Mechanisms and effects of the immunomodulator P-MAPA in the treatment of prostate cancer and non-muscle invasive bladder cancer: interfaces between energy metabolism, oxidative balance, angiogenesis and signaling pathway of toll-like receptors

Abstract

Cancer cells face two distinct metabolic challenges: (1) how to modify their cellular metabolism to support enhanced cell growth and proliferation, and (2) how to engage strategies of metabolic adaptation to survive environmental fluctuations and the availability of nutrients and oxygen when the tumor growth exceeds the supply capacity of existing vasculature. Further, the oxygen consumption by tumor cells may be directly associated with the generation of free radicals (FR), since these are normally produced at low doses during the process of cellular respiration. These facts make the study of the association of Prostate Cancer (PC) and bladder cancer (BC) with FR, angiogenesis and energy metabolism an important step towards the understanding of these types of tumor, especially when related to these events with normal condition of cells. Another relevant point is the study of the interaction of different therapeutic modalities with the modulation of the immune system through the signaling pathways of toll-like receptors (TLRs) 2 and 4. In this scenario stands out P-MAPA, which in versatility and minimal cytotoxicity, revealed by preliminary studies in vivo and in vitro, opens a new perspective for combating some types of cancers, including PC and BC. The multifaceted process of angiogenesis in malignant tumors suggests that the combination of drugs with antiangiogenic agents that modulate the immune system, the cellular energy metabolism, as well as the pro-and antioxidant species may be more effective than therapies involving only a single agent. Therefore, the association between immunomodulator P-MAPA and blocking angiogenesis TNP-470 in cases of PC and BC can be considered a promising therapeutic combination. Furthermore, several studies have demonstrated an increased risk for simultaneous occurrence of PC and BC. Many of these studies have demonstrated a possible molecular association between these tumors, so that the clinical implications of this association are potentially significant. Thus, the objectives of this project are to characterize and compare the immunologic, histopathologic, molecular and biochemical effects of antiangiogenic therapy (TNP-470) combined with immunotherapy with P-MAPA in the treatment of PC and BC chemically induced in animal models (rats) and how to establish possible mechanisms of action of these therapies involving cellular energy metabolism, oxidative balance, angiogenesis and signaling pathways of TLRs. Furthermore, we intend to investigate the occurrence of common mechanisms in carcinogenesis of the prostate and urinary bladder. We want, in short, to know how much and how the P-MAPA used alone and also in combination with other antiangiogenic drugs (TNP-470) alters the metabolism of tumor cells, thereby stopping its growth, as already noted (see preliminary results). (AU)