1,1-Bis(3'-indolyl)-1-(p-bromophenyl)methane and related compounds repress survivin and decrease gamma-radiation-induced survivin in colon and pancreatic cancer cells.
1,1-Bis(3'-indolyl)-1-(p-bromophenyl)methane (DIM-C-pPhBr) and the 2,2'-dimethyl analog (2,2'-diMeDIM-C-pPhBr) inhibit proliferation and induce apoptosis in SW480 colon and Panc28 pancreatic cancer cells. In this study, treatment with 10-20 microM concentrations of these compounds for 24 h induced cleaved PARP and decreased survivin protein and mRNA expression in both cell lines. However, results of time course studies show that DIM-C-pPhBr and 2,2'-diMeDIM-C-pPhBr decrease survivin protein within 2 h after treatment, whereas survivin mRNA levels were decreased only at later time-points indicating activation of transcription-independent and -dependent pathways for downregulation of survivin. In addition, we also observed that gamma-radiation inhibited pancreatic and colon cancer cell growth and this was associated with enhanced expression of survivin after 24 (SW480) or 24 and 48 h (Panc28) and correlated with previous studies on the role of survivin in radiation-resistance. However, in cells co-treated with gamma-radiation plus DIM-C-pPhBr or 2,2'-diMeDIM-C-pPhBr, induction of survivin by gamma-radiation was inhibited after co-treatment with both compounds, suggesting applications for these drugs in combination cancer chemotherapy with gamma-radiation.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466, USA.
Sandeep
S
Sreevalsan
Indira
I
Jutooru
Gayathri
G
Chadalapaka
Michael
M
Walker
Stephen
S
Safe
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015536:Down-Regulation; D005720:Gamma Rays; D015870:Gene Expression / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000187:drug effects* / Q000528:radiation effects*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D011836:Radiation Tolerance / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077022:Survivin; D014162:Transfection
D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D000077022:Survivin; C016392:3,3'-diindolylmethane