Tumor selective cytotoxic action of a thiomorpholin hydroxamate inhibitor (TMI-1) in breast cancer.

Abstract

BACKGROUND:

Targeted therapies, associated with standard chemotherapies, have improved breast cancer care. However, primary and acquired resistances are frequently observed and the development of new concepts is needed. High-throughput approaches to identify new active and safe molecules with or without an "a priori" are currently developed. Also, repositioning already-approved drugs in cancer therapy is of growing interest. The thiomorpholine hydroxamate compound TMI-1 has been previously designed to inhibit metalloproteinase activity for the treatment of rheumatoid arthritis. We present here the repositioning of TMI-1 drug in breast cancer.

METHODOLOGY/PRINCIPAL FINDINGS:

We tested the effect of TMI-1 on luminal, basal and ERBB2-overexpressing breast tumor cell lines and on MMTV-ERBB2/neu tumor evolution. We measured the effects on i) cell survival, ii) cell cycle, iii) extrinsic and intrinsic apoptotic pathways, iv) association with doxorubicin, docetaxel and lapatinib, v) cancer stem cells compartment. In contrast with conventional cytotoxic drugs, TMI-1 was highly selective for tumor cells and cancer stem cells at submicromolar range. All non-malignant cells tested were resistant even at high concentration. TMI-1 was active on triple negative (TN) and ERBB2-overexpressing breast tumor cell lines, and was also highly efficient on human and murine "primary" ERBB2-overexpressing cells. Treatment of transgenic MMTV-ERBB2/neu mice with 100 mg/kg/day TMI-1 alone induced tumor apoptosis, inhibiting mammary gland tumor occurrence and development. No adverse effects were noticed during the treatment. This compound had a strong synergistic effect in association with docetaxel, doxorubicin and lapatinib. We showed that TMI-1 mediates its selective effects by caspase-dependent apoptosis. TMI-1 was efficient in 34/40 tumor cell lines of various origins (ED50: 0.6 µM to 12.5 µM).

CONCLUSIONS/SIGNIFICANCE:

This is the first demonstration of the tumor selective cytotoxic action of a thiomorpholin hydroxamate compound. TMI-1 is a novel repositionable drug not only for the treatment of adverse prognosis breast cancers but also for other neoplasms.

• Authors: Lynda Mezil, Carole Berruyer-Pouyet, Olivier Cabaud, Emmanuelle Josselin, Sébastien Combes, Jean-Michel Brunel, Patrice Viens, Yves Collette, Daniel Birnbaum, Marc Lopez
• Journal: PloS one (PLoS One) Vol. 7 Issue 9 Pg. e43409 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23028451 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Morpholines
• apratastat
• Receptor, ErbB-2
• Metalloproteases
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology, toxicity)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism)
• Caspases (metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Female
• Humans
• Metalloproteases (antagonists & inhibitors)
• Mice
• Mice, Transgenic
• Mitochondria (drug effects, metabolism)
• Morpholines (pharmacology, toxicity)
• Neoplastic Stem Cells (drug effects, metabolism)
• Receptor, ErbB-2 (metabolism)
• Signal Transduction (drug effects)
• Spheroids, Cellular (drug effects)
• Tumor Cells, Cultured