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    • Our results show furthermore that higher concentrations of b

    2022-08-11

    Our results show furthermore, that higher concentrations of butyric ezh2 pathway additionally affect GSTP1 mRNA stability leading to a strongly reduced half-life. Concentration-dependent effects of butyric acid on RNA stability and cell signaling pathways involved in the regulation of GSTP1 expression remain to be elucidated but our results are confirmed by a number of reports where butyric acid reduces the half-life of selected mRNA including decay-accelerating factor (DAF) mRNA expressed in colon cancer cells [27], the cholesterol acyltransferase mRNA expressed in HepG2 cells [28] and the surfactant protein (SP) A, B and C mRNA expressed in fetal rat lung [29]. Decreased mRNA stability explains the even stronger reduction of GSTP1 transcript level after treatment at 2mM butyric acid versus 1mM. In future, it will be interesting to investigate the effect of chemical derivatives of butyrate on GSTP1 expression as the clinical use of butyric acid salt derivatives is limited by an extremely short half-life due to a rapid metabolism [30]. The long-term goal of this research aims to determine the molecular mechanisms of leukemia cell resistance to anticancer drugs during differentiation and to identify compounds, which do not trigger resistance mechanisms. We conclude that butyric acid-induced megakaryocytic differentiation prevents adverse effects like GSTP1 up-regulation that could be observed with hemin and anthracyclines during erythroid differentiation. Nevertheless, the rate of differentiation with butyric acid remains low compared to hemin and it is noteworthy to mention that butyric acid does not generate a homogenous population of differentiated cells at a given concentration, which should not lower its therapeutic potential.
    Acknowledgements
    Introduction Among the GST family, GSTP1 gene (also known as GST-π) has important role in several cellular processes including catalysis as well as detoxification of electrophilic xenobiotics (Ali-Osman et al., 1997, Moyer et al., 2008), oxidative stress regulation (Di Pietro et al., 2010, Shawahna et al., 2013), cell signalling (Johansson, 2002) and carcinogenesis (Sau et al., 2010) etc. Nonetheless, activity of GSTP1 may fluctuate owing to polymorphisms, resulting in an individual's increased susceptibility to certain diseases. Individuals with the allele encoding the GSTP1 variant with Val rather than Ile in position 105 are at higher risk for developing cancer (Harries et al., 1997; Ryberg et al., 1997, Rybicki et al., 2006, Oliveira et al., 2013), neuropathy (Mir et al., 2009) etc. GSTP1 rs1695 polymorph has been linked with increased deterioration of lung function, asthma and allergy under the impact of traffic-related and environmental pollutants SOx, NOx, ozone etc. (Lee et al., 2004, Romieu et al., 2006, Li et al., 2006, Salam et al., 2007, Melen et al., 2008). Likewise, it is known to impact allergen-provoked airway inflammation in patients with atopic asthma (Hoskins et al., 2013). On the other end, it has also been reported to cause early onset of peripheral neuropathy in response to oxaliplatin (Inada et al., 2010). However, a decreased risk of developing severe oxaliplatin-related cumulative neuropathy has also been reported (Lecomte et al., 2006). GSTP1 Ile105Val polymorphism has been targeted by >20 trials for investigating relation to peripheral neuropathy and a positive correlation with chemotherapy induced peripheral neuropathies has been established in half of the studies (Grisold et al., 2012). It has been linked to oxaliplatin-induced neuropathy in individuals with colorectal cancer (in Japanese population) (Kanai et al., 2010). Similarly, haematological toxicity has been observed in chemoradiotherapy receiving preoperative colorectal patients with this polymorphism (Agostini et al., 2008). This mutation exacerbates bladder cancer risk (Wang et al., 2013) and documented to cause increased susceptibility to urinary system cancer among Asians (Zhang et al., 2016). Some role of this mutation in instigating colorectal cancer has also been documented in the Bulgarian population (Vlaykova et al., 2007). Individuals exposed at high levels to occupational polyaromatic hydrocarbons with this mutation are pronounced to be at increased risk for prostate cancer (Rybicki et al., 2006).