Hyperoxia and PARP inhibition differentially modulate transcription profile and inflammation in aggressive melanoma and non-transformed lung epithelial cells

Abstract

The local conditions of tumor cell growth, known as the tumor microenvironment (TME), are characterized by low oxygen supply (hypoxia) caused by insufficient blood delivery. Hypoxia cancers have a strong invasive potential, metastasis, resistance to therapy and a poor clinical prognosis. The key regulator of adaptation to tumor hypoxia is hypoxia inducible factor 1-¿ (HIF-1¿). Despite its significance, the underlying transformations that cause this highly aggressive behaviour are poorly understood, specific pharmacological inhibition of HIF-1¿ activation in the tumor are not available. Our group has shown that PARP inhibitors can modulate HIF-1¿ levels and its activation. On the other hand, hyperoxia could be a treatment of medical interest to fight tumors that present with hypoxia; nevertheless, its use may involve clinically unacceptable lung damage. AIMS: In this study, we aim to demonstrate that the use of PARP inhibitors (1) will interfere with the adaptation of the tumor to the hypoxic microenvironment (which is recreated with the hypoxia-mimetic,CoCl2), in combination with the use with oxygen to induce hyperoxia and (2) will decrease the lung damage induced by reactive oxygen species. Therefore, the combined use of oxygen and PARP inhibitors in metastatic melanoma (expressing high levels of HIF-1) could delay metastasis and improve the efficacy of anti-tumor therapy.