Asong Gladys M, Amissah Felix, Voshavar Chandrashekhar, Nkembo Augustine T, Ntantie Elizabeth, Lamango Nazarius S, Ablordeppey Seth Y
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, Florida 32307, United States.
College of Pharmacy, Ferris State University, Big Rapids, Michigan 49307, United States.
ACS Omega. 2020 Dec 16;5(51):32907-32918. doi: 10.1021/acsomega.0c03495. eCollection 2020 Dec 29.
Triple-negative breast cancer (TNBC) is one of the most malignant cancers associated with early metastasis, poor clinical prognosis, and high recurrence rate. TNBC is a distinct subtype of breast cancer that lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 receptors (HER2). Development of effective TNBC therapies has been limited partially due to the lack of specific molecular targets and chemotherapy involving different cytotoxic drugs suffers from significant side effects and drug-resistance development. Therefore, there is an unmet need for the development of novel and efficient therapeutic drugs with reduced side effects to treat TNBC. We have previously reported that certain analogues of haloperidol (a typical antipsychotic drug used for treating mental/mood disorders such as schizophrenia and bipolar disorder) suppress the viability of a variety of solid tumor cell lines, and we have identified 4-(4-(4-chlorophenyl)-1,4-diazepan-1-yl)-1-(4-fluoro-phenyl)butan-1-one (SYA013) with such antiproliferative properties. Interestingly, unlike haloperidol, SYA013 shows moderate selectivity toward σ receptors. In this study, we explored the potential of SYA013 in modulating the important biological events associated with cell survival and progression as well as the mechanistic aspects of apoptosis in a representative TNBC cell line (MDA-MB-231). Our results indicate that SYA013 inhibits the proliferation of MDA-MB-231 cells in a concentration-dependent manner and suppresses cell migration and invasion. Apoptotic studies were also conducted in MDA-MB-468 cells (cells derived from a 51-year old Black female with metastatic adenocarcinoma of the breast.). In addition, we have demonstrated that SYA013 induces MDA-MB-231 cell death through the intrinsic apoptotic pathway and may suppress tumor progression and metastasis. Taken together, our study presents a mechanistic pathway of the anticancer properties of SYA013 against TNBC cell lines and suggests a potential for exploring SYA013 as a lead agent for development against TNBC.
三阴性乳腺癌（TNBC）是最具侵袭性的癌症之一，与早期转移、临床预后不良和高复发率相关。TNBC是乳腺癌的一种独特亚型，缺乏雌激素受体（ER）、孕激素受体（PR）和人表皮生长因子2受体（HER2）。有效TNBC疗法的开发受到一定限制，部分原因是缺乏特异性分子靶点，且涉及不同细胞毒性药物的化疗存在显著副作用和耐药性问题。因此，迫切需要开发新型高效、副作用小的治疗药物来治疗TNBC。我们之前报道过，某些氟哌啶醇类似物（一种用于治疗精神/情绪障碍如精神分裂症和双相情感障碍的典型抗精神病药物）可抑制多种实体瘤细胞系的活力，并且我们已鉴定出具有这种抗增殖特性的4-(4-(4-氯苯基)-1,4-二氮杂环庚烷-1-基)-1-(4-氟苯基)丁烷-1-酮（SYA013）。有趣的是，与氟哌啶醇不同，SYA013对σ受体表现出适度的选择性。在本研究中，我们探讨了SYA013在调节与细胞存活和进展相关的重要生物学事件以及在代表性TNBC细胞系（MDA-MB-231）中凋亡机制方面的潜力。我们的结果表明，SYA013以浓度依赖性方式抑制MDA-MB-231细胞的增殖，并抑制细胞迁移和侵袭。还在MDA-MB-468细胞（源自一名51岁患有乳腺转移性腺癌的黑人女性的细胞）中进行了凋亡研究。此外，我们已证明SYA013通过内在凋亡途径诱导MDA-MB-231细胞死亡，并可能抑制肿瘤进展和转移。综上所述，我们的研究揭示了SYA013对TNBC细胞系抗癌特性的作用机制，并表明探索SYA013作为抗TNBC开发的先导药物具有潜力。
