683 10.1038/nrd1468 15286734

2. Reichert J.M. Trends in development and approval times for new therapeutics in the United States Nat. Rev. Drug Discov. 2003 2 695 702 10.1038/nrd1178 12951576

3. Gilbert J. Henske P. Singh A. Rebuilding big pharma’s business model Vivo 2003 21 73 80

4. The Academy of Medical Sciences Multimorbidity: A Priority for Global Health Research 2018 Available online: https://acmedsci.ac.uk/file-download/82222577 (accessed on 10 January 2023)

5. World Health Organization Global Status Report on Noncommunicable Diseases 2014 Available online: https://apps.who.int/iris/handle/10665/148114 (accessed on 10 January 2023)

6. World Health Organization Noncommunicable Diseases Available online: https://www.who.int/health-topics/noncommunicable-diseases#tab=tab_1 (accessed on 10 January 2023)

7. World Health Organization Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 Available online: https://www.who.int/publications/i/item/9789241506236 (accessed on 10 January 2023)

8. World Health Organization Implementation Roadmap 2023–2030 for the Global Action Plan for the Prevention and Control of NCDs 2013–2030 Available online: https://www.who.int/teams/noncommunicable-diseases/governance/roadmap (accessed on 10 January 2023)

9. World Health Organization Cancer Available online: https://www.who.int/news-room/fact-sheets/detail/cancer (accessed on 10 January 2023)

10. Sung H. Ferlay J. Siegel R.L. Laversanne M. Soerjomataram I. Jemal A. Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA Cancer J. Clin. 2021 71 209 249 10.3322/caac.21660 33538338

11. Sleire L. Førde-Tislevoll H.E. Netland I.A. Leiss L. Skeie B.S. Enger P.Ø. Drug repurposing in cancer Pharmacol. Res. 2017 124 74 91 10.1016/j.phrs.2017.07.013 28712971

12. Ghafouri-Fard S. Abak A. Tondro Anamag F. Shoorei H. Fattahi F. Javadinia S.A. Basiri A. Taheri M. 5-Fluorouracil: A Narrative Review on the Role of Regulatory Mechanisms in Driving Resistance to This Chemotherapeutic Agent Front. Oncol. 2021 11 658636 10.3389/fonc.2021.658636 33954114 PMC8092118

13. Hua Y. Dai X. Xu Y. Xing G. Liu H. Lu T. Chen Y. Zhang Y. Drug repositioning: Progress and challenges in drug discovery for various diseases Eur. J. Med. Chem. 2022 234 114239 10.1016/j.ejmech.2022.114239 35290843 PMC8883737

14. Corsello S.M. Nagari R.T. Spangler R.D. Rossen J. Kocak M. Bryan J.G. Humeidi R. Peck D. Wu X. Tang A.A. Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling Nat. Cancer 2020 1 235 248 10.1038/s43018-019-0018-6 32613204 PMC7328899

15. Page M.J. McKenzie J.E. Bossuyt P.M. Boutron I. Hoffmann T.C. Mulrow C.D. Shamseer L. Tetzlaff J.M. Akl E.A. Brennan S.E. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews BMJ 2021 29 372 10.1136/bmj.n71 PMC8005924 33782057

16. Miller S.A. Forrest J.L. Enhancing your practice through evidence-based decision making: PICO, learning how to ask good questions J. Evid.-Based Dent. Pract. 2001 1 136 141 10.1016/S1532-3382(01)70024-3

17. Granholm A. Alhazzani W. Møller M.H. Use of the GRADE approach in systematic reviews and guidelines Br. J. Anaesth. 2019 123 554 559 10.1016/j.bja.2019.08.015 31558313

18. Ryan R. Hill S. How to GRADE the Quality of the Evidence. Cochrane Consumers and Communication Group. CCCG. Version 3.0 December 2016 Available online: http://cccrg.cochrane.org/author-resources (accessed on 1 January 2023)

19. Patil V.M. Bhelekar A. Menon N. Bhattacharjee A. Simha V. Abhinav R. Abhyankar A. Sridhar E. Mahajan A. Puranik A.D. Reverse swing-M, phase 1 study of repurposing mebendazole in recurrent high-grade glioma Cancer Med. 2020 9 4676 4685 10.1002/cam4.3094 32400117 PMC7333848

20. Patil V.M. Menon N. Chatterjee A. Tonse R. Choudhari A. Mahajan A. Puranik A.D. Epari S. Jadhav M. Pathak S. Mebendazole plus lomustine or temozolomide in patients with recurrent glioblastoma: A randomised open-label phase II trial EClinicalMedicine 2022 49 101449 10.1016/j.eclinm.2022.101449 35747192 PMC9156991

21. Gallia G.L. Holdhoff M. Brem H. Joshi A.D. Hann C.L. Bai R.Y. Staedtke V. Blakeley J.O. Sengupta S. Jarrell T.C. Mebendazole and temozolomide in patients with newly diagnosed high-grade gliomas: Results of a phase 1 clinical trial Neurooncol. Adv. 2020 3 vdaa154 10.1093/noajnl/vdaa154 33506200 PMC7817892

22. O’Rawe M. Wickremesekera A.C. Pandey R. Young D. Sim D. FitzJohn T. Burgess C. Kaye A.H. Tan S.T. Treatment of glioblastoma with re-purposed renin-angiotensin system modulators: Results of a phase I clinical trial J. Clin. Neurosci. 2022 95 48 54 10.1016/j.jocn.2021.11.023 34929651

23. Huang J. Campian J.L. Gujar A.D. Tran D.D. Lockhart A.C. DeWees T.A. Tsien C.I. Kim A.H. A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy J. Neurooncol. 2016 128 259 266 10.1007/s11060-016-2104-2 26966095

24. Brown J.R. Walker S.R. Heppler L.N. Tyekucheva S. Nelson E.A. Klitgaard J. Nicolais M. Kroll Y. Xiang M. Yeh J.E. Targeting constitutively active STAT3 in chronic lymphocytic leukemia: A clinical trial of the STAT3 inhibitor pyrimethamine with pharmacodynamic analyses Am. J. Hematol. 2021 96 E95 E98 10.1002/ajh.26084 33373063 PMC7954938

25. Rosenzweig M. Palmer J. Tsai N.C. Synold T. Wu X. Tao S. Hammond S.N. Buettner R. Duarte L. Htut M. Repurposing leflunomide for relapsed/refractory multiple myeloma: A phase 1 study Leuk. Lymphoma 2020 61 1669 1677 10.1080/10428194.2020.1742900 32268821 PMC7384948

26. Masuda T. Noda M. Kogawa T. Kitagawa D. Hayashi N. Jomori T. Nakanishi Y. Nakayama K.I. Ohno S. Mimori K. Phase I dose-escalation trial to repurpose propagermanium, an oral CCL2 inhibitor, in patients with breast cancer Cancer Sci. 2020 111 924 931 10.1111/cas.14306 31943636 PMC7060487

27. Parikh A.B. Marrone K.A. Becker D.J. Brahmer J.R. Ettinger D.S. Levy B.P. A pooled analysis of two phase II trials evaluating metformin plus platinum-based chemotherapy in advanced non-small cell lung cancer Cancer Treat. Res. Commun. 2019 20 100150 10.1016/j.ctarc.2019.100150 31102920

28. Schweizer M.T. Haugk K. McKiernan J.S. Gulati R. Cheng H.H. Maes J.L. Dumpit R.F. Nelson P.S. Montgomery B. McCune J.S. A phase I study of niclosamide in combination with enzalutamide in men with castration-resistant prostate cancer PLoS ONE 2018 13 e0198389 10.1371/journal.pone.0198389 29856824 PMC5983471

29. Antonarakis E.S. Heath E.I. Smith D.C. Rathkopf D. Blackford A.L. Danila D.C. King S. Frost A. Ajiboye A.S. Zhao M. Repurposing itraconazole as a treatment for advanced prostate cancer: A noncomparative randomized phase II trial in men with metastatic castration-resistant prostate cancer Oncologist 2013 18 163 173 10.1634/theoncologist.2012-314 23340005 PMC3579600

30. Gao R.W. Teraphongphom N. de Boer E. van den Berg N.S. Divi V. Kaplan M.J. Oberhelman N.J. Hong S.S. Capes E. Colevas A.D. Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers Theranostics 2018 8 2488 2495 10.7150/thno.24487 29721094 PMC5928904

31. Parikh A.B. Kozuch P. Rohs N. Becker D.J. Levy B.P. Metformin as a repurposed therapy in advanced non-small cell lung cancer (NSCLC): Results of a phase II trial Investig. New Drugs 2017 35 813 819 10.1007/s10637-017-0511-7 28936567

32. Traore F. Togo B. Pasquier E. Dembélé A. André N. Preliminary evaluation of children treated with metronomic chemotherapy and valproic acid in a low-income country: Metro-Mali-02 Indian J. Cancer 2013 50 250 253 10.4103/0019-509X.118741 24061467

33. Todd J.A. Evangelou M. Cutler A.J. Pekalski M.L. Walker N.M. Stevens H.E. Porter L. Smyth D.J. Rainbow D.B. Ferreira R.C. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial PLoS Med. 2016 13 e1002139 10.1371/journal.pmed.1002139 27727279 PMC5058548

34. Imamura K. Izumi Y. Banno H. Uozumi R. Morita S. Egawa N. Ayaki T. Nagai M. Nishiyama K. Watanabe Y. Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study: Protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients BMJ Open 2019 9 e033131 10.1136/bmjopen-2019-033131 PMC7003406 31796494

35. Hegazy S.K. El-Azab G.A. Zakaria F. Mostafa M.F. El-Ghoneimy R.A. Mebendazole; from an anti-parasitic drug to a promising candidate for drug repurposing in colorectal cancer Life Sci. 2022 299 120536 10.1016/j.lfs.2022.120536 35385794

36. Alghandour R. Ebrahim M.A. Elshal A.M. Ghobrial F. Elzaafarany M. ELbaiomy M.A. Repurposing metformin as anticancer drug: Randomized controlled trial in advanced prostate cancer (MANSMED) Urol. Oncol. 2021 39 831.e1 831.e10 10.1016/j.urolonc.2021.05.020 34167872

37. Marrone K.A. Zhou X. Forde P.M. Purtell M. Brahmer J.R. Hann C.L. Kelly R.J. Coleman B. Gabrielson E. Rosner G.L. A Randomized Phase II Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy-Naïve Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer Oncologist 2018 23 859 865 10.1634/theoncologist.2017-0465 29487223 PMC6058336

38. Knight J.M. Kerswill S.A. Hari P. Cole S.W. Logan B.R. D’Souza A. Shah N.N. Horowitz M.M. Stolley M.R. Sloan E.K. Repurposing existing medications as cancer therapy: Design and feasibility of a randomized pilot investigating propranolol administration in patients receiving hematopoietic cell transplantation BMC Cancer 2018 18 593 10.1186/s12885-018-4509-0 29793446 PMC5968588

39. Taghizadeh Kermani A. Hosseini S. Fanipakdel A. Joudi Mashhad M. Akhavan Rezayat K. Zardadi M. Gholami A. Javadinia S.A. Ferns G.A. Avan A. A randomized clinical trial on the antitumoral effects of low molecular weight heparin in the treatment of esophageal cancer J. Cell. Physiol. 2019 234 4191 4199 10.1002/jcp.27177 30362518

40. Shaashua L. Shabat-Simon M. Haldar R. Matzner P. Zmora O. Shabtai M. Sharon E. Allweis T. Barshack I. Hayman L. Perioperative COX-2 and β-Adrenergic Blockade Improves Metastatic Biomarkers in Breast Cancer Patients in a Phase-II Randomized Trial Clin. Cancer Res. 2017 23 4651 4661 10.1158/1078-0432.CCR-17-0152 28490464 PMC5559335

41. Kordes S. Pollak M.N. Zwinderman A.H. Mathôt R.A. Weterman M.J. Beeker A. Punt C.J. Richel D.J. Wilmink J.W. Metformin in patients with advanced pancreatic cancer: A double-blind, randomised, placebo-controlled phase 2 trial Lancet Oncol. 2015 16 839 847 10.1016/S1470-2045(15)00027-3 26067687

42. Zeyen T. Potthoff A.L. Nemeth R. Heiland D.H. Burger M.C. Steinbach J.P. Hau P. Tabatabai G. Glas M. Schlegel U. Phase I/II trial of meclofenamate in progressive MGMT-methylated glioblastoma under temozolomide second-line therapy-the MecMeth/NOA-24 trial Trials 2022 23 57 10.1186/s13063-021-05977-0 35045869 PMC8767701

43. McCarthy C. Sacco J. Fedele S. Ho M. Porter S. Liloglou T. Greenhalf B. Robinson M. Young B. Cicconi S. SAVER: Sodium valproate for the epigenetic reprogramming of high-risk oral epithelial dysplasia-a phase II randomised control trial study protocol Trials 2021 22 428 10.1186/s13063-021-05373-8 34225765 PMC8256209

44. Hüttner F.J. Rooman I. Bouche G. Knebel P. Hüsing J. Mihaljevic A.L. Hackert T. Strobel O. Büchler M.W. Diener M.K. Pancreatic resection with perioperative drug repurposing of propranolol and etodolac: Trial protocol of the phase-II randomised placebo controlled PROSPER trial BMJ Open 2020 10 e040406 10.1136/bmjopen-2020-040406 PMC7528424 32998931

45. Polster S.P. Stadnik A. Akers A.L. Cao Y. Christoforidis G.A. Fam M.D. Flemming K.D. Girard R. Hobson N. Koenig J.I. Atorvastatin Treatment of Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) Trial Neurosurgery 2019 85 843 853 10.1093/neuros/nyy539 30476251 PMC7054711

46. Jakola A.S. Werlenius K. Mudaisi M. Hylin S. Kinhult S. Bartek J. Jr. Salvesen Ø. Carlsen S.M. Strandéus M. Lindskog M. Disulfiram repurposing combined with nutritional copper supplement as add-on to chemotherapy in recurrent glioblastoma (DIRECT): Study protocol for a randomized controlled trial F1000Research 2018 7 1797 10.12688/f1000research.16786.1 30647912 PMC6325620

47. Aman J. Duijvelaar E. Botros L. Kianzad A. Schippers J.R. Smeele P.J. Azhang S. Bartelink I.H. Bayoumy A.A. Bet P.M. Imatinib in patients with severe COVID-19: A randomised, double-blind, placebo-controlled, clinical trial Lancet Respir. Med. 2021 9 957 968 10.1016/S2213-2600(21)00237-X 34147142 PMC8232929

48. Atmowihardjo L. Schippers J.R. Bartelink I.H. Bet P.M. van Rein N. Purdy K. Cavalla D. Comberiati V. McElroy A. Snape S.D. The INVENT COVID trial: A structured protocol for a randomized controlled trial investigating the efficacy and safety of intravenous imatinib mesylate (Impentri ® ) in subjects with acute respiratory distress syndrome induced by COVID-19 Trials 2022 23 158 10.1186/s13063-022-06055-9 35172891 PMC8848942

49. Butler T. Goldberg J.D. Galvin J.E. Maloney T. Ravdin L. Glodzik L. de Leon M.J. Hochman T. Bowen R.L. Atwood C.S. Rationale, study design and implementation of the LUCINDA Trial: Leuprolide plus Cholinesterase Inhibition to reduce Neurologic Decline in Alzheimer’s Contemp. Clin. Trials 2021 107 106488 10.1016/j.cct.2021.106488 34166841 PMC8550816

50. Emadi A. Chua J.V. Talwani R. Bentzen S.M. Baddley J. Safety and Efficacy of Imatinib for Hospitalized Adults with COVID-19: A structured summary of a study protocol for a randomised controlled trial Trials 2020 21 897 10.1186/s13063-020-04819-9 33115543 PMC7594416

51. Giovannucci E. Harlan D.M. Archer M.C. Bergenstal R.M. Gapstur S.M. Habel L.A. Pollak M. Regensteiner J.G. Yee D. Diabetes and cancer: A consensus report Diabetes Care 2010 33 1674 1685 10.2337/dc10-0666 20587728 PMC2890380

52. Evans J.M. Donnelly L.A. Emslie-Smith A.M. Alessi D.R. Morris A.D. Metformin and reduced risk of cancer in diabetic patients BMJ 2005 330 1304 1305 10.1136/bmj.38415.708634.F7 15849206 PMC558205

53. Jiralerspong S. Palla S.L. Giordano S.H. Meric-Bernstam F. Liedtke C. Barnett C.M. Hsu L. Hung M.C. Hortobagyi G.N. Gonzalez-Angulo A.M. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer J. Clin. Oncol. 2009 27 3297 3302 10.1200/JCO.2009.19.6410 19487376 PMC2736070

54. Yao K. Zheng H. Li T. Association Between Metformin Use and the Risk, Prognosis of Gynecologic Cancer Front. Oncol. 2022 12 942380 10.3389/fonc.2022.942380 35898873 PMC9309370

55. Barakat H.E. Hussein R.R.S. Elberry A.A. Zaki M.A. Elsherbiny Ramadan M. Factors influencing the anticancer effects of metformin on breast cancer outcomes: A systematic review and meta-analysis Expert Rev. Anticancer 2022 22 415 436 10.1080/14737140.2022.2051482 35259320

56. Wang Z. Lai S.T. Xie L. Zhao J.D. Ma N.Y. Zhu J. Ren Z.G. Jiang G.L. Metformin is associated with reduced risk of pancreatic cancer in patients with type 2 diabetes mellitus: A systematic review and meta-analysis Diabetes Res. Clin. Pract. 2014 106 19 26 10.1016/j.diabres.2014.04.007 24837144

57. Lin J.J. Gallagher E.J. Sigel K. Mhango G. Galsky M.D. Smith C.B. LeRoith D. Wisnivesky J.P. Survival of patients with stage IV lung cancer with diabetes treated with metformin Am. J. Respir. Crit. Care Med. 2015 191 448 454 10.1164/rccm.201407-1395OC 25522257 PMC4351595

58. Wink K.C. Belderbos J.S. Dieleman E.M. Rossi M. Rasch C.R. Damhuis R.A. Houben R.M. Troost E.G. Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy Radiother. Oncol. 2016 118 453 459 10.1016/j.radonc.2016.01.012 26861738

59. Hitron A. Adams V. Talbert J. Steinke D. The influence of antidiabetic medications on the development and progression of prostate cancer Cancer Epidemiol. 2012 36 e243 e250 10.1016/j.canep.2012.02.005 22417708

60. Jafarzadeh E. Montazeri V. Aliebrahimi S. Sezavar A.H. Ghahremani M.H. Ostad S.N. Combined regimens of cisplatin and metformin in cancer therapy: A systematic review and meta-analysis Life Sci. 2022 304 120680 10.1016/j.lfs.2022.120680 35662589

61. Coyle C. Cafferty F.H. Vale C. Langley R.E. Metformin as an adjuvant treatment for cancer: A systematic review and meta-analysis Ann. Oncol. 2016 27 2184 2195 10.1093/annonc/mdw410 27681864 PMC5178140

62. Chevalier B. Pasquier D. Lartigau E.F. Chargari C. Schernberg A. Jannin A. Mirabel X. Vantyghem M.C. Escande A. Metformin: (future) best friend of the radiation oncologist? Radiother. Oncol. 2020 151 95 105 10.1016/j.radonc.2020.06.030 32592892

63. Jiao Y. Liu D. Sun Y. Chen Z. Liu S. Survival Benefit of Metformin as an Adjuvant Treatment for Head and Neck Cancer: A Systematic Review and Meta-Analysis Front. Pharm. 2022 13 850750 10.3389/fphar.2022.850750 PMC9136048 35645803

64. World Health Organization Model List of Essential Medicines-22nd List, 2021 World Health Organization Geneva, Switzerland 2021 Available online: https://www.who.int/publications/i/item/WHO-MHP-HPS-EML-2021.02 (accessed on 10 January 2023)

65. Cejuela M. Martin-Castillo B. Menendez J.A. Pernas S. Metformin and Breast Cancer: Where Are We Now? Int. J. Mol. Sci. 2022 23 2705 10.3390/ijms23052705 35269852 PMC8910543

66. Soukas A.A. Hao H. Wu L. Metformin as Anti-Aging Therapy: Is It for Everyone? Trends Endocrinol. Metab. 2019 30 745 755 10.1016/j.tem.2019.07.015 31405774 PMC6779524

67. Triggle C.R. Mohammed I. Bshesh K. Marei I. Ye K. Ding H. MacDonald R. Hollenberg M.D. Hill M.A. Metformin: Is it a drug for all reasons and diseases? Metabolism 2022 133 155223 10.1016/j.metabol.2022.155223 35640743

68. Brugmans J.P. Thienpont D.C. van Wijngaarden I. Vanparijs O.F. Schuermans V.L. Lauwers H.L. Mebendazole in enterobiasis. Radiochemical and pilot clinical study in 1,278 subjects JAMA 1971 217 313 316 10.1001/jama.1971.03190030039008 5109194

69. Mukhopadhyay T. Sasaki J. Ramesh R. Roth J.A. Mebendazole elicits a potent antitumor effect on human cancer cell lines both in vitro and in vivo Clin. Cancer Res. 2002 8 2963 2969 12231542

70. Sasaki J. Ramesh R. Chada S. Gomyo Y. Roth J.A. Mukhopadhyay T. The anthelmintic drug mebendazole induces mitotic arrest and apoptosis by depolymerizing tubulin in non-small cell lung cancer cells Mol. Cancer Ther. 2002 1 1201 1209 12479701

71. Pantziarka P. Bouche G. Meheus L. Sukhatme V. Sukhatme V.P. Repurposing drugs in oncology (ReDO)-cimetidine as an anti-cancer agent Ecancermedicalscience 2014 8 485 10.3332/ecancer.2014.485 25525463 PMC4268104

72. Guerini A.E. Triggiani L. Maddalo M. Bonù M.L. Frassine F. Baiguini A. Alghisi A. Tomasini D. Borghetti P. Pasinetti N. Mebendazole as a Candidate for Drug Repurposing in Oncology: An Extensive Review of Current Literature Cancers 2019 11 1284 10.3390/cancers11091284 31480477 PMC6769799

73. Gales L. Forsea L. Mitrea D. Stefanica I. Stanculescu I. Mitrica R. Georgescu M. Trifanescu O. Anghel R. Serbanescu L. Antidiabetics, Anthelmintics, Statins, and Beta-Blockers as Co-Adjuvant Drugs in Cancer Therapy Medicina 2022 58 1239 10.3390/medicina58091239 36143915 PMC9503803

74. Nath J. Paul R. Ghosh S.K. Paul J. Singha B. Debnath N. Drug repurposing and relabeling for cancer therapy: Emerging benzimidazole antihelminthics with potent anticancer effects Life Sci. 2020 258 118189 10.1016/j.lfs.2020.118189 32781060

75. Larsen A.R. Bai R.Y. Chung J.H. Borodovsky A. Rudin C.M. Riggins G.J. Bunz F. Repurposing the antihelmintic mebendazole as a hedgehog inhibitor Mol. Cancer Ther. 2015 14 3 13 10.1158/1535-7163.MCT-14-0755-T 25376612 PMC4297232

76. Martarelli D. Pompei P. Baldi C. Mazzoni G. Mebendazole inhibits growth of human adrenocortical carcinoma cell lines implanted in nude mice Cancer Chemother. Pharmacol. 2008 61 809 817 10.1007/s00280-007-0538-0 17581752

77. Dakshanamurthy S. Issa N.T. Assefnia S. Seshasaye A. Peters O.J. Madhavan S. Uren A. Brown M.L. Byers S.W. Predicting new indications for approved drugs using a proteochemometric method J. Med. Chem. 2012 55 6832 6848 10.1021/jm300576q 22780961 PMC3419493

78. Blom K. Senkowski W. Jarvius M. Berglund M. Rubin J. Lenhammar L. Parrow V. Andersson C. Loskog A. Fryknäs M. The anticancer effect of mebendazole may be due to M1 monocyte/macrophage activation via ERK1/2 and TLR8-dependent inflammasome activation Immunopharmacol. Immunotoxicol. 2017 39 199 210 10.1080/08923973.2017.1320671 28472897

79. Zhang L. Bochkur Dratver M. Yazal T. Dong K. Nguyen A. Yu G. Dao A. Bochkur Dratver M. Duhachek-Muggy S. Bhat K. Mebendazole Potentiates Radiation Therapy in Triple-Negative Breast Cancer Int. J. Radiat. Oncol. Biol. Phys. 2019 103 195 207 10.1016/j.ijrobp.2018.08.046 30196056 PMC6457649

80. Bai R.Y. Staedtke V. Aprhys C.M. Gallia G.L. Riggins G.J. Antiparasitic mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme Neuro-Oncology 2011 13 974 982 10.1093/neuonc/nor077 21764822 PMC3158014

81. Meco D. Attinà G. Mastrangelo S. Navarra P. Ruggiero A. Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers Int. J. Mol. Sci. 2023 24 1334 10.3390/ijms24021334 36674870 PMC9862092

82. Doudican N.A. Byron S.A. Pollock P.M. Orlow S.J. XIAP downregulation accompanies mebendazole growth inhibition in melanoma xenografts Anti-Cancer Drugs 2013 24 181 188 10.1097/CAD.0b013e32835a43f1 23059386

83. Simbulan-Rosenthal C.M. Dakshanamurthy S. Gaur A. Chen Y.S. Fang H.B. Abdussamad M. Zhou H. Zapas J. Calvert V. Petricoin E.F. The repurposed anthelmintic mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma Oncotarget 2017 8 12576 12595 10.18632/oncotarget.14990 28157711 PMC5355037

84. Walf-Vorderwülbecke V. Pearce K. Brooks T. Hubank M. van den Heuvel-Eibrink M.M. Zwaan C.M. Adams S. Edwards D. Bartram J. Samarasinghe S. Targeting acute myeloid leukemia by drug-induced c-MYB degradation Leukemia 2018 32 882 889 10.1038/leu.2017.317 29089643

85. Elayapillai S. Ramraj S. Benbrook D.M. Bieniasz M. Wang L. Pathuri G. Isingizwe Z.R. Kennedy A.L. Zhao Y.D. Lightfoot S. Potential and mechanism of mebendazole for treatment and maintenance of ovarian cancer Gynecol. Oncol. 2021 160 302 311 10.1016/j.ygyno.2020.10.010 33131904 PMC8820236

86. Williamson T. Bai R.Y. Staedtke V. Huso D. Riggins G.J. Mebendazole and a non-steroidal anti-inflammatory combine to reduce tumor initiation in a colon cancer preclinical model Oncotarget 2016 7 68571 68584 10.18632/oncotarget.11851 27612418 PMC5356574

87. Dobrosotskaya I.Y. Hammer G.D. Schteingart D.E. Maturen K.E. Worden F.P. Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma Endocr. Pract. 2011 17 e59 e62 10.4158/EP10390.CR 21454232

88. Nygren P. Larsson R. Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer Acta Oncol. 2014 53 427 428 10.3109/0284186X.2013.844359 24160353

89. Black J.W. Crowther A.F. Shanks R.G. Smith L.H. Dornhorst A.C. A new adrenergic betareceptor antagonist Lancet 1964 1 1080 1081 10.1016/S0140-6736(64)91275-9 14132613

90. Gillam P.M. Prichard B.N. Use of propranolol in angina pectoris Br. Med. J. 1965 2 337 339 10.1136/bmj.2.5457.337 14314452 PMC1845554

91. Lee J.C. Modiri O. England R.W. Shawber C.J. Wu J.K. Propranolol Therapy in Infantile Hemangioma: It Is Not Just About the Beta Plast. Reconstr. Surg. 2021 147 875 885 10.1097/PRS.0000000000007699 33776033

92. Chen T. Gudipudi R. Nguyen S.A. Carroll W. Clemmens C. Should Propranolol Remain the Gold Standard for Treatment of Infantile Hemangioma? A Systematic Review and Meta-Analysis of Propranolol Versus Atenolol Ann. Otol Rhinol. Laryngol. 2023 132 332 340 10.1177/00034894221089758 35466712

93. Novoa M. Baselga E. Beltran S. Giraldo L. Shahbaz A. Pardo-Hernandez H. Arevalo-Rodriguez I. Interventions for infantile haemangiomas of the skin Cochrane Database Syst. Rev. 2018 4 CD006545 10.1002/14651858.CD006545.pub3 29667726 PMC6513200

94. Park P.G. Merryman J. Orloff M. Schuller H.M. Beta-adrenergic mitogenic signal transduction in peripheral lung adenocarcinoma: Implications for individuals with preexisting chronic lung disease Cancer Res. 1995 55 3504 3508 7627955

95. Masur K. Niggemann B. Zanker K.S. Entschladen F. Norepinephrine-induced migration of SW 480 colon carcinoma cells is inhibited by beta-blockers Cancer Res. 2001 61 2866 2869 11306460

96. Sommers Smith S.K. Smith D.M. Beta blockade induces apoptosis in cultured capillary endothelial cells In Vitro Cell. Dev. Biol. Anim. 2002 38 298 304 10.1290/1071-2690(2002)038<0298:BBIAIC>2.0.CO;2 12418927

97. Ji Y. Chen S. Xiao X. Zheng S. Li K. β-blockers: A novel class of antitumor agents Onco Targets Ther. 2012 5 391 401 10.2147/OTT.S38403 23226026 PMC3513911

98. Satilmis H. Verheye E. Vlummens P. Oudaert I. Vandewalle N. Fan R. Knight J.M. De Beule N. Ates G. Massie A. Targeting the β2 -adrenergic receptor increases chemosensitivity in multiple myeloma by induction of apoptosis and modulating cancer cell metabolism J. Pathol. 2023 259 69 80 10.1002/path.6020 36245401 PMC10953387

99. Grytli H.H. Fagerland M.W. Fosså S.D. Taskén K.A. Håheim L.L. Use of β-blockers is associated with prostate cancer-specific survival in prostate cancer patients on androgen deprivation therapy Prostate 2013 73 250 260 10.1002/pros.22564 22821802

100. Jansen L. Hoffmeister M. Arndt V. Chang-Claude J. Brenner H. Stage-specific associations between beta blocker use and prognosis after colorectal cancer Cancer 2014 120 1178 1186 10.1002/cncr.28546 24415516

101. Schmidt S.A. Schmidt M. Beta-blockers and improved survival from ovarian cancer: New miracle treatment or another case of immortal person-time bias? Cancer 2016 22 324 325 10.1002/cncr.29721 26445397

102. Hwa Y.L. Shi Q. Kumar S.K. Lacy M.Q. Gertz M.A. Kapoor P. Buadi F.K. Leung N. Dingli D. Go R.S. Beta-blockers improve survival outcomes in patients with multiple myeloma: A retrospective evaluation Am. J. Hematol. 2017 92 50 55 10.1002/ajh.24582 27733010 PMC5217079

103. Kozanoglu I. Yandim M.K. Cincin Z.B. Ozdogu H. Cakmakoglu B. Baran Y. New indication for therapeutic potential of an old well-known drug (propranolol) for multiple myeloma J. Cancer Res. Clin. Oncol. 2013 139 327 335 10.1007/s00432-012-1331-y 23080133 PMC11824266

104. Knight J.M. Rizzo J.D. Hari P. Pasquini M.C. Giles K.E. D’Souza A. Logan B.R. Hamadani M. Chhabra S. Dhakal B. Propranolol inhibits molecular risk markers in HCT recipients: A phase 2 randomized controlled biomarker trial Blood Adv. 2020 4 467 476 10.1182/bloodadvances.2019000765 32027744 PMC7013267

105. Del Toro R. Méndez-Ferrer S. Autonomic regulation of hematopoiesis and cancer Haematologica 2013 98 1663 1666 10.3324/haematol.2013.084764 24186311 PMC3815164

106. Mendelson A. Frenette P.S. Hematopoietic stem cell niche maintenance during homeostasis and regeneration Nat. Med. 2014 20 833 846 10.1038/nm.3647 25100529 PMC4459580

107. Benish M. Bartal I. Goldfarb Y. Levi B. Avraham R. Raz A. Ben-Eliyahu S. Perioperative use of beta-blockers and COX-2 inhibitors may improve immune competence and reduce the risk of tumor metastasis Ann. Surg Oncol. 2008 15 2042 2052 10.1245/s10434-008-9890-5 18398660 PMC3872002

108. Haldar R. Ricon-Becker I. Radin A. Gutman M. Cole S.W. Zmora O. Ben-Eliyahu S. Perioperative COX2 and β-adrenergic blockade improves biomarkers of tumor metastasis, immunity, and inflammation in colorectal cancer: A randomized controlled trial Cancer 2020 126 3991 4001 10.1002/cncr.32950 32533792

109. Kern M.A. Haugg A.M. Koch A.F. Schilling T. Breuhahn K. Walczak H. Fleischer B. Trautwein C. Michalski C. Schulze-Bergkamen H. Cyclooxygenase-2 inhibition induces apoptosis signaling via death receptors and mitochondria in hepatocellular carcinoma Cancer Res. 2006 66 7059 7066 10.1158/0008-5472.CAN-06-0325 16849551

110. Jones M.K. Wang H. Peskar B.M. Levin E. Itani R.M. Sarfeh I.J. Tarnawski A.S. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing Nat. Med. 1999 5 1418 1423 10.1038/70995 10581086

111. Ménétrier-Caux C. Bain C. Favrot M.C. Duc A. Blay J.Y. Renal cell carcinoma induces interleukin 10 and prostaglandin E2 production by monocytes Br. J. Cancer 1999 79 119 130 10.1038/sj.bjc.6690021 10408703 PMC2362183

112. Regulska K. Regulski M. Karolak B. Murias M. Stanisz B. Can cardiovascular drugs support cancer treatment? The rationale for drug repurposing Drug Discov. Today 2019 24 1059 1065 10.1016/j.drudis.2019.03.010 30878563

113. Ma S.N. Mao Z.X. Wu Y. Liang M.X. Wang D.D. Chen X. Chang P.A. Zhang W. Tang J.H. The anti-cancer properties of heparin and its derivatives: A review and prospect Cell Adhes. Migr. 2020 14 118 128 10.1080/19336918.2020.1767489 PMC7513850 32538273

114. Kuderer N.M. Khorana A.A. Lyman G.H. Francis C.W. A meta-analysis and systematic review of the efficacy and safety of anticoagulants as cancer treatment: Impact on survival and bleeding complications Cancer 2007 110 1149 1161 10.1002/cncr.22892 17634948

115. Stevenson J.L. Varki A. Borsig L. Heparin attenuates metastasis mainly due to inhibition of P- and L-selectin, but non-anticoagulant heparins can have additional effects Thromb. Res. 2007 120 S107 S111 Erratum in: Thromb. Res. 2008 , 123 , 187–190 10.1016/S0049-3848(07)70138-X 18023703

116. Hejna M. Raderer M. Zielinski C.C. Inhibition of metastases by anticoagulants J. Natl. Cancer Inst. 1999 91 22 36 10.1093/jnci/91.1.22 9890167

117. Alyahya R. Sudha T. Racz M. Stain S.C. Mousa S.A. Anti-metastasis efficacy and safety of non-anticoagulant heparin derivative versus low molecular weight heparin in surgical pancreatic cancer models Int. J. Oncol. 2015 46 1225 1231 10.3892/ijo.2014.2803 25530018

118. Atallah J. Khachfe H.H. Berro J. Assi H.I. The use of heparin and heparin-like molecules in cancer treatment: A review Cancer Treat. Res. Commun. 2020 24 100192 10.1016/j.ctarc.2020.100192 32673846

119. Malik J.A. Ahmed S. Momin S.S. Shaikh S. Alafnan A. Alanazi J. Said Almermesh M.H. Anwar S. Drug Repurposing: A New Hope in Drug Discovery for Prostate Cancer ACS Omega 2022 8 56 73 10.1021/acsomega.2c05821 36643505 PMC9835086

120. Zhang C. Jin H. Wen Y.F. Yin G. Efficacy of COVID-19 Treatments: A Bayesian Network Meta-Analysis of Randomized Controlled Trials Front. Public Health 2021 9 729559 10.3389/fpubh.2021.729559 34650951 PMC8506153

121. Cheng Q. Chen J. Jia Q. Fang Z. Zhao G. Efficacy and safety of current medications for treating severe and non-severe COVID-19 patients: An updated network meta-analysis of randomized placebo-controlled trials Aging 2021 13 21866 21902 10.18632/aging.203522 34531332 PMC8507270