Redox-Mediated Suberoylanilide Hydroxamic Acid Sensitivity in Breast Cancer.

Abstract

AIMS:

Vorinostat (suberoylanilide hydroxamic acid; SAHA) is a histone deacetylase inhibitor (HDACi) approved in the clinics for the treatment of T-cell lymphoma and with the potential to be effective also in breast cancer. We investigated the responsiveness to SAHA in human breast primary tumors and cancer cell lines.

RESULTS:

We observed a differential response to drug treatment in both human breast primary tumors and cancer cell lines. Gene expression analysis of the breast cancer cell lines revealed that genes involved in cell adhesion and redox pathways, especially glutathione metabolism, were differentially expressed in the cell lines resistant to SAHA compared with the sensitive ones, indicating their possible association with drug resistance mechanisms. Notably, such an association was also observed in breast primary tumors. Indeed, addition of buthionine sulfoximine (BSO), a compound capable of depleting cellular glutathione, significantly enhanced the cytotoxicity of SAHA in both breast cancer cell lines and primary breast tumors.

INNOVATION:

We identify and validate transcriptional differences in genes involved in redox pathways, which include potential predictive markers of sensitivity to SAHA.

CONCLUSION:

In breast cancer, it could be relevant to evaluate the expression of antioxidant genes that may favor tumor resistance as a factor to consider for potential clinical application and treatment with epigenetic drugs (HDACis).

• Authors: Ferdinando Chiaradonna, Iros Barozzi, Claudia Miccolo, Gabriele Bucci, Roberta Palorini, Lorenzo Fornasari, Oronza A Botrugno, Giancarlo Pruneri, Michele Masullo, Alfonso Passafaro, Viviana E Galimberti, Valeria R Fantin, Victoria M Richon, Salvatore Pece, Giuseppe Viale, Pier Paolo Di Fiore, Giulio Draetta, Pier Giuseppe Pelicci, Saverio Minucci, Susanna Chiocca
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 23 Issue 1 Pg. 15-29 (Jul 01 2015) ISSN: 1557-7716 [Electronic] United States
• PMID: 25897982 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Histone Deacetylase Inhibitors
• Hydroxamic Acids
• Buthionine Sulfoximine
• Vorinostat

Topics

• Antineoplastic Agents (metabolism, pharmacology)
• Breast Neoplasms (genetics, metabolism, pathology)
• Buthionine Sulfoximine (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Hydroxamic Acids (metabolism, pharmacology, toxicity)
• Oxidation-Reduction (drug effects)
• Primary Cell Culture
• Vorinostat