Effect of suberoylanilide hydroxamic acid (SAHA) on breast cancer cells within a tumor-stroma microfluidic model.

ABSTRACT

Metastatic cancer is regarded as one of the largest contributors to disease-related deaths worldwide. Poor patient prognosis and treatment outcome is tied to the lack of efficacious anti-cancer therapies, which is due in part to the lack of physiologically relevant in vitro screening systems that can mimic the native tumor microenvironment. Conventional drug-screening platforms, which are often used in the pharmaceutical industry, are either two-dimensional (2D) assays or three-dimensional (3D) hydrogel-based matrices that lack precise control over cell distribution, matrix architecture, and organization. Despite the significance of in vivo models, they have limitations as it is difficult to control and analyze the influence of specific variables within their tumor microenvironment. Thus, there is still a crucial need to develop tumor models that enable precise control of microenvironmental cues (e.g. matrix composition, soluble factors, cellular organization) to assess the efficacy of anti-cancer drugs. Herein, we report the development and validation of a 3D microfluidic invasion platform for anti-cancer drug studies. Our platform allowed for compartmentalization of tumor and stromal fibroblasts in a defined architecture, thereby enabling pharmacokinetic drug transport to a cell-dense tumor region. We analyzed the effect of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor, on the behavior of SUM159 breast cancer cells. Many HDAC inhibitors, including SAHA, have been a subject of controversy with highly conflicting results for the treatment of solid tumors in vitro as well as in clinical trials. We found that SAHA significantly inhibited cellular migration/proliferation, and decreased microtubule polarization.