Cytotoxic Effects of Jay Amin Hydroxamic Acid (JAHA), a Ferrocene-Based Class I Histone Deacetylase Inhibitor, on Triple-Negative MDA-MB231 Breast Cancer Cells

The histone deacetylase inhibitors (HDACis) are a class of chemically heterogeneous anticancer agents of which suberoylanilide 0 hydroxamic acid (SAHA) is a prototypical member. SAHA derivatives e. 0 may be obtained by three-dimensional manipulation of SAHA aryl cap, such as the incorporation of a ferrocene unit like that present in Jay Amin hydroxamic acid (JAHA) and homo-JAHA [Spencer, et al. (2011) ACS Med. Chem. Lett. 2, 358-362]. These metal-based SAHA analogues have been tested for their cytotoxic activity toward triple-negative MDA-MB231 breast cancer cells. The results obtained indicate that of the two compounds tested, only JAHA was prominently active on breast cancer cells with an IC50 of 8.45 mu M at 72 h of treatment. Biological assays showed that exposure of MDA-MB231 cells to the HDACi resulted in cell cycle perturbation with an alteration of S phase entry and a delay at G(2)/M transition and in an early reactive oxygen species production followed by mitochondrial membrane potential (MMP) dissipation and autophagy inhibition. No annexin binding was observed after short- (5 h) and longer (24 and 48 h) term incubation with JAHA, thereby excluding the promotion of apoptosis by the HDACi. Although caution must be exercised in extrapolation of in vitro results to the in vivo situation for which research on animals and human trials are needed, nevertheless JAHA treatment possesses the potential for its development as an agent for prevention and/or therapy of aggressive breast carcinoma, thus prompting us to get more insight into the molecular basis of its antibreast cancer activity.