Critical role for reactive oxygen species in apoptosis induction and cell migration inhibition by diallyl trisulfide, a cancer chemopreventive component of garlic

• Published in: Breast cancer research and treatment 2013-02, Vol.138 (1), p.69-79
• Main Authors: Chandra-Kuntal, Kumar, Lee, Joomin, Singh, Shivendra V.
• Format: Article
• Language: English
• Subjects: Allyl Compounds - pharmacology; Analysis; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; bcl-2 Homologous Antagonist-Killer Protein - metabolism; Biological and medical sciences; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cadherins - metabolism; Cancer; Cancer research; Cancer therapies; Care and treatment; Cell Line, Tumor; Cell Migration Inhibition - drug effects; Cell Survival - drug effects; Cellular biology; Development and progression; Female; Fluorescence; Garlic; Garlic - chemistry; Gene Expression; Genetic engineering; Gynecology. Andrology. Obstetrics; Heme Oxygenase-1 - metabolism; Humans; Mammary gland diseases; MCF-7 Cells; Medical sciences; Medicine; Medicine & Public Health; Oncology; Preclinical Study; Prevention; Reactive Oxygen Species - metabolism; Stem cells; Sulfides - pharmacology; Superoxide; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Toy industry; Tumors; Zinc compounds
• ISSN: 0167-6806; 1573-7217
• DOI: 10.1007/s10549-013-2440-2

Diallyl trisulfide (DATS) is a structurally simple but biologically active constituent of processed garlic with in vivo activity against chemically induced as well as oncogene-driven cancer in experimental rodents. This study offers novel insights into the mechanisms underlying anticancer effects of DATS using human breast cancer cells as a model. Exposure of human breast cancer cells (MCF-7 and MDA-MB-231) and a cell line derived from spontaneously developing mammary tumor of a transgenic mouse (BRI-JM04) to DATS resulted in a dose-dependent inhibition of cell viability that was accompanied by apoptosis induction. A non-tumorigenic normal human mammary cell line (MCF-10A) was resistant to growth inhibition and apoptosis induction by DATS. The DATS-induced apoptosis in MDA-MB-231, MCF-7, and BRI-JM04 cells was associated with reactive oxygen species (ROS) production as evidenced by fluorescence microscopy and flow cytometry using a chemical probe (MitoSOX Red). Overexpression of Cu,Zn-superoxide dismutase (Cu,Zn-SOD) as well as Mn-SOD conferred significant protection against DATS-induced ROS production and apoptotic cell death in MDA-MB-231 and MCF-7 cells. Activation of Bak, but not Bax, resulting from DATS treatment was markedly suppressed by overexpression of Mn-SOD. The DATS treatment caused ROS generation, but not activation of Bax or Bak, in MCF-10A cells. Furthermore, the DATS-mediated inhibition of cell migration was partially but significantly attenuated by Cu,Zn-SOD and Mn-SOD overexpression in association with changes in levels of proteins involved in epithelial–mesenchymal transition. The DATS-mediated induction of heme oxygenase-1 was partially attenuated by overexpression of Mn-SOD. These results provide novel mechanistic insights indicating a critical role for ROS in anticancer effects of DATS.