Modulation by polyamines of apoptotic pathways triggered by procyanidins in human metastatic SW620 cells

Abstract

We showed previously that inhibition of polyamine catabolism with the polyamine oxidase inhibitor MDL 72527 (MDL) potentiates the apoptotic effects of apple procyanidins (Pcy) in SW620 cells. Here we report that Pcy caused an activation of the intrinsic apoptotic pathway through enhanced polyamine catabolism and mitochondrial membrane depolarization. MDL in the presence of Pcy caused a profound intracellular depletion of polyamines and exerted a protective effect on mitochondrial functions. MDL potentiation of Pcy-triggered apoptosis was reversed by addition of exogenous polyamines. In addition, MDL in combination with Pcy activated the extrinsic apoptotic pathway through enhanced TRAIL-death receptor (DR4/DR5) expression. Potentiation of Pcy-triggered apoptosis by MDL was inhibited when cells were exposed to specific inhibitors of DR4/DR5. These data indicate that the depletion of intracellular polyamines by MDL in the presence of Pcy caused a switch from intrinsic to extrinsic apoptotic pathways in human colon cancer-derived metastatic cells.

Differential activation of Fas (CD95) mediated apoptosis by apple procyanidins in human colon cancer cells SW480 and their derived metastatic cells SW620

“…However, the cellular and molecular mechanisms by which Pcy induce apoptosis in cancer cells are not well understood. Previously, we reported that TRAIL-DR4/DR5 blocking antibodies increased Pcy-triggered apoptosis in SW620 cells 4 . These data suggested the activation of an alternative death pathway.…”

“…Although Pcy did not overcome the Fas-resistance of SW620 cells, Pcy may activate alternative apoptotic pathways. We have previously shown that Pcy initiated in SW620 cells a cross-talk between the TRAIL (extrinsic) apoptotic pathway and the mitochondrial (intrinsic) apoptotic pathway involving enhanced expression of TRAIL-DR4/DR5 receptors in SW480 and SW620 cells, and activated the polyamine catabolism leading to ROS production, which participated in mitochondria disruption 4,5 .…”

“…Pcy have recently gained interest because of potential health promoting effects by acting as antioxidant, anticarcinogen, cardio-preventive, antimicrobial, antiviral, and neuro-protective agents 2 . We have recently reported that apple Pcy inhibit the growth of human metastatic colon adenocarcinoma-derived SW620 cells through the inhibition of protein kinase C activity, down-regulation of polyamine biosynthesis and activation of polyamine catabolism, and through Pcytriggered apoptosis involving TRAIL receptor-mediated pathway [3][4][5] . It was also reported that apple Pcy can inhibit the promotion/progression phases of colon carcinogenesis in rats 3 .…”

“…We examined whether Pcy and/or CH-11 had an effect on mitochondrial membrane using flow cytometry after staining cells with DiOC 2 (3), using CCCP as a positive control as described in the Materials and methods section. DiOC 2 (3) accumulates in the mitochondrial matrix and is released in the cytosol after membrane depolarization (membrane with reduced ∆Ψm corresponding to a reduced green fluorescence) 4 . As shown in Figure 2C SW620 cells Pcy induced an increased percentage of cells with loss of ∆Ψm (46%); however, this effect was not modified after the combined treatment with CH-11 (43%).…”

On the natural chemoprevention of cancer

“…However when the two compounds are added together at fixed doses there is a potentiation of the inhibition of ODC compared to the procyanidin treatment alone. There are also significant decreases in the intracellular polyamine pools, particularly in putrescine, spermine and the acetylated forms of the polyamines [19,40]. The combination of MDL 72527 and procyanidins also caused a decrease in the histone deacetylation activity [40].…”