Repurposing of host-based therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19): A link between antiviral and anticancer mechanisms?

Abstract

Repurposing, also called repositioning or rediscovering, refers to the process of developing a known drug for a novel use, which is different from its original clinical indication. This concept has focused greater attention on the search for viable treatments in the context of the current pandemic. The article recently published by Serafin et al. in the International Journal of Antimicrobial Agents [1] presented a selection of repurposing drug candidates for potential use in the management of coronavirus disease 2019 (COVID-19). The authors conducted a systematic research through PubMed, Scopus and Web of Science databases, and identified recent studies investigating drugs from different pharmaceutical classes with antiviral activity against SARS-CoV-2 and SARS-CoV. Remarkably, at least four drugs reported by Serafin et al. with promising early results in COVID-19 [1], including hydroxychloroquine, chloroquine, nitazoxanide and metformin, have also been previously explored as anticancer agents. The antimalarials hydroxychlroquine and chlroquine are known to inhibit autophagic pathways in aggressive metastatic cells, and potentiate the efficacy of chemotherapy in various types of cancers. Autophagy is considered a cytoprotective mechanism that confers drug resistance, representing a key obstacle to effective cancer treatment [2]. Likewise, the antiparasitic drug nitazoxanide induces cancer cell cytotoxicity under hypoxic conditions and it could be an excellent candidate to target dormant cancer cells in hypoxic regions of tumors in combination with chemotherapy agents [3]. Metformin, an effective medication used in type 2 diabetes mellitus, is able to modulate tumor cell signaling and metabolism. Although the underlying mechanisms have not been completely characterized, metformin reduces tumor cell growth, inhibits the expression of microRNAs associated with tumorigenesis and limits energy availability by affecting mitochondrial metabolism [4]. Moreover, cell starvation caused by metformin triggers the release of cytokines such as interleukins IL-6 and IL-8, and promotes recruitment of immune cells in tumor microenvironment [5]. We would like to add some comments regarding the importance of drug repurposing as an emerging approach for the development of host-based antiviral agents, highlighting similarities between antiviral and antitumor mechanisms, when considering other drugs like lovastatin and ivermectin. Development of host-based antiviral strategies is emerging as an attractive approach to complement the treatment of patients with severe COVID-19 at risk for acute respiratory disease syndrome (ARDS). Clinically approved drugs could be used to target viral entry or viral replication, and to modulate innate immune responses [6]. Mechanisms essential for viral infection such as host-cell proteolytic processing, endocytosis, nuclear transport and intracellular signal transduction, among others, have been indicated as better targets to identify broad spectrum antiviral agents, with some advantages over direct-acting antivirals targeting viral components. For instance, host-based therapeutics could overcome limitations associated to drug resistance or viral mutations. Well-tolerated compounds with documented antitumor properties are attractive as potential host-based drug candidates for the management of critically ill COVID-19 patients. Lovastatin, a fungal antibiotic used in the treatment of hypercholesterolemia since the mid-1980s, has been demonstrated to produce potent antitumor effects in experimental mouse models at non-cytotoxic concentrations [7]. In particular, it holds promise for the clinical management of triple-negative breast cancer [8]. The compound reduces membrane localization of Rho proteins, thus affecting signaling molecules involved in the regulation of actin cytoskeleton during tumor cell migration and metastatic colonization [9]. Interestingly, it is known that RhoA signaling is also associated with cellular functions that are relevant to the pathogenesis of several viral infections, including actin organization and production of proinflammatory cytokines [10]. It seems that cholesterol depletion by lovastatin causes the shutdown of host cell signals required for viral pathogenesis, in similarity to the effects on tumor cell signaling. Lovastatin and other lipophilic statins such as simvastatin and atorvastatin also have profound effects on endothelial cell biology, and it is known that angiostatic action plays a key role in statin-induced antitumor activity [11]. Likewise, by targeting the host response to infection, statins act on endothelial dysfunction and may contribute to the return to homeostasis in patients with severe COVID-19 [12]. Statins, as well as angiotensin receptor blockers, are able to upregulate angiotensin-converting enzyme 2 (ACE2) [13,14], which is the viral entry receptor for SARS-CoV-2 [15]. However, there is presently no evidence indicating that these medications enhance viral entry into host cells. In fact, once COVID-19 infection has progressed, ACE2 mediates protective effects against lung injury [16], and elevated levels of ACE2 are associated with a reduced severity of ARDS [17]. Hence, treatment strategies which modulate host response by manipulating the renin-angiotensin system might attenuate the destructive lung disease associated with COVID-19 [12,16]. The well-known antiparasitic drug ivermectin has been reported to possess antiviral activity against a wide range of viruses, and also to display promising antitumor effects in different preclinical models of aggressive cancers [18]. Ivermectin seems to produce pleiotropic actions in virus-infected host cells and malignant tumor cells, but the precise mechanisms are not completely understood. Among other actions, ivermectin affects tumor cell growth, induces caspase-dependent apoptosis and causes immunogenic cell death [19]. A few years ago, ivermectin was reported to affect the interaction between the integrase protein of human immunodeficiency virus HIV-1 and the importin heterodimer α/β1. The drug was later confirmed to behave as a potent inhibitor of the nuclear import mechanisms of viral proteins in host cells, including SV40 simian virus large tumor antigen and dengue virus non-structural proteins [20]. Very recently, it was proposed as a mechanism for inhibiting the entry and replication of SARS-CoV-2 [21]. Interestingly, this mechanism of inhibition of nuclear protein trafficking had been suggested as a potential universal target against RNA viruses [22], and could also explain part of the antitumor properties of ivermectin [23]. In this regard, nuclear transport plays a central role in cancer by moving key mediators of carcinogenesis across the nuclear pore [24]. All together these evidences stress the importance of host-based strategies in the rapid identification of therapies for COVID-19 patients and, particularly, underscore the potential of certain repurposed drugs with known antitumor activity. Drug repurposing permits reduced development time and cost, and implies lesser safety concerns as data on long-term pharmacovigilance for adverse effects are available. Table 1 presents a summary of selected repurposed drugs, their original medical indications and potential mechanisms of action. Drugs such as lovastatin, ivermectin, metformin and nitazoxanide constitute promising therapeutic approaches that deserve clinical testing in COVID-19, either alone or as components of antiviral therapy regimens. Table 1 Selected repurposed drugs with antitumor effects and potential antiviral activity against SARS-CoV-2. Table 1 Drug Original indication Potential antitumor/antiviral mechanisms of action References Lovastatin* Cholesterol-lowering drug Inhibits Rho signaling associated with tumor spread and viral pathogenesis. Counteracts tumor angiogenesis and endothelial dysfunction in ARDS. Fedson et al. 2020 [12] Farina et al. 2002 [9] Ivermectin Antiparasitic agent Inhibits nuclear import mechanisms of oncoproteins and viral proteins. Induces immunogenic cell death. Caly et al. 2020 [21] Draganov et al. 2015 [19] Metformin Hypoglycemiant drug Among various effects, triggers cytokine release and recruits immune cells. Püschel et al. 2020 [5] Serafin et al. 2020 [1] Nitazoxanide Antiparasitic agent Not clearly defined. Induces cell cytotoxicity under hypoxic conditions. Senkowski et al. 2015 [3] Serafin et al. 2020 [1] ⁎ Other lipophilic statins such as simvastatin and atorvastin share similar antitumor and/or antiviral effects.