Growth inhibitory effects of diallyl disulfide on human breast cancer cell lines

Abstract

Diallyl disulfide (DADS) is an oil-soluble organosulfur compound found in garlic. The effect of synthetic DADS on the growth of estrogen receptor (ER)-positive (KPL-1 and MCF-7) and -negative (MDA-MB-231 and MKL-F) human breast cancer cell lines was examined. In an in vitro MTT assay, regardless of ER status, DADS at an IC(50) of 1.8-18.1 microM after 72 h incubation caused inhibition of growth in all four cell lines examined. Growth inhibition was due to apoptosis as seen by the appearance of a sub G1 fraction. In MDA-MB-231 cells, the apoptosis cascade comprised up-regulation of Bax protein (142%), down-regulation of Bcl-X(L) protein (38%) and activation of caspase-3 (438%) compared with controls. In an in vivo assay by orthotopic (right thoracic mammary fat pad) transplantation of KPL-1 cells in female nude mice, intraperitoneal injection of 1 or 2 mg DADS three times a week from the day of tumor cell inoculation until the end of the experiment (after 35 days) caused growth retardation and 43% reductions in primary tumor weight, respectively, compared with DADS-untreated mice without apparent side effects. Cell proliferation as evaluated by proliferating cell nuclear antigen (PCNA)-labeling in transplanted tumor of DADS-untreated mice was 59.6%, and 1 and 2 mg DADS-treated mice was 44.6 and 44.5%, respectively. In MDA-MB-231 cells, DADS antagonized the effect of linoleic acid (LA), a potent breast cancer cell stimulator (at DADS = 1.8 microM and LA > or = 6.5x10(2) microM concentration), and synergized the effect of eicosapentaenoic acid (EPA), a potent breast cancer cell suppressor (at DADS >3 x 10(-3) microM and EPA > 6.3 x 10(-1) microM concentration). Thus, DADS could be a promising anticancer agent for both hormone-dependent and -independent breast cancers, and may harmonize with polyunsaturated fatty acids known as modulators of breast cancer cell growth.

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

“…The DADS-induced apoptosis in colon cancer cells correlated positively with an increase in the level of intracellular free calcium (Sundaram and Milner, 1996). In MDA-MB-231 human breast cancer cell line, the DADS-induced apoptosis was associated with upregulation of Bax, downregulation of Bcl-X L and activation of caspase-3 (Nakagawa et al, 2001). The DATS-induced apoptosis in BGC823 human gastric cancer cell line was associated with downregulation of Bcl-2 and activation of caspase-3 (Lan and Lu, 2004).…”

“…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).…”

Cytotoxicity of synthesized 1,4-naphthoquinone analogues on selected human cancer cell lines

“…This is supported by the very low percentage of viable cells seen after only 24 h. The compounds 2-5 and 19 significantly inhibited the growth of HeLa and DU-145 cells in vitro, possibly by either down-regulation of antiapoptotic Bcl-X L and up-regulation of proapoptotic Bax or by increasing the p21 waf1/cip1 protein, which is involved in cell cycle arrest in G 1 or G 2 phase. 36 Copeland et al has reported that 2,3-dichloro-5,8-dimethoxy-1,4-naphthoquinone exhibits cytoxicity on androgen-dependent and -independent prostate cancer cell lines inducing apoptosis by arresting cell cycle at G 1 phase. 37 The cell cycle alterations indicate that cell cycle arrest is one of the primary mechanisms responsible for the anticancer activity of synthesized 7-MJ derivatives in HeLa and DU-145 cells.…”

Growth inhibitory effect and Chk1-dependent signaling involved in G2/M arrest on human gastric cancer cells induced by diallyl disulfide

“…Garlic oil, or more specifically its diallyl disulfide (DADS) content, has become a quite appealing anti-carcinogenic agent. This is due, in part, to its ability to induce apoptosis in vitro (4) and to inhibit the formation and growth of tumors in vivo (5,6). DADS has been shown to inhibit the in vitro and in vivo growth of breast, liver, lung, gastric, colon, and prostate cancers, as well as neuroblastoma and leukemia cell lines (5,(7)(8)(9)(10)(11)(12)(13)(14).…”