Quince peel polyphenolic extract blocks human colon adenocarcinoma LS174 cell growth and potentiates 5-fluorouracil efficacy

Abstract

BackgroundDevelopment of alternative cancer-specific drugs would be of paramount importance to overcome toxicity toward normal tissues and tumor resistance. Here, we investigated the potential anti-tumoral effect of peel (Peph) and pulp polyphenolic extracts from the Tunisian quince Cydonia oblonga Miller on both no-tumorigenic cells NIH 3T3 Fibroblasts and HEK 293 cells and human colon adenocarcinoma LS174 cells.MethodsCell proliferation and cytotoxicity were measured with MTT and LDH assays respectively. Cell cycle distribution and the apoptosis levels were assessed by flow cytometry. Intracellular reactive oxygen species (ROS) levels were determined using the fluorescent probe CM-H2DCFDA. Western blot was used to further characterize cell death and analyze the signaling pathways affected by Peph treatment. The expression level of VEGF-A was evaluated by real time quantitative PCR and further verified by quantifying the secreted cytokines by enzyme-linked immunosorbent assay.ResultsWe found that Peph extract displayed the highest anti-proliferative effect specifically on LS174 cells. However, each Peph phenolic compound alone did not exhibit any anti-proliferative activity, suggesting a synergistic effect of phenolic molecules. Such effect was associated with a cell cycle arrest in the G1/S phase, a caspase-independent apoptosis and an increase of the ROS production. Peph extract inhibited the pro-survival signaling pathway NFκB and suppressed the expression of various cellular markers known to be involved in cell cycling (cyclin D1) and angiogenesis (Vascular Endothelial Growth Factor, VEGF). Interestingly, the combination Peph extract and 5-FU exerted synergistic inhibitory effect on cell viability.ConclusionThese data propose the quince Peph extract as a promising cost effective non toxic drug to employ alone or in combination with conventional anti-colorectal cancer. Moreover, quince rich regimen may prevent the development and the progress of colon cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-016-0276-7) contains supplementary material, which is available to authorized users.

Histone Deacetylase Inhibitor-Induced Autophagy in Tumor Cells: Implications for p53

“…For HDACi, a variety of mechanisms have been attributed that initiate the activation of autophagy including inactivation of mTOR signaling combined with transcriptional upregulation of LC3 and/or Beclin-1 and/or ATG expression as well as responding to induced endoplasmic reticulum stress [ 170 , 171 , 173 , 177 , 178 , 180 , 181 , 197 , 198 ] ( Table 2 ). Several studies also implicate accumulation of ROS, the upregulation of the cell cycle kinase protein p21, and acetylation of the p53 tumor suppressor protein by HDAC class III inhibitors, respectively [ 182 , 199 , 200 , 201 , 202 , 203 , 204 ].…”

“…Several studies also implicate accumulation of ROS, the upregulation of the cell cycle kinase protein p21, and acetylation of the p53 tumor suppressor protein by HDAC class III inhibitors, respectively [ 182 , 199 , 200 , 201 , 202 , 203 , 204 ]. Single reports also implicate nuclear translocation of the apoptosis inducing factor (AIF), apoptosome inactivation, deficiency of p53, transcriptional activity by FoxO1, the stimulation of NF-κB activity in prostate cancer cells, and upregulation of death-associated protein kinase (DAPK) expression as regulatory mechanisms in HDACi-induced autophagy [ 12 , 176 , 197 , 205 , 206 , 207 ]. However, inactivation of PI3K-Akt-mTOR signaling is by far the most reported pathway in several tumor models depending not exclusively on SAHA treatment.…”

“…Akt plasmid transfection and RNA interference supported Akt and tuberous sclerosis 2 (TSC2) involvement in this process. Our group previously could demonstrate that the HDACi SAHA suppresses the autophagic key molecular determinant mTOR in the endometrial sarcoma cells [ 171 , 197 ]. Furthermore, phospho-S6 ribosomal protein (S6rp) which controls cell cycle progression and plays a regulatory role in the mTOR pathway was found to be downregulated.…”

Mitochondria as a Target for the Cardioprotective Effects of Cydonia oblonga Mill. and Ficus carica L. in Doxorubicin-Induced Cardiotoxicity

“…Cydonia oblonga Mill. belongs to the Rosaceae family and has antihypertensive, antiproliferative, hypolipidaemic, hepatoprotective, and renoprotective effects [10][11][12][13]. Recently, we reported the preventive effect of quince fruit against hepatocellular carcinoma and against carbon tetrachloride-induced hepatotoxicity [14,15].…”

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“…"Quince" fruit includes phenolic compounds such as chlorogenic acid with antioxidant and antiinflammatory effect 25,26 . This combination can cause the reduction of swelling and inflammation, reduction of neutrophils migration and incidence of inflammatory mediators 27 .…”