Ester derivatives of salinomycin efficiently eliminate breast cancer cells via ER-stress-induced apoptosis.

The polyether ionophore salinomycin (SAL) has been found to selectively target breast cancer cells, including those with stem-like phenotype. On the other hand, SAL amides and esters obtained through derivatisation of the C1 carboxyl of the ionophore were found to exhibit anticancer properties, whilst reducing potential toxicity issues which often occur during standard chemotherapy. However, the studies on the activity and especially on the mechanisms of action of this class of semi-synthetic products against breast cancer cells are very limited. Therefore, in this work, we confirmed the anti-breast cancer activity of SAL, and further investigated the potential of its selected C1 amide and ester analogs to destroy breast cancer cells, including the highly aggressive triple-negative MDA-MB-231 cells. Importantly, SAL esters were found to be more potent than the native structure and their amide counterparts. Our data revealed that SAL ester derivatives, particularly compounds 5 and 7 (2,2,2-trifluoroethyl and benzotriazole ester of SAL, respectively), increase the level of p-eIF2α (Ser51) and IRE1α proteins. Additionally, an increased level of DNA damage indicators such as γH2AX protein and modified guanine (8-oxoG) was observed. These findings suggest that the apoptosis of MCF-7 and MDA-MB-231 cells induced by the most promising esters derived from SAL may result from the interaction between ER stress and DNA damage response mechanisms.

Breast Cancer Prevention-Is there a Future for Sulforaphane and Its Analogs?

Breast cancer is the most prevalent type of cancer among women worldwide. There are several recommended methods of breast cancer prevention, including chemoprevention. There are several approved drugs used to prevent breast cancer occurrence or recurrence and metastasizing. There are also a number of new substances undergoing clinical trials and at the stage of initial study. Studies suggest that dietary factors play a crucial role in breast cancer etiology. Epidemiological studies indicate that in particular vegetables from the Brassicaceae family are a rich source of chemopreventive substances, with sulforaphane (SFN) being one of the most widely studied and characterized. This review discusses potential applicability of SFN in breast cancer chemoprevention. A comprehensive review of the literature on the impact of SFN on molecular signalling pathways in breast cancer and breast untransformed cells is presented. The presented results of in vitro and in vivo studies show that this molecule has a potential to act as a preventive molecule either to prevent disease development or recurrence and metastasizing, and as a compound protecting normal cells against the toxic effects of cytostatics. Finally, the still scanty attempts to develop an improved analog are also presented and discussed.

Fluoroaryl analogs of sulforaphane - A group of compounds of anticancer and antimicrobial activity.

A series of new sulforaphane analogs bearing various (poly)fluoroaryl substituents bonded to the sulfinyl sulfur atom in place of the original methyl group and having different number of methylene groups in the central alkyl chain were synthesized and fully characterized. The new compounds were tested in vitro for their anticancer, antibacterial, antifungal and antiviral properties. Some of them demonstrated a much higher anticancer activity against selected lines of cancer: skin (MALME-3M), colon (HT-29) and breast (MCF7 and MDA-MB-231) cells than that exhibited by native sulforaphane (SFN). Related lines of untransformed (normal) cells, taken from the same organs as the cancer ones, i.e. MALME3, CRL-1790 and MCF10, respectively, were checked, which allowed for the determination of the selectivity indexes (SI). In certain cases, the latter exceeded 3.2. Concerning the antibacterial activity, gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) were susceptible to some newly synthesized SFN analogs, while the selected probiotic strains were from 10 to 100 fold more resistant to them, which gives a possibility of protection of symbiont strains during a potential therapy with such compounds. The antifungal activity of the new compounds possessing the fluorophenyl substituent was found to be higher than the activity of the parent SFN. In turn, most of the new compounds showed generally no anti-HIV activity. The influence of the particular structural differences in the new molecules, analogs of SFN, on their biological activity is discussed.