Title

Abstract 285: Disulfiram, a dual MGMT and aldehyde dehydrogenase inhibitor, sensitizes ER-positive breast cancer cells to temozolomide and cyclophosphamide

Aurora Affiliations

Aurora Health Care

Abstract

Background: O6 methylguanine DNA methyltransferase (MGMT) is overexpressed in a majority of cancers, including breast cancer. MGMT is a DNA repair protein leading to chemo resistance. MGMT expression directly correlates with ER expression and tamoxifen resistance. Aldehyde Dehydrogenase (ALDH) activity, as a progenitor/stem cell marker, while it has been reported to inversely correlate with MGMT expression in other cancers, has also been linked to chemotherapy and radiation resistance.

Methods: We have tested the effect of Antabuse (disulfiram, DSF), as a dual MGMT and ALDH inhibitor, at nontoxic doses, in combination with Temozolomide (TMZ) or/and Cyclophosphamide (CP) on ER+ breast cancer cells.

Results: DSF at very low doses (achievable in human serum with standard DSF clinical dosing) decreases ER+ breast cancer cell growth (MCF7, T47D and ZR75) in a dose-dependent manner. DSF further sensitizes breast cancer cells to TMZ or/and CP and significantly inhibits breast cancer growth without causing unwanted side effects on the normal breast epithelial cells. Dose effect and isobologram studies confirm synergistic activity of DSF + CP and moderate synergism for DSF + TMZ. DSF, alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP), significantly inhibits expression of MGMT, aldehyde dehydrogenase, ERα, E2F and BIRC5 gene (survivin) - all involved in breast cancer tumorigenesis. DSF, alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP) caused significant apoptosis in breast cancer cells. In a dose dependent manner, DSF inhibited colony formation, effect which was further enhanced by addition of TMZ/CP (DSF ± TMZ/CP). Similarly, DSF alone or in combination with TMZ (DSF ± TMZ) and/or CP (DSF ± CP) decreased the metastatic potential of breast cancer cells.

Conclusions: Our findings suggest that DSF as dual inhibitor of MGMT and ALDH significantly enhances the antitumor effect of alkylators as CP and TMZ in ER+ breast cancer

Document Type

Abstract

DOI

10.1158/1538-7445.AM2016-285