1,1-Bis(3'-indolyl)-1-(p-biphenyl)methane inhibits basal-like breast cancer growth in athymic nude mice

Authors:
Su Y, Vanderlaag K, Ireland C, Ortiz J, Grage H, Safe S, Frankel AE.
In:
Source: Breast Cancer Res
Publication Date: (2007)
Issue: 9(4): R56
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Skeletal Muscle Myoblast, (HSMM) human
Species: human
Tissue Origin: skeletal muscle
Skeletal Muscle Cells, (SkMC) human
Species: human
Tissue Origin: skeletal muscle
Experiment

Cytotoxicity of CDIM9: Two different cell cytotoxicity assays were performed. Protein synthesis inhibition assay revealed that that two different human basal-like breast cancer cells, namely MD-MB231 and BT549, exhibited comparable sensitivities to CDIM9, with EC50 values of 5 and 3 ┬Ámol/l, respectively, after treatment for 48 hours (Figure 1a). In comparison, SKMCs and HSMMs were less sensitive to CDIM9 than were tumor cells, with EC50 values of 17 and 22 ┬Ámol/l, respectively.

Abstract

INTRODUCTION: 1,1-Bis (3'-indolyl#-1-#p-biphenyl# methane (CDIM9) has been identified as a new peroxisome proliferator-activated receptor (PPAR)-gamma agonist that exhibits both receptor dependent and independent antitumor activities. CDIM9 has not previously been studied with respect to its effects against basal-like breast cancer. Our goal in the present study was to investigate the anti-basal-like breast tumor activity of CDIM9 in vitro and in vivo. METHODS: The effects of CDIM9 on cell protein and DNA syntheses were determined in basal-like breast cancer MDA-MB231 and BT549 cells in vitro. Maximum tolerated dose and dose-limited toxicity were determined in BalB/c mice, and antitumor growth activities were assessed in MDA-MB231 basal-like breast tumor xenografts in athymic nude mice. RESULTS: CDIM9 exhibited selective cell cytotoxicity and anti-proliferation effects on basal-like breast cancer lines. In MDA-MB231 cell, CDIM9 induced caveolin-1 and p27 expression, which was significantly downregulated by co-treatment with the PPAR-gamma antagonist GW9662. Nonsteroidal anti-inflammatory drug-activated gene-1 and activating transcription factor-3 were upregulated by CDIM9 through a PPAR-gamma independent pathway. CDIM9 (40 mg/kg daily, intraperitoneally, for 35 days) inhibited the growth of subcutaneous MDA-MB231 tumor xenografts by 87%, and produced a corresponding decrease in proliferation index. Nearly half of the treated mice (46%) had complete durable remissions, confirmed by histology. The growth of an established tumor was inhibited by CDIM9 treatment (64 mg/kg daily, intraperitoneally, for 10 days), with a mean tumor growth inhibition of 67% as compared with controls. CDIM9 induced increases in tumor caveolin-1 and p27 in vivo, which may contribute to its antitumor activity in basal-like breast cancer. CONCLUSION: CDIM9 showed potent antiproliferative effects on basal-like breast cancer cell in tissue culture and dramatic growth inhibition in animal models at safe doses. These findings justify further development of this drug for treatment of basal-like breast cancer.