Hypoxia-inducible factor HIF-1α modulates drugs resistance in colon cancer cells

• Published in: Revista de la Facultad de Medicina, Universidad Nacional de Colombia Vol. 66; no. 4; pp. 543 - 550
• Main Authors: Pinzón-Daza, Martha Leonor, Cuellar, Yenith, Ondo, Alejandro, Matheus, Luisa, Del Riesgo, Lilia, Castillo, Fabio, Garzón, Ruth
• Format: Journal Article
• Language: English
• Published: Universidad Nacional de Colombia 01.10.2018
• Subjects: Apoptosis; Cell Hypoxia; Colon Cancer; Doxorubicin; MEDICINE, GENERAL & INTERNAL; Cell Hypoxia; Cáncer del colon; Doxorubicin (MeSH); Colon Cancer; Hipoxia celular; Doxorrubicina (DeCS); Apoptosis
• ISSN: 0120-0011; 2357-3848
• DOI: 10.15446/revfacmed.v66n4.55149

Introduction: Drug resistance mechanisms may be associated with decreased cell death and its induction may depend on the response to oxidative stress caused by hypoxia. The correlation between hypoxia-inducible factor HIF-1α, the number of reactive oxygen species and their effect on cell survival has not yet been evaluated.Objective: The purpose of this study was to evaluate the effect of HIF-1α activity and reactive oxygen species (ROS) accumulation in apoptosis of colon cancer cells.Materials and methods: HT29 colon cancer cells were treated with CoCl2 or doxorubicin and the activity of HIF-1α was determined by ELISA assay. ROS were determined using fluorescence probe carboxy-H2DFFDA. Apoptosis was assessed by caspase-3 activation analysis, and PUMA and BAX mRNA levels by qRT-PCR. The reduction of the antiapoptotic effect due to hypoxia was attenuated by use of the endonuclease APE-1 (E3330) inhibitor. The endonuclease E3330 APE-1 inhibitor allowed evaluating the effect of ROS generated by doxorubicin and CoCl2 on apoptosis.Results: Chemical hypoxia in combination with doxorubicin is an oxidative stressor in HT29 cells and induces a reduction in the apoptotic process in a time-dependent manner.Conclusion: Resistance to hypoxia and doxorubicin-mediated cell death could be controlled by a mechanism related to the activity of HIF-1α and the amount of reactive oxygen species generated.