Increased toll-like receptors and p53 levels regulate apoptosis and angiogenesis in non-muscle invasive bladder cancer: mechanism of action of P-MAPA biological response modifier

Abstract

BackgroundThe new modalities for treating patients with non-muscle invasive bladder cancer (NMIBC) for whom BCG (Bacillus Calmette-Guerin) has failed or is contraindicated are recently increasing due to the development of new drugs. Although agents like mitomycin C and BCG are routinely used, there is a need for more potent and/or less-toxic agents. In this scenario, a new perspective is represented by P-MAPA (Protein Aggregate Magnesium-Ammonium Phospholinoleate-Palmitoleate Anhydride), developed by Farmabrasilis (non-profit research network). This study detailed and characterized the mechanisms of action of P-MAPA based on activation of mediators of Toll-like Receptors (TLRs) 2 and 4 signaling pathways and p53 in regulating angiogenesis and apoptosis in an animal model of NMIBC, as well as, compared these mechanisms with BCG treatment.ResultsOur results demonstrated the activation of the immune system by BCG (MyD88-dependent pathway) resulted in increased inflammatory cytokines. However, P-MAPA intravesical immunotherapy led to distinct activation of TLRs 2 and 4-mediated innate immune system, resulting in increased interferons signaling pathway (TRIF-dependent pathway), which was more effective in the NMIBC treatment. Interferon signaling pathway activation induced by P-MAPA led to increase of iNOS protein levels, resulting in apoptosis and histopathological recovery. Additionally, P-MAPA immunotherapy increased wild-type p53 protein levels. The increased wild-type p53 protein levels were fundamental to NO-induced apoptosis and the up-regulation of BAX. Furthermore, interferon signaling pathway induction and increased p53 protein levels by P-MAPA led to important antitumor effects, not only suppressing abnormal cell proliferation, but also by preventing continuous expansion of tumor mass through suppression of angiogenesis, which was characterized by decreased VEGF and increased endostatin protein levels.ConclusionsThus, P-MAPA immunotherapy could be considered an important therapeutic strategy for NMIBC, as well as, opens a new perspective for treatment of patients that are refractory or resistant to BCG intravesical therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2474-z) contains supplementary material, which is available to authorized users.

Toll‐like receptors: The role in bladder cancer development, progression and immunotherapy

“…Therefore, some of TLR properties such as specificity in ligand, cell distribution, downstream signalling and gene expressing profiles are considered as new potential therapeutic strategy for the treatment of a wide range of diseases . Nowadays, TLRs and their associated ligands or regulators are considered as striking candidates for research on new treatments for cancers, including NMIBC …”

“…BCG therapy has been used for the effective treatment of bladder cancer for more than 4 decades . It stimulates TLR2 and TLR4 through several bacterial cell wall components, leading to activation of MyD88 and NF‐κB and consequently enhancement of TNF‐α production …”

“…99 Nowadays, TLRs and their associated ligands or regulators are considered as striking candidates for research on new treatments for cancers, including NMIBC. 100 Toll-like receptors increase T cell responses and decrease suppressive effects of Tregs, so they could be serve as valuable vaccine adjuvants. Microbial derivatives are currently considered as potent activators of the innate and adaptive immune responses through induction of TLR signalling; therefore, they are used for improving tumour immunotherapy.…”

Biogenic Synthesis of Important Environmental Minerals: Magnesium Phosphate Compounds and Perspectives

“…65,83 A few years ago, P-MAPA appeared as a potential candidate for intravesical therapy for non-muscle invasive bladder cancer (NMIBC). This immunomodulator was found to be important in the treatment of these types of urinary bladder cancer, 76,82,84,86,87 as well as in the prostate cancer 88 and of pancreatic cancer. 89 The most recent results with respect to NMIBC demonstrated that the immune system by BCG activation (MyD88-dependent pathway) leads to an increased inflammatory cytokines production.…”

“…In addition, induction by P-MAPA of an interferon signaling pathway simultaneously with increased p53 protein levels resulted in an important antitumor effect, not only by suppressing Santos et al, 2009;Durán and Fávaro, 2016) 66,95 abnormal proliferation, but also by preventing continuous tumor mass growth by suppression of angiogenesis, observable by a decrease in vascular endothelial growth factor (VEGF) and an increase in endostatin protein levels ( Figure 5). 84 Another important mechanism of action of P-MAPA intravesical immunotherapy in NMIBC treatment is regulation of steroid hormone receptors (androgen and estrogen receptors), as well as the association of these receptors with the immune system (toll-like receptors). Garcia et al 85 first demonstrated the control activity of androgen receptor (AR) and estrogen receptors alpha (ERα) and beta (ERβ) through Siah-2 ubiquitin ligase and co-repressor N-CoR in the NMIBC.…”