An Evaluation of the Anticancer Properties of SYA014, a Homopiperazine-Oxime Analog of Haloperidol in Triple Negative Breast Cancer Cells

SIMPLE SUMMARY: Triple negative breast cancer (TNBC) is one of the most challenging and hard to treat breast cancer types due to the lack of the receptor targets that are commonly found in breast cancers. It is aggressive in nature with a high recurrence rate. Chemotherapy, radiotherapy, and surgery are the available options. However, conventional chemotherapy drugs have not been effective and new treatment strategies are needed. To this end, we tested SYA014, a compound that binds to the sigma-2 receptor, for its anticancer properties against two different TNBC cell lines. SYA014 was able to kill the cancer cells by interfering with key cellular events associated with cell proliferation. SYA014 induced cytotoxicity in the TNBC cell lines and was evaluated for the involvement of the sigma-2 receptor. Finally, SYA014 was tested in combination with the well-known anticancer drug, cisplatin, in both TNBC cells and non-cancer cells, to improve the treatment outcome. ABSTRACT: Triple negative breast cancer (TNBC) is a type of breast cancer associated with early metastasis, poor prognosis, high relapse rates, and mortality. Previously, we demonstrated that SYA013, a selective σ2RL, could inhibit cell proliferation, suppress migration, reduce invasion, and induce mitochondria-mediated apoptosis in MDA-MB-231 cell lines, although we were unable to demonstrate the direct involvement of sigma receptors. This study aimed to determine the anticancer properties and mechanisms of action of SYA014, [4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluorophenyl)butan-1-one oxime], an oxime analogue of SYA013, the contribution of its sigma-2 receptor (σ2R) binding, and its possible synergistic use with cisplatin to improve anticancer properties in two TNBC cell lines, MDA-MB-231 (Caucasian) and MDA-MB-468 (Black). In the present investigation, we have shown that SYA014 displays anticancer properties against cell proliferation, survival, metastasis and apoptosis in the two TNBC cell lines. Furthermore, a mechanistic investigation was conducted to identify the apoptotic pathway by which SYA014 induces cell death in MDA-MB-231 cells. Since SYA014 has a higher binding affinity for σ2R compared to σ1R, we tested the role of σ2R on the antiproliferative property of SYA014 with a σ2R blockade. We also attempted to evaluate the combination effect of SYA014 with cisplatin in TNBC cells.