Apoptosis of human breast carcinoma cells in the presence of disialosyl gangliosides: II. Treatment of SKBR3 cells with GD3 and GD1b gangliosides

Abstract

Apoptosis, or programmed cell death, plays an important role in many physiological and diseased conditions. Induction of apoptosis in cancer cells has been monitored during the cells' progression to apoptosis by anti-cancer drugs and inhibitors of the cell surface glycolipids, gangliosides and SA-Le(x) biosyntheses [Basu, S (1991) Glycobiology, 1, 469-475; and ibid, 427-435] in animal tissues and human carcinoma cells, respectively. Induction of apoptosis in cancer cells by cell surface glycolipids in the human breast cancer (SKBR3) cells is the aim in this study. We have employed the disialosyl gangliosides (GD3 and GD1b) to initiate apoptosis in SKBR3 cells grown in culture in the presence of (14)C-L-Serine. At lower concentrations (0-20 microM) of exogenously added non-radioactive GD3, GD1b, or bovine ganglioside mixture (GM1:GD1a:GD1b:GT1a 2:4:4:2), the incorporation of radioactivity in both (14)C-sphingolipid and (14)C-ceramide was higher. However, at higher concentrations (20-100 microM), wherein apoptosis occurred in high frequency, the (14)C-incorporation decreased in both GSLs and ceramide. Apoptosis induction was monitored by the concomitant appearance of caspase-3 activation and the binding of a fluorescent dye PSS-380 to the outer leaflet of phosphatidyl-serine. These results indicated that, in addition to many unknown cell surface glycoconjugates GD3 or GD1b (disialosyl ganglioside) could play an important role in the regulation of breast carcinoma cell death.

Apoptosis of Breast Cancer Cells: Modulation of Genes for Glycoconjugate Biosynthesis and Targeted Drug Delivery

“…Several Inhibitors of glycosphingolipid biosynthesis were recently found to trigger apoptosis in many carcinoma cells including breast cancer SKBR-3, MCF-7, and MDA-468 cells through either intrinsic or extrinsic apoptotic pathways (Fig. 16.3 ), as we have previously reported (Basu et al 2004a, b, c ;Ma et al 2004Ma et al , 2009Ma et al , 2011Boyle et al 2006 ;Kessler et al 2007b ) . These inhibitors of glucosylceramide biosynthesis (Radin 1999 ) could increase ceramide concentration (Basu et al 2004a ) by blocking the functions of glycolipid glycosyltransferases (GLTs; Fig.…”

“…Using highly metastatic breast carcinoma cells (SKBR-3, MDA-468, and MCF-7), we have reported in recent years (Basu et al 2004a, b, c ;Ma et al 2004 ;Boyle et al 2006 ) apoptotic induction by d -/ l -PPMP, d -PDMP (inhibitors of GSL biosynthesis), cisplatin (inhibitor of DNA biosynthesis), betulinic acid (a triterpenoid used as an anticancer agent in China as an alternative medicine), tamoxifen (a common anticancer agent used for the treatment of breast cancers today), GD3, GD1b, and melphalan (a scrambler for Golgi bodies) in the range of 2-16 m M concentrations (Fig. 16.2 ) (Basu et al 2004a, b, c ;Ma et al 2004 ;Boyle et al 2006 ) .…”

“…16.2 ) (Basu et al 2004a, b, c ;Ma et al 2004 ;Boyle et al 2006 ) . Inhibition of cell growth (IC-50) was different with three different metastatic breast cancer cell lines when tested with a single apoptotic agent ( l -PPMP) for 24 h (Boyle et al 2006 ) .…”

“…Targeting mitochondria as a cancer therapeutic strategy is of interest in recent years. Besides recognition of inhibitors of GSL biosynthesis ( l -PPMP, d -PPMNP, and d -PDMP) and DNA biosynthesis (cisplatin) in our laboratory (Basu et al 2004a, b, c ;Ma et al 2004 ;Boyle et al 2006 ) several other different chemicals have been tested as apoptosis inducing agents (via intrinsic mitochondrial or extrinsic receptor pathways) in breast cancer cells Patil et al 2010 ;Banerjee et al 2010Banerjee et al , 2011Shirure et al 2011 ;Cazet et al 2010 ;Jada et al 2008 ;Domingo-Domenech et al 2008 ;Nakagawa et al 2007 ;Nakajima et al 2007 ;Sato-Cerrato et al 2005 ;Balabhadrapatharuni et al 2005 ;Hatasukari et al 2003 ;Chung et al 2002 ;Hansen et al 2000 ;Fromigue et al 2003 ;Elton et al 2000 ;Distefano et al 1998 ;Han et al 1998 ;Schwartz et al 1997 ;Sarkar et al 2007 ;Singh et al 2009 ;Lu et al 2006 ;Somers-Edgar and Rosegren 2009 ;Neuzil et al 2007 ;Fulda et al 1997 ;Li et al 2010a ;Chaouki et al 2010 a;Mullauer et al 2011a ;Kessler et al 2007a ;Laszczyk 2009 ;Bzesk et al 2006a ;Goldoni et al 2008 a;Ellerby et al 1999 ) .…”

“…These inhibitors regulate GLT gene expression posttranslationally as well as posttranscriptionally (Ma et al 2009(Ma et al , 2011Kessler et al 2007b ) . Apoptotic effects initiate activation of caspases (-3, -8, and -9) (Basu et al 2004a, b, c ;Ma et al 2004Ma et al , 2009Ma et al , 2011Boyle et al 2006 ;Kessler et al 2007b ) . Using novel DNA-microarrays speci fi cally designed for screening over 340 Glyco-related genes, transcriptional-regulation of several glycosyltransferases involved in the biosyntheses of Sialo-LeX and SialoLea (cancer cell surface antigens) was observed with l -PPMP (Ma et al 2009(Ma et al , 2011Kessler et al 2007b ) .…”