Department of Pharmaceutical Sciences, School of Pharmacy, Pacific University, United States.
Department of Medical Education, Dell Medical School, University of Texas at Austin, United States; Live Strong Cancer Institutes, Dell Medical School, University of Texas at Austin, United States; Department of Oncology, Dell Medical School, University of Texas at Austin, United States.
Eur J Pharmacol. 2018 Sep 15;835:61-74. doi: 10.1016/j.ejphar.2018.07.057. Epub 2018 Jul 31.
Breast cancer is one of the leading causes of cancer-related death among women. A significant challenge in treating breast cancer is the limited array of therapeutic options and the rapid development of resistance to existing agents. Indeed, breast cancer patients, particularly those with hormone-receptor (HR)-positive breast cancer, initially respond to systemic treatment with cytotoxic, hormonal, and immunotherapeutic agents but frequently progress to a more advanced disease that is refractory to therapy. Thus, new agents are needed to improve the effectiveness of current agents, decrease the emergence of resistance, and increase disease-free survival. To this end, numerous agents have been investigated for use in combination with existing therapies. Histone deacetylase (HDAC) inhibitors are a class of potent epigenetic modulators that have been investigated recently for their potential use in the treatment of breast cancer. In this review, we will discuss the underlying molecular rationale for using HDAC inhibitors for the treatment of breast cancer. In particular, we will focus our discussion on the FDA approved HDAC inhibitor valproic acid (VPA) which has been shown to alter proliferation, survival, cell migration, and hormone receptor expression of breast cancer cells in both the pre-clinical and clinical settings. We also discuss the promising pre-clinical data suggesting that VPA can be repurposed as an adjunctive agent in combination with many cytotoxic, hormonal, and immunotherapeutic agents for the treatment of breast cancer. Finally, we will examine the current models used to study the actions of VPA on breast cancer alone and in tandem with other agents.
乳腺癌是女性癌症相关死亡的主要原因之一。治疗乳腺癌的一个重大挑战是治疗选择有限，以及现有药物迅速产生耐药性。事实上，乳腺癌患者，尤其是激素受体（HR）阳性乳腺癌患者，最初对细胞毒性、激素和免疫治疗药物的全身治疗有反应，但经常进展为对治疗产生抗性的更晚期疾病。因此，需要新的药物来提高现有药物的疗效，减少耐药性的出现，并增加无病生存期。为此，已经研究了许多药物与现有疗法联合使用。组蛋白去乙酰化酶（HDAC）抑制剂是一类有效的表观遗传调节剂，最近已被研究用于治疗乳腺癌。在这篇综述中，我们将讨论使用 HDAC 抑制剂治疗乳腺癌的潜在分子原理。特别是，我们将重点讨论已被证明可改变乳腺癌细胞增殖、存活、细胞迁移和激素受体表达的 FDA 批准的 HDAC 抑制剂丙戊酸（VPA），无论是在临床前还是临床环境中。我们还讨论了有前途的临床前数据，表明 VPA 可以作为辅助剂与许多细胞毒性、激素和免疫治疗药物联合用于治疗乳腺癌。最后，我们将检查目前用于单独研究 VPA 对乳腺癌的作用以及与其他药物联合使用的模型。
