**Acknowledgements**

blood vessels and the establishment of specific microenvironment within the tumor. These

**Figure 6.** Effect of portacaval anastomosis on thiobarbituric acid reactive substances (TBARS) assay supplemented with FeSO4 50 (μM) of liver homogenate, subcellular fractions and serum. Sham, false‐operated rats (white bars); shunt, rats with portacaval anastomosis for 6‐8 weeks (black bars). Data are average ± SEM from at least eight independent

Warburg's effect [99]; hypoxia also induces adaptive responses as the expression of special‐ ized proteins named hypoxia‐inducible factors (HIFs) [100]. HIF‐1 is a transcription factor formed by two subunits (HIF‐1α and HIF‐1β). Although HIF‐1 is constitutively expressed in normoxic conditions, HIF‐α is constantly degraded by prolyl‐hydroxylases; hydroxylated residues serve as docking site for von Hippel‐Lindau tumor suppressor protein that is a con‐ stituent of an E3 ubiquitin ligase complex. The ubiquitinated HIF‐1α suffers proteasomal deg‐ radation [101]. Low oxygen tension and some proinflammatory cytokines stabilize HIF‐1α and allow its nuclear translocation to regulate key genes for the hypoxic response [100]. HIF‐1α mediates the expression of genes that supports tumor growth such as NADH dehydrogenase (ubiquinone) 1α subcomplex, 4‐like 2 (NDUFA4L2), a protein that attenuates the activity of

It was shown that the kinase inhibitor sorafenib, an antineoplasic extensively used in oncol‐ ogy with potent antiangiogenic effects, induces intratumor oxidative stress that favor drug resistance in HCC; the insensibility to the drug requires the action of HIF‐1α regulating the

concentration environment with

conditions [102].

favors the onset of aerobic glycolysis, by the

adaptations make the tumor cells adapt to highly variable O2

Significant statistical difference by *t*‐student test, *p* < 0.05.

the mitochondrial complex I, reducing the ROS production in low O2

successive lapses of hypoxia‐reperfusion [98].

observations. \*

170 Redox - Principles and Advanced Applications

From the metabolic point of view, lack of O2

M.D‐M. research investigation is supported by DGAPA, PAPIIT grant no. IN200815. We thank LN Fernando López‐Barrera for his artistic assistance and Jééssica González‐Norris for critically editing the text.
