Effects of the garlic compound diallyl disulfide on the metabolism, adherence and cell cycle of HT-29 colon carcinoma cells: evidence of sensitive and resistant sub-populations

Abstract

Diallyl disulfide (DADS) is a major organosulphur compound present in garlic with an anti-mitotic potential against colon neoplastic lesions in vivo and colon tumour cell growth in vitro. Using the human colon adenocarcinoma HT-29 Glc(-/+) cell line we identified sub-populations of tumoural cells with markedly different characteristics in terms of metabolic capacities, adhesion properties and distribution in the cell cycle phases. After 1 and 2 days treatment with 100 microM DADS HT-29 cells were largely released into the culture medium. These floating cells accumulated in the G(2)/M phase and were characterized by a 5-fold reduction in cell capacity for de novo protein synthesis. Polyamine metabolism, which is necessary for intestinal epithelial cell attachment and growth, was also severely affected, since 3-fold reductions in polyamine biosynthesis and net accumulation of putrescine were measured after DADS treatment. However, oxidation of L-glutamine, the main precursor of the tricarboxylic acid cycle in these cells, and de novo synthesis of glutathione, a tripeptide involved in tumoural cell chemoresistance, were not affected by DADS treatment. In contrast, the adherent sub-population of HT-29 cells, although partially accumulated in G(2)/M phase, were characterized by unaffected metabolic capacities when compared with control cells except for putrescine accumulation, which was transiently decreased, and L-glutamine oxidation, which was increased 2-fold. DADS-resistant cells selected within 5 days were then able to proliferate at a similar rate to control untreated cells. The DADS-induced changes in HT-29 metabolic capacities, adhesion properties and the cell cycle are discussed from a causal perspective.

Diallyl trisulfide-induced G2–M phase cell cycle arrest in human prostate cancer cells is caused by reactive oxygen species-dependent destruction and hyperphosphorylation of Cdc25C

“…More recent studies including those from our laboratory have revealed that some naturally occurring OSC analogues can inhibit proliferation of cultured cancer cells by causing apoptosis and/or cell cycle arrest (Sundaram and Milner, 1996;Milner, 1998, 2000;Nakagawa et al, 2001;Robert et al, 2001;Shirin et al, 2001;Kwon et al, 2002;Li and Lu, 2002;Filomeni et al, 2003;Xiao et al, 2003;Lan and Lu, 2004;Xiao et al, 2004). Milner and co-workers were the first to report apoptosis induction and cell cycle arrest by DADS in human colon cancer cells (Sundaram and Milner, 1996;Milner, 1998, 2000).…”

Upregulation of miR-34a by diallyl disulfide suppresses invasion and induces apoptosis in SGC-7901 cells through inhibition of the PI3K/Akt signaling pathway

“…Similar to the majority of plant products, DADS exerts anticarcinogenic activity in certain types of cancer, including human breast (9), colon (10,11) and prostate cancer (8,12), as well as hepatoma cells (13). It has been observed that DADS, as an effective modulator of protein kinases/phosphatases, inhibits the initiation and promotion phases of cancer (5).…”

Diallyl trisulfide-induced apoptosis in human prostate cancer cells involves c-Jun N-terminal kinase and extracellular-signal regulated kinase-mediated phosphorylation of Bcl-2

“…More recent studies have shown that some OSC analogues can inhibit proliferation of cultured cancer cells by causing apoptosis and/or cell cycle arrest (Sundaram and Milner, 1996;Milner, 1998, 2001;Nakagawa et al, 2001;Robert et al, 2001;Shirin et al, 2001;Kwon et al, 2002;Filomeni et al, 2003;Xiao et al, 2003a). Milner and co-workers were the first to report apoptosis induction by DADS in HCT-15 human colon cancer cells, which correlated positively with an increase in intracellular free calcium levels (Sundaram and Milner, 1996).…”