TY - JOUR
T1 - 5,5′-Dibromo-bis(3′-indolyl)methane induces Krüppel-like factor 4 and p21 in colon cancer cells
AU - Sung, Dae Cho
AU - Chintharlapalli, Sudhakar
AU - Abdelrahim, Maen
AU - Papineni, Sabitha
AU - Liu, Shengxi
AU - Guo, Jingjing
AU - Lei, Ping
AU - Abudayyeh, Ala
AU - Safe, Stephen
PY - 2008
Y1 - 2008
N2 - Bis(3′-indolyl)methane (DIM) is a metabolite of the phytochemical indole-3-carbinol, and both compounds exhibit a broad spectrum of anticancer activities. We have developed a series of synthetic symmetrical ring-substituted DIM analogues, including 5,5′-dibromoDIM, which are more potent than DIM as inhibitors of cancer cell and tumor growth. In colon cancer cells, 5,5′-dibromoDIM decreased cell proliferation and inhibited G 0-G1- to S-phase progression, and this was accompanied by induction of the cyclin-dependent kinase inhibitor p21 in HT-29 and RKO colon cancer cells. Mechanistic studies showed that induction of p21 in both RKO (p53 wild-type) and HT-29 (p53 mutant) cells by 5,5′-dibromoDIM was Krüppel-like factor 4 (KLF4) dependent, and induction of p53 in RKO cells was also KLF4 dependent. Analysis of the p21 promoter in p53-dependent RKO cells showed that 5,5′-dibromoDIM activated p21 gene expression through the proximal GC-rich sites 1 and 2, and chromatin immunoprecipitation assays showed that KLF4 and p53 bound to this region of the promoter, whereas in HT-29 cells unidentified upstream cis-elements were required for induction of p21. 5,5′-DibromoDIM (30 mg/kg/d) also inhibited tumor growth and induced p21 in athymic nude mice bearing RKO cells as xenografts, showing that ring-substituted DIM such as 5,5′-dibromoDIM represent a novel class of mechanism-based drugs for clinical treatment of colon cancer.
AB - Bis(3′-indolyl)methane (DIM) is a metabolite of the phytochemical indole-3-carbinol, and both compounds exhibit a broad spectrum of anticancer activities. We have developed a series of synthetic symmetrical ring-substituted DIM analogues, including 5,5′-dibromoDIM, which are more potent than DIM as inhibitors of cancer cell and tumor growth. In colon cancer cells, 5,5′-dibromoDIM decreased cell proliferation and inhibited G 0-G1- to S-phase progression, and this was accompanied by induction of the cyclin-dependent kinase inhibitor p21 in HT-29 and RKO colon cancer cells. Mechanistic studies showed that induction of p21 in both RKO (p53 wild-type) and HT-29 (p53 mutant) cells by 5,5′-dibromoDIM was Krüppel-like factor 4 (KLF4) dependent, and induction of p53 in RKO cells was also KLF4 dependent. Analysis of the p21 promoter in p53-dependent RKO cells showed that 5,5′-dibromoDIM activated p21 gene expression through the proximal GC-rich sites 1 and 2, and chromatin immunoprecipitation assays showed that KLF4 and p53 bound to this region of the promoter, whereas in HT-29 cells unidentified upstream cis-elements were required for induction of p21. 5,5′-DibromoDIM (30 mg/kg/d) also inhibited tumor growth and induced p21 in athymic nude mice bearing RKO cells as xenografts, showing that ring-substituted DIM such as 5,5′-dibromoDIM represent a novel class of mechanism-based drugs for clinical treatment of colon cancer.
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U2 - 10.1158/1535-7163.MCT-07-2311
DO - 10.1158/1535-7163.MCT-07-2311
M3 - Article
C2 - 18645021
AN - SCOPUS:51049100003
SN - 1535-7163
VL - 7
SP - 2109
EP - 2120
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 7
ER -