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Review
. 2022 Sep 9;14(18):4385.
doi: 10.3390/cancers14184385.

Development and Challenges of Diclofenac-Based Novel Therapeutics: Targeting Cancer and Complex Diseases

Ayeman Amanullah  1 , Arun Upadhyay  1 , Rohan Dhiman  2 , Sarika Singh  3 , Amit Kumar  4 , Dinesh Kumar Ahirwar  5 , Ravi Kumar Gutti  6 , Amit Mishra  1
Affiliations
Review

Development and Challenges of Diclofenac-Based Novel Therapeutics: Targeting Cancer and Complex Diseases

Ayeman Amanullah et al. Cancers (Basel). .

Abstract

Diclofenac is a highly prescribed non-steroidal anti-inflammatory drug (NSAID) that relieves inflammation, pain, fever, and aches, used at different doses depending on clinical conditions. This drug inhibits cyclooxygenase-1 and cyclooxygenase-2 enzymes, which are responsible for the generation of prostaglandin synthesis. To improve current diclofenac-based therapies, we require new molecular systematic therapeutic approaches to reduce complex multifactorial effects. However, the critical challenge that appears with diclofenac and other drugs of the same class is their side effects, such as signs of stomach injuries, kidney problems, cardiovascular issues, hepatic issues, and diarrhea. In this article, we discuss why defining diclofenac-based mechanisms, pharmacological features, and its medicinal properties are needed to direct future drug development against neurodegeneration and imperfect ageing and to improve cancer therapy. In addition, we describe various advance molecular mechanisms and fundamental aspects linked with diclofenac which can strengthen and enable the better designing of new derivatives of diclofenac to overcome critical challenges and improve their applications.

Keywords: COX; NSAIDs; ageing; cancer; diclofenac; neurodegeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure, mechanism of action, mode of drug administration, and metabolism of diclofenac. Cell damage results in release of arachidonic acid, a constituent of plasma membrane. Arachidonic acid in presence of enzyme cyclooxygenase and lipoxygenase is metabolized into prostaglandins, prostacyclins, and cytokines. These components are responsible for the generation of anti-inflammatory responses at the site of injury, causing pain and inflammation. Inhibition of platelet aggregation and cell proliferation by diclofenac have also been reported. The anti-inflammatory and analgesic effect of diclofenac is ascribed to its ability to hinder cyclooxygenase and lipoxygenase enzyme actions. Diclofenac metabolism mainly occurs in the liver and the major metabolic component of diclofenac is 4′ hydroxyl diclofenac metabolite. Other minor metabolites such as 5′ hydroxy diclofenac are also formed. The activation/formation and inhibition are depicted with arrows and blunt heads, respectively.
Figure 2
Figure 2
Therapeutic value and adverse drug–drug interactions of diclofenac. The potential use of diclofenac in combination therapies targeting various conditions has been assessed in numerous studies. However, some combinations of drugs with diclofenac have shown adverse effects. These include diclofenac in combination with ACE inhibitors, cyclosporine, anticoagulants, quinolones, and lithium/methotrexate. These combinations have resulted in increased blood pressure, nephrotoxicity, bleeding complications, seizures, and toxicity, respectively. In addition, with regard to its anti-inflammatory effects, studies have shown the therapeutic value of diclofenac in various diseases and conditions, such as autoimmune disorders, nociception, pancreatitis, amyloid fibril formation, seizures, cancer, and as an antimicrobial agent. The activation/formation and inhibition are depicted with arrows and blunt heads, respectively. The dotted blunt end represents an inhibitory effect that requires further investigations on diclofenac’s mechanism of action.
Figure 3
Figure 3
Possible and known applications of diclofenac. Diclofenac can act as an analgesic agent by activating transient outward potassium channels in neurons and simultaneously reducing the production of prostaglandins. Diclofenac can also act as a potent inhibitor of oligomerization of β-amyloid fibrils and plaque formation, which can be used in the development of therapies for diseases involving amyloid aggregation. Alternatively, diclofenac also interferes with the activation of glial cells, which may further contribute to its neuroprotective properties. Diclofenac has both inhibitory and inducing effects on cell death under different conditions. Endoplasmic reticulum stress generated by thapsigargin leads to activation of caspases and causes mitochondrial depolarization. Diclofenac suppresses the intrinsic pathway of apoptosis by interfering with caspase activation and mitochondrial depolarization. On the other hand, diclofenac treatment can result in proteasomal dysfunction generating downstream apoptotic signals such as mitochondrial cytochrome c release, causing stimulation of caspases leading to apoptosis. The pathway shown under dotted dual faced arrow curve in the top right shows the role of diclofenac in the inhibition of β-amyloid fibrils and plaque formation. The activation/formation and inhibition are depicted with arrows and blunt heads, respectively. The green color coding on arrows and blunt ends depicts the cell survival, whereas, the red color indicates cell death promoting signals.
Figure 4
Figure 4
Schematic depiction of mechanisms of diclofenac-mediated apoptosis and cell cycle arrest. Diclofenac is found to obstruct cell cycle in different cell lines, such as neural stem cells, human lymphatic endothelial cells (HLEC), osteoblasts, glioblastomas (GBM), ovarian cells, and VSMC. Studies found an upregulation of cell cycle inhibitory proteins, such as p27, p21, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and downregulation of inducers of cell proliferation, such as E2F1 transcription factor and cyclin D1, all crucial factors responsible for causing cell cycle arrest after diclofenac treatment. Diclofenac has also been shown to have pro-apoptotic effects. The major downstream mechanisms that have been thought to be the reason for diclofenac-mediated apoptosis includes ROS-induced downregulation of the PI 3-kinase/Akt signaling pathway, inhibition of NF-kB activity, disturbance in proteasome activity, interference with COX enzyme activity, and induction of the JNK pathway via AP1 transcription factors. The activation/formation and inhibition are depicted with arrows and blunt heads, respectively. The upward and downward small arrows in bold depicts elevation and depletion in corresponding proteins or pathway. The bold arrows or blunt ends (on top left and right sections) points to downstream proteins or cancer types, respectively indicating the effect of diclofenac. The normal arrows or blunt ends in lower section represents individual pathways known to be involved in diclofenac mediated apoptosis.
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