A novel approach to target hypoxic cancer cells via combining β-oxidation inhibitor etomoxir with radiation

Abstract

Background:

Hypoxia in tumors is associated with resistance towards various therapies including radiotherapy. In this study, we assessed if hypoxia in cancer spheres could be effectively reduced by adding etomoxir (a β-oxidation inhibitor) immediately after cell irradiation.

Methods:

We employed cancer cells’ sphere model to target hypoxia. Confocal imaging was used to analyze hypoxia and expression of specific biomarkers in spheres following various treatments (radiation and/or etomoxir).

Results:

Etomoxir (32.5 μM) treatment improved the radiation (2.5 Gy) efficacy against growth of lung adenocarcinoma H460 spheres. More importantly, radiation and etomoxir combination significantly reduced the hypoxic regions (pimonidazole+ areas) in H460 spheres compared to either treatment alone. Also, etomoxir and radiation combination treatment reduced the protein level of biomarkers for proliferation (Ki-67 and cyclin D1), stemness (CD44) and β-oxidation (CPT1A) in H460 spheres. We observed similar efficacy of etomoxir against growth of prostate cancer LNCaP cells’ spheres when combined with radiation. Further, radiation treatment strongly reduced the hypoxic regions (pimonidazole+ areas) in CPT1 knockdown LNCaP cells’ spheres.

Conclusions:

Together, these results offer a unique approach to target hypoxia in solid tumors via combining etomoxir with radiation, thereby improving therapeutic efficacy.

Keywords::

• Hypoxia
• radiation
• β-oxidation
• Etomoxir
• CPT1A

Data sharing statement

The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We thank Dr Barbara Frederick for her helpful inputs in this project.We acknowledge the grant support from Colorado Clinical and Translational Science Institute and NCI R21 CA199628 (to GD), K01 CA168934 (to IRS), and R01 CA102514 (to RA).

Author contributions

AD performed the experiments and wrote the manuscript; CA contributed in cell culture and manuscript writing; IRS, DR, RS, and RA provided the reagents and contributed in experimental design and manuscript writing; and GD developed the original hypothesis, study design, supervised the experiments, provided reagents, and contributed in manuscript writing. All authors contributed toward data analysis, drafting and revising the paper and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.