1,1-Bis(3 '-indolyl)-1-(p-substituted phenyl) methanes induce autophagic cell death in estrogen receptor negative breast cancer | Academic Article individual record

BACKGROUND: A novel series of methylene-substituted DIMs (C-DIMs), namely 1,1-bis(3'-indolyl)-1-(p-substituted phenyl)methanes containing t-butyl (DIM-C-pPhtBu) and phenyl (DIM-C-pPhC6H5) groups inhibit proliferation of invasive estrogen receptor-negative MDA-MB-231 and MDA-MB-453 human breast cancer cell lines with IC50 values between 1-5 uM. The main purpose of this study was to investigate the pathways of C-DIM-induced cell death. METHODS: The effects of the C-DIMs on apoptotic, necrotic and autophagic cell death were determined using caspase inhibitors, measurement of lactate dehydrogenase release, and several markers of autophagy including Beclin and light chain associated protein 3 expression (LC3). RESULTS: The C-DIM compounds did not induce apoptosis and only DIM-C-pPhCF3 exhibited necrotic effects. However, treatment of MDA-MB-231 and MDA-MB-453 cells with C-DIMs resulted in accumulation of LC3-II compared to LC3-I protein, a characteristic marker of autophagy, and transient transfection of green fluorescent protein-LC3 also revealed that treatment with C-DIMs induced a redistribution of LC3 to autophagosomes after C-DIM treatment. In addition, the autofluorescent drug monodansylcadaverine (MDC), a specific autophagolysosome marker, accumulated in vacuoles after C-DIM treatment, and western blot analysis of lysates from cells treated with C-DIMs showed that the Beclin 1/Bcl-2 protein ratio increased. CONCLUSION: The results suggest that C-DIM compounds may represent a new mechanism-based agent for treating drug-resistant ER-negative breast tumors through induction of autophagy.

author list (cited authors)
Vanderlaag, K., Su, Y., Frankel, A. E., Burghardt, R. C., Barhoumi, R., Chadalapaka, G., Jutooru, I., & Safe, S.
publication date
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  • Immunohistochemistry
  • Biomarkers, Tumor
  • Tumor Markers, Biological
  • Caspase Inhibitors
  • Indoles
  • Receptors, Estrogen
  • Cell Line, Tumor
  • Cysteine Proteinase Inhibitors
  • Amino Acid Chloromethyl Ketones
  • Proto-Oncogene Proteins C-bcl-2
  • Antineoplastic Agents
  • Humans
  • Apoptosis
  • L-Lactate Dehydrogenase
  • Animals
  • Caspases
  • Mice, Nude
  • Microtubule-Associated Proteins
  • Apoptosis Regulatory Proteins
  • Mice, Inbred BALB C
  • Time Factors
  • Breast Neoplasms
  • Autophagy
  • Cell Proliferation
  • Blotting, Western
  • Membrane Proteins
  • Necrosis
  • Xenograft Model Antitumor Assays
  • Recombinant Fusion Proteins
  • Female
  • Mice
  • Transfection
  • Beclin-1
  • Macrolides