**3.5 NO donors**

296 Advances in Cancer Therapy

counteracted by the dramatic decrease in oxygen consumption by tumor cells (i.e. insulin and NS-398). In addition, regarding NO-mediated treatments, our models showed that the radiotherapeutic response not only depended on the tumor pO2 but also on the net level of NO achieved at the time of irradiation, NO itself being able to stabilize irradiation-induced

The first drug that was described to inhibit oxygen consumption in tumors was metaiodobenzylguanidine (MIBG), which causes an inhibition of the mitochondrial site I electron transfer, inhibition of NAD(P)H oxidation, and is described to alter tumor glycolysis by inhibiting oxygen consumption (Biaglow et al., 1998). We consecutively focused on different innovative treatments that may alter oxygen consumption by tumor cells, as listed below.

This hormone was known to increase blood flow in human skeletal muscle and was postulated to be an important modulator of tumor oxygenation (Jordan et al., 2002). Indeed, we showed that insulin had a profound effect on tumor oxygenation that was not due to an increase in tumor blood flow but to a decrease in tumor cell oxygen consumption. The increase in tumor oxygenation resulted in an important enhancement in the sensitivity of tumors to irradiation. The likely scenario involves a stimulation of eNOS and a consequent increase in NO release. As NO regulates mitochondrial respiration by virtue of reversible interactions with cytochrome c oxidase (complex IV), an increase in NO release consequently decreased cell respiration (Jordan et al., 2002). A preclinical study confirmed the dose-dependant increase in tumor oxygenation and radiation sensitivity by insulin,

without any increase in the radiation toxicity for normal tissues (Jordan et al., 2006a).

improvement of the radiation efficacy by a factor of 1.7 (Crokart et al., 2007).

Earlier work had demonstrated that the administration of cortisone to rats resulted in both the inhibition of oxygen consumption and the uncoupling of oxidative phosphorylation in liver mitochondria (Kimberg et al., 1968). Glucocorticoids seemed to decrease the cytochrome c oxidase (complex IV) activity of isolated rat kidney mitochondria by a direct mechanism (Simon et al., 1998). Our group showed an important increase in tumor oxygenation induced by an effect on oxygen consumption. Decreased oxygen consumption could be explained by the capacity of glucocorticoids to inhibit cytochrome c oxidase of the mitochondrial respiratory chain. The result of this increase in tumor oxygenation was an

Several reports indicated that many non-steroidal anti-inflammatory drugs (NSAIDs) uncouple mitochondrial oxidative phosphorylation with important consequences on cell oxygen consumption. However, it was suggested that the response was dependent on the dose as well as on the type of NSAIDs. For the first time, our group reported that the administration of NSAIDs induced a dramatic increase in tumor oxygenation explained by reduced oxygen consumption. An increase in the tumor response was observed when the

Chronic alteration in the thyroid status has been shown to affect mitochondrial oxygen consumption in skeletal muscle (Gredilla et al., 2001). Also, studies have demonstrated that

irradiation was applied at the time of maximal reoxygenation (Crokart et al., 2005).

DNA lesions *in vivo* (Jordan et al., 2004).

**3.1 Insulin** 

**3.2 Glucocorticoids** 

**3.3 Anti-inflammatory drugs** 

**3.4 Thyroid hormones** 

We recently tested whether *S*-nitrosocaptopril, a molecule combining a NO donor and an angiotensin converting enzyme inhibitor (ACE inhibitor), could temporarily improve the hemodynamic status of experimental tumors. We identified a time window during which tumor oxygenation was improved, as a result of a combined effect on tumor blood flow and oxygen consumption. Consequently, the administration of *S*-nitrosocaptopril contributed to the increase in efficacy of radiation therapy, an effect that was not observed with captopril alone (Jordan et al., 2010a).
