Poster abstracts

Poster number 81 submitted by Matthew Sobo

LLL-3, a novel chemotherepeutic agent, inhibits the ability of STAT-3 to transcribe its target DNA and leads to apoptosis

Matthew Sobo (Center for Childhood Cancer at The Research Institute at Nationwide Childrens Hospital. Graduate Program of Molecular, Cellular, and Developmental Biology), Elizabeth Foust (The Ohio State University), Lauren Friedman (The Center for Childhood Cancer at The Research Insitute at Nationwide Childrens Hospital.), Chenglong Li (School of Pharmacy. The Ohio State University.), Tom Li (School of Pharmacy. The Ohio State University.), Jiayuh Lin (Center for Childhood Cancer. The Research Institute at Nationwide Childrens Hospital.)

Abstract:
The American Cancer Society estimates that 1,444,920 Americans will have been diagnosed with cancer in 2007 and 559,650 will succumb to their affliction (Jemal 2007). Of these cases, breast cancer is one of the most common forms, with over 180,510 people being diagnosed and 40,910 dying this year from a cancer of the breast (Jemal 2007). Though survival rates have increased recently—both for cancer in general and breast cancer in specific—it remains the second most common cause of death for all Americans following only heart disease in mortality and it is therefore of paramount importance to develop new effective and specific drugs for the treatment of cancer (Jemal 2007). Epidemiological studies have shown that Signal Transducer and Activator of Transcription 3 (STAT-3) is highly activated in a wide range of different cancer types and is sufficient for the induction of tumors but is not activated in normal, healthy tissue (Bowman 2000, Bromberg 1998, Buettner 2002). It has therefore been suggested that STAT-3 is a viable target for therapeutic intervention (Buettner 2002). A previous in silico experiment revealed the structure of a compound, STA-21, that would be capable of binding STAT-3 in such a way as to prevent its downstream effects, namely bind and transcribe DNA (Song 2005). Our collaborators have recently synthesized several compounds based on STA-21 that are hypothesized to be more effective at blocking STAT-3 activation then the test compound. Here, we show that one of these new compounds, LLL-3, has profound cellular effects stemming from STAT-3’s inability to cross the nuclear membrane and drive transcription of its target genes leading to a massive fall-off in cellular viability and increased apoptosis.

References:
Jemal, A., Sigel, R., Ward, El, Murray, T.., Xu, J., Thun, M.J., 2007. Cancer Statistics, 2007. CA: Cancer J Clin 2007; 57; 43-66.
Bowman, T., Garcia, R., Turkson, J., Jove, R., 2000. STATs in oncogenesis. Oncogene 19, 2474-2488.
Bromberg, J.F., Horvath, C.M., Besser, D., Lathem, W.W., Darnell, J.E.J., 1998. Stat3 activation is required for cellular transformation by v-src. Mol. Cell. Biol. 18, 2553-2558.
Buettner, R., Mora, L., Jove, R., 2002. Activated STAT signaling in human tumors provides novel molecular targets for therapeutic intervention. Clin. Cancer. Res. 8, 945-954.
Song, H., Wang, R., Wang, S, Lin, J., 2005. A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells. PNAS 102:13, 4700-4705.

Keywords: Stat3, Cancer