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Ralph et al. J Cancer Metastasis Treat 2018;4:49 Journal of Cancer
DOI: 10.20517/2394-4722.2018.42 Metastasis and Treatment

Review Open Access

NSAID celecoxib: a potent mitochondrial pro-oxidant
cytotoxic agent sensitizing metastatic cancers and

cancer stem cells to chemotherapy

Stephen John Ralph , Sam Nozuhur , Rafael Moreno-Sánchez , Sara Rodríguez-Enríquez , Rhys
1
1
2
2
Pritchard 1
1 School of Medical Science, Griffith University, Southport 4222, Gold Coast, Australia.
2 Departmento de Bioquímica, Instituto Nacional de Cardiologia, Tlalpan 14080, Mexico.
Correspondence to: Dr. Steve Ralph, School of Medical Science, Griffith University, Southport 4222, Gold Coast, Australia.
E-mail: s.ralph@griffith.edu.au
How to cite this article: Ralph SJ, Nozuhur S, Moreno-Sánchez R, Rodríguez-Enríquez S, Pritchard R. NSAID celecoxib: a potent
mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy. J Cancer
Metastasis Treat 2018;4:49. http://dx.doi.org/10.20517/2394-4722.2018.42

Received: 30 Jun 2018 First Decision: 27 Jul 2018 Revised: 2 Aug 2018 Accepted: 9 Aug 2018 Published: 20 Sep 2018

Science Editor: Lucio Miele Copy Editor: Yuan-Li Wang Production Editor: Zhong-Yu Guo

ABSTRACT
Intermittent hypoxia within tumor microenvironments causes pro-oxidative stress impairing oxidative phos-
phorylation (OxPhos) and increases mitochondrial production of reactive oxygen species (ROS). In primary tu-
mors this provokes metabolic reprogramming of both tumor cells and cancer stem cells and emergence of highly
metastatic cancer cells. Tumor reprogramming is initiated by activating nuclear respiratory factors and hypoxia-
inducible factors in response to changes in oxygen and ROS levels. Hence, hypoxia-induced pro-oxidative stress
drives invasion and metastasis. However, it is also the Achilles’ heel of metastatic cancer cells because pro-oxi-
dative agents further overload the mitochondria and intracellular milieu with excessive ROS to trigger apoptosis,
whereas antioxidant agents promote their survival and tumor progression. Herein lies the metastatic tumor cell
sensitivity to non-steroidal anti-inflammatory drugs (NSAIDs) and we and others have shown that the NSAID
celecoxib exerts powerful pro-oxidative anticancer effects by directly targeting mitochondria to increase ROS
production and trigger cancer cell death, including metastatic cancer cells and cancer stem cells. This review
highlights the considerable benefits from appropriate NSAID use in humans against post-diagnosis metastatic
tumors and the need to further develop their use as adjuvant therapy for advanced stage metastatic disease
where they are already showing significantly improved clinical outcomes.

Keywords: Non-steroidal anti-inflammatory drug, celecoxib, metastasis, anticancer, mitocans, chemosensitizing,
cancer stem cells, therapy

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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