Inflammation and Cancer: Triggers, Mechanisms, and Consequences.

The British National Formulary.

Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective.

Cancer incidence is rising and this global challenge is further exacerbated by tumour resistance to available medicines. A promising approach to meet the need for improved cancer treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (also known by the trade name Antabuse), an old alcohol-aversion drug that has been shown to be effective against diverse cancer types in preclinical studies. Our nationwide epidemiological study reveals that patients who continuously used disulfiram have a lower risk of death from cancer compared to those who stopped using the drug at their diagnosis. Moreover, we identify the ditiocarb–copper complex as the metabolite of disulfiram that is responsible for its anti-cancer effects, and provide methods to detect preferential accumulation of the complex in tumours and candidate biomarkers to analyse its effect on cells and tissues. Finally, our functional and biophysical analyses reveal the molecular target of disulfiram’s tumour-suppressing effects as NPL4, an adaptor of p97 (also known as VCP) segregase, which is essential for the turnover of proteins involved in multiple regulatory and stress-response pathways in cells.

Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4

Lysosomes are membrane-enclosed organelles that mediate the intracellular degradation of macromolecules. They play an essential role in calcium regulation and have emerged as key signaling hubs in controlling the nutrient response. Maintaining lysosomal integrity and function is therefore crucial for cellular homeostasis. Different forms of stress can induce lysosomal membrane permeabilization (LMP), resulting in the translocation to the cytoplasm of intralysosomal components, such as cathepsins, inducing lysosomal-dependent cell death (LDCD). Here, we review recent advances that have furthered our understanding of the molecular mechanisms of LMP and the methods used to detect it. We discuss several endolysosomal damage-response mechanisms that mediate the repair or elimination of compromised lysosomes and summarize the role of LMP and cathepsins in LDCD and other cell death pathways. Finally, with the emergence of lysosomes as promising therapeutic targets for several human diseases, we review a variety of therapeutic strategies that seek to either destabilize lysosomes or to maintain, enhance or restore lysosomal function.

Lysosomal membrane permeabilization and cell death.

Cimetidine, the first H2 receptor antagonist in widespread clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical and clinical studies for a number of different cancer types. These data are summarised and discussed in relation to a number of distinct mechanisms of action. Based on the evidence presented, it is proposed that cimetidine would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of cimetidine as an anti-cancer therapeutic is warranted. Furthermore, there is compelling evidence that cimetidine administration during the peri-operative period may provide a survival benefit in some cancers. A number of possible combinations with other drugs are discussed in the supplementary material accompanying this paper.

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Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent

The Repurposing Drugs in Oncology (ReDO) Project seeks to repurpose well-known and well-characterised non-cancer drugs for new uses in oncology. The rationale for this project is presented, examining current issues in oncological drug development, challenges for health systems, and existing and future patient needs. In addition to discussing the advantages of repurposing, the paper also outlines some of the characteristics used in the selection of drug candidates by this project. Challenges in moving candidate drugs into clinical trial and subsequent practice are also discussed.

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The Repurposing Drugs in Oncology (ReDO) Project

Chloroquine (CQ) and hydroxychloroquine (HCQ) are well-known 4-aminoquinoline antimalarial agents. Scientific evidence also supports the use of CQ and HCQ in the treatment of cancer. Overall, preclinical studies support CQ and HCQ use in anti-cancer therapy, especially in combination with conventional anti-cancer treatments since they are able to sensitise tumour cells to a variety of drugs, potentiating the therapeutic activity. Thus far, clinical results are mostly in favour of the repurposing of CQ. However, over 30 clinical studies are still evaluating the activity of both CQ and HCQ in different cancer types and in combination with various standard treatments. Interestingly, CQ and HCQ exert effects both on cancer cells and on the tumour microenvironment. In addition to inhibition of the autophagic flux, which is the most studied anti-cancer effect of CQ and HCQ, these drugs affect the Toll-like receptor 9, p53 and CXCR4-CXCL12 pathway in cancer cells. In the tumour stroma, CQ was shown to affect the tumour vasculature, cancer-associated fibroblasts and the immune system. The evidence reviewed in this paper indicates that both CQ and HCQ deserve further clinical investigations in several cancer types. Special attention about the drug (CQ versus HCQ), the dose and the schedule of administration should be taken in the design of new trials.

/pdf/repurposing-drugs-in-oncology-redo-chloroquine-and-u4tcd0hlva.pdf

Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents.

Mebendazole, a well-known anti-helminthic drug in wide clinical use, has anti-cancer properties that have been elucidated in a broad range of pre-clinical studies across a number of different cancer types. Significantly, there are also two case reports of anti-cancer activity in humans. The data are summarised and discussed in relation to suggested mechanisms of action. Based on the evidence presented, it is proposed that mebendazole would synergise with a range of other drugs, including existing chemotherapeutics, and that further exploration of the potential of mebendazole as an anti-cancer therapeutic is warranted. A number of possible combinations with other drugs are discussed in the Appendix.

/pdf/repurposing-drugs-in-oncology-redo-itraconazole-as-an-anti-47eottqsea.pdf

Repurposing Drugs in Oncology (ReDO)-itraconazole as an anti-cancer agent.

Fluvoxamine is a well-tolerated, widely available, inexpensive selective serotonin reuptake inhibitor that has been shown in a small, double-blind, placebo-controlled, randomized study to prevent clinical deterioration of patients with mild coronavirus disease 2019 (COVID-19). Fluvoxamine is also an agonist for the sigma-1 receptor, through which it controls inflammation. We review here a body of literature that shows important mechanisms of action of fluvoxamine and other SSRIs that could play a role in COVID-19 treatment. These effects include: reduction in platelet aggregation, decreased mast cell degranulation, interference with endolysosomal viral trafficking, regulation of inositol-requiring enzyme 1α-driven inflammation and increased melatonin levels, which collectively have a direct antiviral effect, regulate coagulopathy or mitigate cytokine storm, which are known hallmarks of severe COVID-19.

/pdf/fluvoxamine-a-review-of-its-mechanism-of-action-and-its-role-4oc7mg8cks.pdf

Vidula Sukhatme

Papers

Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent

The Repurposing Drugs in Oncology (ReDO) Project

Repurposing Drugs in Oncology (ReDO)-chloroquine and hydroxychloroquine as anti-cancer agents.

Repurposing Drugs in Oncology (ReDO)-itraconazole as an anti-cancer agent.

Fluvoxamine: A Review of Its Mechanism of Action and Its Role in COVID-19