1,1-Bis(3'-indolyl)-1-(p-substituted phenyl)methanes induce autophagic cell death in estrogen receptor negative breast cancer.

Abstract

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.

• Authors: Kathy Vanderlaag, Yunpeng Su, Arthur E Frankel, Robert C Burghardt, Rola Barhoumi, Gayathri Chadalapaka, Indira Jutooru, Stephen Safe
• Journal: BMC cancer (BMC Cancer) Vol. 10 Pg. 669 (Dec 03 2010) ISSN: 1471-2407 [Electronic] England
• PMID: 21129193 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 1,1-bis(3'-indolyl)-1-(4-biphenyl)methane
• 1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane
• Amino Acid Chloromethyl Ketones
• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BECN1 protein, human
• Beclin-1
• Biomarkers, Tumor
• Caspase Inhibitors
• Cysteine Proteinase Inhibitors
• Indoles
• Macrolides
• Membrane Proteins
• Microtubule-Associated Proteins
• Proto-Oncogene Proteins c-bcl-2
• Receptors, Estrogen
• Recombinant Fusion Proteins
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• bafilomycin A1
• L-Lactate Dehydrogenase
• Caspases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (metabolism)
• Autophagy (drug effects)
• Beclin-1
• Biomarkers, Tumor (analysis)
• Blotting, Western
• Breast Neoplasms (chemistry, drug therapy, pathology)
• Caspase Inhibitors
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cysteine Proteinase Inhibitors (pharmacology)
• Female
• Humans
• Immunohistochemistry
• Indoles (pharmacology)
• L-Lactate Dehydrogenase (metabolism)
• Macrolides (pharmacology)
• Membrane Proteins (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Microtubule-Associated Proteins (genetics, metabolism)
• Necrosis
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Receptors, Estrogen (analysis)
• Recombinant Fusion Proteins (metabolism)
• Time Factors
• Transfection
• Xenograft Model Antitumor Assays