Deciphering the Molecular Mechanism Underlying the Inhibitory Efficacy of Taiwanese Local Pomegranate Peels against Urinary Bladder Urothelial Carcinoma

Abstract

Pomegranate (Punica granatum L.) fruit has been demonstrated to have the inhibitory activities to various tumors. In this study, we try to uncover the molecular mechanism underlying the inhibitory capability of Taiwanese local pomegranate fruit to urinary bladder urothelial carcinoma. The results collected from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated that the ethanol extract of pomegranate peel exhibited better inhibitory activity to human urinary bladder urothelial carcinoma T24 and J82 cells than that of pulp. Furthermore, the ethylacetate layer of peel ethanol extract was observed to have the best inhibitory activity against urinary bladder urothelial carcinoma cells. One of the eight fractions (PEPE2 fraction) collected from the ethylacetate layer with Diaion HP-20 column chromatography demonstrated the highest inhibitory activity in urinary bladder urothelial carcinoma cells. The results of the flow cytometry and apoptotic pathway studies suggested that the inhibitory activity of PEPE2 fraction were attributed to the UBUC cell apoptosis. To confirm the above results, our results of xenograft-induced bladder tumor in nude mice showed that the oral consumption of the ethylacetate layer (2, 5, 10 and 100 mg/kg) could decrease the volume and weight of T24 tumors and caused the apoptosis in the xenografted tumors, which was observed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay. This study provided the likelihood that the traditionally non-edible pomegranate peel waste is re-utilized to make an affordable and promising chemopreventive product to prevent UBUC incidence or recurrence.

Preventive effect of pomegranate juice against chemically induced bladder cancer: An experimental study

“…Few studies have been done regarding the protective effect of pomegranate against BC. All of them were In vitro studies ( Chang et al., 2018 ; Lee et al., 2013 ; Zhou et al., 2015 ). Therefore, we decided in the present study to investigate the effectiveness of PJ in inhibiting BC induced by N -butyl- N -(4-hydroxybutyl)-nitrosamine (BBN) in rats.…”

Clinical Potential of Fruit in Bladder Cancer Prevention and Treatment

“…A summary of the anticancer effects and mechanisms of pomegranate action is presented in Figure 1. cell proliferation [41], glycolysis [53][54][55], and cell cycle [59,60] as well as apoptosis [23,41,42,47,48,51,53,54,61,62,69,71]. The summary of anticancer effects and mechanisms of pomegranate action.…”

“…Pomegranate ( Punica granatum L.) is an edible fruit widely grown in Mediterranean countries, northern India, northern/southern America, Europe, and even in Taiwan, mainly as gardening trees [ 23 ]. Pomegranate fruits consist of white to dark purple edible seeds embedded in a white spongy astringent membrane surrounded by a thick reddish skin or pericarp.…”

Ongoing and potential novel trends of pomegranate fruit peel; a comprehensive review of its health benefits and future perspectives as nutraceutical

“…Several in vitro and in vivo studies demonstrated the anticancer effect of PP and its constituents (Adhami et al, 2009) different cancer types, that is, colon (Waly et al, 2014), liver (Li et al, 2019), thyroid Liu et al, 2017), uterine, breast (Dikmen et al, 2011;Fazio et al, 2018), bladder (Chang et al, 2018), prostate (Deng et al, 2017), leukemia (Panth et al, 2017), and osteosarcoma (Li et al, 2014). Moreover, its ellagitannins enhanced the chemotoxicity of 5-fluorouracil in colorectal cancer cell lines through apoptosis potentiation and to lessen its side effects in rats (Chen, Lam, et al, 2018).…”

“…Anti-tumor action mechanisms of PPE and its constituents is exerted via multiple targets, that is, antioxidant (Waly et al, 2014), antiangiogenic (Ceci et al, 2018;Naseri et al, 2018), anti-proliferative (Dikmen et al, 2011;Fazio et al, 2018;Li, Ye, et al, 2017;Li, Liu, et al, 2017), anti-metastatic (Deng et al, 2017;, and apoptosis induction (Chang et al, 2018;Li et al, 2019). Furthermore, it inhibited several oncogenic signaling pathways, for example, NF-κB, PI3K/AKT/Mtor (Khwairakpam et al, 2018), oncogenes expression responsible for cancer development (e.g., anti-apoptotic genes (Dikmen et al, 2011), and MMPs (Deng et al, 2017;Khwairakpam et al, 2018;Li, Ye, et al, 2017;Li, Liu, et al, 2017), concurrent with the induction of pro-apoptotic protein caspase-3 activity Deng et al, 2017;Li et al, 2014), BCL-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2) ratio (Deng et al, 2017;Dikmen et al, 2011;Li et al, 2014) and the apoptosis-associated protein, P53, expression (Song et al, 2016).…”