Cancer cell killing by Celecoxib: Reality or just in vitro precipitation‐related artifact?

Abstract

Among NSAIDs Celecoxib is one of the most efficient in triggering in vitro cancer cell death, and from this perspective has been subject of numerous studies. However, it is still controversial whether this in vitro-observed effect can also occur in vivo and contribute to the antitumor action of the drug. Moreover, besides common agreement on the involvement of COX-independent pathways, the mechanisms underlying Celecoxib toxicity are still unclear. In an attempt to shed light on these mechanisms, I found that cell death only occurs at insoluble concentrations of the drug, and follows irreversible binding and damage of the plasmamembrane by precipitates. This evidence strongly suggests that Celecoxib is devoid of true molecular toxicity. Moreover, since plasma levels reached during therapy are far below the threshold of toxic precipitation, direct cytotoxicity by Celecoxib is unlikely to occur on tumor cells in vivo. Thus the antitumor effect might be only due to COX inhibition, which requires significantly lower levels of the drug. Nonetheless, direct cytotoxicity might not be confined to an in vitro artifact, but contribute to the upper gastrointestinal side effects of Celecoxib. Overall, these findings represent an important basis for further studies on Celecoxib, where true molecular actions of the drug should be discriminated from the precipitate-dependent ones, and the relationship between in vitro and in vivo effects considered at the light of the precipitate-dependent model. Moreover, remarkably, this article indicates a model of critical analysis that can be extended to other poorly soluble drugs.

In-vitro characterisation of a novel celecoxib microbead formulation for the treatment and prevention of colorectal cancer

“…In strong contrast to the results obtained for Celebrex and CLX API, there was a significant inhibitory effect observed for both formulation A and B without exerting a significant necrotic effect. The strong apoptotic effect for formulations A and B is very significant as it suggests that these formulations caused HT29 cell death via molecular mechanisms and thereby is a new development on the data presented by Sacchetti[14] in which it was found that in‐vitro cell death for CRC cell lines only occurred at insoluble concentrations of CLX. The data presented here suggest that a molecular toxic effect is possible for CLX if the drug is optimally presented to the cells (i.e., in a stable solubilised state).…”

“…Although the necrotic effect of the various formulations are discussed here, it is acknowledged that further studies involving a time course Annexin V/PI apoptosis assay, microscopic analysis or an alternative apoptotic assay (e.g., TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling)) could be performed to support the proposed necrotic effect observations for CLX API. There exists a theory that the cancer‐killing effect of CLX may be related to direct cytotoxicty (resulting from irreversible binding and damage to the plasma membrane by CLX precipitates) as opposed to molecular toxicity [14]. Based on this theory, it could be argued that the concentration of Celebrex used (50 μ m ) was not sufficient to result in direct cytotoxicty.…”

“…In order to counteract this poor bioavailability, the drug is administered in high doses, which may thereby result in more CV and GI adverse side effects. In the case of GI side effects, the administration of the drug in a soluble form and at a lower dose has the potential to alleviate GI irritation,[14,15] whereas CV side effects could be reduced by lowering the systemic dose [16]…”

“…In order to counteract this poor bioavailability, the drug is administered in high doses, which may thereby result in more CV and GI adverse side effects. In the case of GI side effects, the administration of the drug in a soluble form and at a lower dose has the potential to alleviate GI irritation, [14,15] whereas CV side effects could be reduced by lowering the systemic dose. [16] The objective of this work was to develop a formulation with the potential to reduce the unwanted CV and GI side effects associated with the marketed CLX product, Celebrex, using the following strategy: (1) by presenting the drug in a soluble format to reduce irritation and also to address the solubility issues of the drug thereby allowing for the use of a lower dose; (2) by incorporating the drug in a multiparticulate format, thereby allowing for better GI distribution and reduced likelihood of local irritation [17] ; and (3) by applying a sustained release polymer to allow for the development of colonic targeted microbeads that would enable local action on colonic tissue and thereby again reduce the dose required.…”

Celecoxib treatment of fibrous dysplasia (FD) in a human FD cell line and FD-like lesions in mice with protein kinase A (PKA) defects

“…Some of the in vitro effects may be because at certain concentrations the drug is insoluble and causes precipitate-dependent effects and cellular toxicity (Sacchetti, A., 2013). However, there are also true biologic effects of Celecoxib, mostly linked to inhibition of PGE2 synthesis and the consequent decrease of this molecule’s induction of stem cell-like cells that are essential for the growth of at least some tumors (Kurtova et al, 2015, Tsujii et al, 1998 and Mazhar et al, 2006).…”