The future of pharmacology and therapeutics of the arachidonic acid cascade in the next decade: Innovative advancements in drug repurposing

Abstract

Many drugs can act on multiple targets or disease pathways, regardless of their original purpose. Drug repurposing involves reevaluating existing compounds for new medical uses. This can include repositioning approved drugs, redeveloping unapproved drugs, or repurposing any chemical, nutraceutical, or biotherapeutic product for new applications. Traditional drug development is slow, expensive, and has high failure rates. Drug repurposing can speed up the process, costing less and saving time. This approach can save 6-7 years of early-stage research time. Drug repurposing benefits from existing compounds with optimized structures and approved for clinical use with associated structure-activity relationship publications, supporting the development of new effective compounds. Drug repurposes can now utilize advanced in silico screening enabled by artificial intelligence (AI) and sophisticated tissue and organ-level in vitro models. These models more accurately replicate human physiology and improve the selection of existing drugs for further pre-clinical testing and, eventually, clinical trials for new indications. This mini-review discusses some examples of drug repurposing and novel strategies for further development of compounds for targets of the arachidonic acid cascade. In particular, we will delve into the prospect of repurposing antiplatelet agents for cancer prevention and addressing the emerging noncanonical functionalities of 5-lipoxygenase, potentially for leukemia therapy.

Keywords: 5-lipoxygenase; antiplatelet agents; cancer; drug repurposing; systems biology and network analysis.

FIGURE 1

The platelet hypothesis of tumorigenesis and mechanisms of antitumor effects of antiplatelet agents and anti-inflammatory drugs. In the early stages of tumor formation, activated platelets release growth and angiogenic factors, thromboxane (TX) A₂ and adenosine diphosphate (ADP), which contribute to the development of an inflammatory microenvironment via the induction of COX-2 (cyclooxygenase-2) expression leading to aberrant generation to prostaglandin (PG) E₂. PGE₂ is a central mediator in inflammation and contributes to acquiring tumor properties, such as proliferation, inhibition of apoptosis, migration, and immune escape. These processes promote the growth and survival of early tumor cells. Tumor progression is associated with immune infiltration, extravasated platelets, and enhanced PGE₂ and TXA₂ generation that contribute to immune escape. In advanced tumors, COX-2-dependent PGE₂ contributes to epithelial-mesenchymal transition (EMT). In the bloodstream, platelets interact with cancer cells, enabling them to spread and colonize other tissues through various mechanisms, including EMT. Antiplatelet agents like aspirin and clopidogrel, by inhibiting platelet activation, prevent the induction of COX-2 and PGE₂, thus affecting early tumor development. Moreover, antiplatelet agents constrain tumor progression and metastasis. Anti-inflammatory drugs, such as coxibs (selective COX-2 inhibitors), can impede cancer development, progression and metastasis by inhibiting the activity of COX-2.