Tau dephosphorylation and microfilaments disruption are upstream events of the anti‐proliferative effects of DADS in SH‐SY5Y cells

Abstract

Garlic organosulphur compounds have been successfully used as redox anti-proliferative agents. In this work, we dissect the effects of diallyl disulphide (DADS) focusing on the events upstream of cell cycle arrest and apoptosis induced in neuroblastoma SH-SY5Y cells. We demonstrate that DADS is able to cause early morphological changes, cytoskeleton oxidation, microfilaments reduction and depolymerization of microtubules. These events are attenuated in cells stably overexpressing the antioxidant enzyme SOD1, suggesting that superoxide plays a crucial role in destabilizing cytoskeleton. Moreover, we evidence that the main microtubules-associated protein Tau undergoes PP1-mediated dephosphorylation as demonstrated by treatment with okadaic acid as well as by immunoreaction with anti-Tau-1 antibody, which specifically recognizes its dephosphorylated forms. Tau dephosphorylation is inhibited by the two-electron reductants NAC and GSH ester but not by SOD1. The inability of DADS to induce apoptosis in neuroblastoma-differentiated cells gives emphasis to the anti-proliferative activity of DADS, which can be regarded as a promising potent anti-neuroblastoma drug by virtue of its widespread cytoskeleton disrupting action on proliferating cells.

Garlic-derived diallyl disulfide modulates peroxisome proliferator activated receptor gamma co-activator 1 alpha in neuroblastoma cells

“…We previously showed that the organosulfur compound diallyl disulfide (DADS) inhibits neuroblastoma cells growth and finally induces mitochondrial-dependent apoptosis [21]. In particular, we demonstrated that the anti-proliferative action of DADS relays on its pro-oxidant function acting at two different levels: i) ROS-mediated induction of apoptotic phosphorylative cascade managed by JNK/cJun; ii) ROS-mediated disruption of cytoskeletal lattice functioning as a widespread anti-cytoskeletal agent against both actin and tubulin [21,22]. However, DADS is not able to induce very high rate of apoptosis in neuroblastoma cells if compared to other cell lines, indicating the occurrence of adaptive responses [23].…”

Naturally Occurring Organic Sulfur Compounds: An Example of a Multitasking Class of Phytochemicals in Anti-Cancer Research

“…A large body of evidence, conversely, indicates that OSCs induce strong alterations of MT re-arrangement (see figure 3 and section 3.2). This property is common to different natural occurring OSCs manifesting apoptogenic properties on the different cancer cell models (Aquilano et al, 2010;Hosono et al, 2005;Li et al, 2002a;Prager-Khoutorsky et al, 2007;Xiao et al, 2005;Xiao et al, 2003).…”

“…These studies suggested that polysulfide/ajoene-induced apoptotic cell death is caused by ROS accumulation and peroxide production (Aquilano et al, 2010;Charlier et al, 2010;Dirsch et al, 1998;Wang, H.C. et al, 2010a). DADS, DATS and DATTS and to a lesser extent the corresponding propylsulfides have been identified as hemolytic agents, as they induce oxidative damage in erythrocytes by the formation of H 2 O 2 in the presence of GSH and haemoglobin (Munday et al, 2003).…”

Role of H2S Donors in Cancer Biology

“…DADS treatment alone was reported to be effective in inhibiting cancer cell growth, inducing apoptosis and causing partial G2/M cell cycle arrest in cancers of colon, pancreas, prostate, lung, brain, and stomach (Aquilano et al 2010;Bo et al 2014;Bottone et al 2002;Gunadharini et al 2006;Song et al 2009;Wu et al 2005). In particular, the anticancer proliferation effects were reported to be associated with an increase in reactive oxygen species (ROS) production.…”

“…In particular, the anticancer proliferation effects were reported to be associated with an increase in reactive oxygen species (ROS) production. For instance, DADS was shown to induce cytoskeleton oxidation and microtubule depolymerization, thence morphological changes in neuroblastoma SH-SY5Y cells (Aquilano et al 2010). However, these effects were reversed by administration of exogenous precursors of cellular antioxidants, N-acetylcysteine (NAC) or glutathione ester.…”