Riluzole synergizes with paclitaxel to inhibit cell growth and induce apoptosis in triple-negative breast cancer.

PURPOSE: One in eight women will develop breast cancer, 15-20% of whom will have triple-negative breast cancer (TNBC), an aggressive breast cancer with no current targeted therapy. We have demonstrated that riluzole, an FDA-approved drug for treating amyotrophic lateral sclerosis, inhibits growth of TNBC. In this study, we explore potential synergism between riluzole and paclitaxel, a chemotherapeutic agent commonly used to treat TNBC, in regulating TNBC proliferation, cell cycle arrest, and apoptosis. METHODS: TNBC cells were treated with paclitaxel and/or riluzole and synergistic effects on cell proliferation were quantified via MTT assay and CompuSyn analysis. Apoptosis was observed morphologically and by measuring cleaved PARP/caspase three products. Microarray analysis was performed using MDA-MB-231 cells to examine cell cycle genes regulated by riluzole and any enhanced effects on paclitaxel-mediated cell cycle arrest, determined by FACS analysis. These results were confirmed in vivo using a MDA-MB-231 xenograft model. RESULTS: Strong enhanced or synergistic effects of riluzole on paclitaxel regulation of cell cycle progression and apoptosis was demonstrated in all TNBC cells tested as well as in the xenograft model. The MDA-MB-231, SUM149, and SUM229 cells, which are resistant to paclitaxel treatment, demonstrated the strongest synergistic or enhanced effect. Key protein kinases were shown to be upregulated in this study by riluzole as well as downstream cell cycle genes regulated by these kinases. CONCLUSIONS: All TNBC cells tested responded synergistically to riluzole and paclitaxel strongly suggesting the usefulness of this combinatorial treatment strategy in TNBC, especially for patients whose tumors are relatively resistant to paclitaxel.

Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1.

Riluzole, the only drug approved by the FDA for treating amyotrophic lateral sclerosis, inhibits melanoma proliferation through its inhibitory effect on glutamatergic signaling. We demonstrated that riluzole also inhibits the growth of triple-negative breast cancer (TNBC) and described a role for metabotropic glutamate receptor-1 (GRM1) in regulating TNBC cell growth and progression. However, the role of GRM1 in mediating riluzole's effects in breast cancer has not been fully elucidated. In this study, we seek to determine how much of riluzole's action in breast cancer is mediated through GRM1. We investigated anti-tumor properties of riluzole in TNBC and ER+ cells using cell growth, invasion, and soft-agar assays and compared riluzole activity with GRM1 levels. Using Lentiviral vectors expressing GRM1 or shGRM1, these studies were repeated in cells expressing high or low GRM1 levels where the gene was either silenced or overexpressed. Riluzole inhibited proliferation, invasion, and colony formation in both TNBC and ER+ cells. There was a trend between GRM1 expression in TNBC cells and their response to riluzole in both cell proliferation and invasion assays. However, silencing and overexpression studies had no effect on cell sensitivity to riluzole. Our results clearly suggest a GRM1-independent mechanism through which riluzole mediates its effects on breast cancer cells. Understanding the mechanism by which riluzole mediates breast cancer progression will be useful in identifying new therapeutic targets for treating TNBC and in facilitating stratification of patients in clinical trials using riluzole in conjunction with conventional therapy.

An electronic medical record-based intervention to improve hepatitis A vaccination rates in the emergency department during a regional outbreak.

BACKGROUND: In response to the severe hepatitis A outbreak that occurred in Michigan between August 2016 and September 2019, our multihospital health system implemented an electronic medical record (EMR)-based vaccination intervention across its nine emergency departments (EDs). The objectives were to explore the impact of this intervention on increasing vaccination rates among high-risk individuals and to assess the barriers to use of a computerised vaccine reminder system. METHODS: All patients who were 18 years or older were screened using an electronic nursing questionnaire. If a patient was at high risk based on the questionnaire, an electronic best practice advisory (BPA) would trigger and give the physician or advanced practice provider the option to order the hepatitis A vaccine. We explored the vaccination rates in the 24-month preintervention and the 18-month intervention periods. We then administered a survey to physicians, advanced practice providers and nurses evaluating their perceptions and barriers to use of the EMR intervention. RESULTS: During the preintervention period, 49 vaccines were ordered (5.5 per 100 000 patient visits) and 32 were administered (3.6 per 100 000 patient visits). During the intervention period, 574 865 patient visits (74.3%) were screened. 2494 vaccines (322 per 100 000 patient visits) were ordered, and 1205 vaccines (155 per 100 000 patients visits) were administered. Physicians and advanced practice providers were initially compliant with the BPA's use, but compliance declined over time. Surveys revealed that the major barrier to use was lack of time. CONCLUSIONS: EMR screening tools and BPAs can be used in the ED as an effective strategy to vaccinate high-risk individuals. This may be translatable to outbreaks of other vaccine-preventable illnesses like influenza, measles or SARS-CoV-2. Providing ongoing education about the public health initiative and giving feedback to physicians, advanced practice providers and nurses about tool compliance are needed to sustain the improvement over time.

Metabotropic glutamate receptor-1 regulates inflammation in triple negative breast cancer.

Breast cancer remains a major cause of death among women. 15% of these cancers are triple negative breast cancer (TNBC), an aggressive subtype of breast cancer for which no current effective targeted therapy exists. We have previously demonstrated a role for mGluR1 in mediating tumor cell growth, endothelial cell proliferation, and tumor-induced angiogenesis in TNBC. In this study, we explore a role for mGluR1 in regulating inflammation in TNBC. GRM1 expression was silenced in MDA-MB-231 cells to study changes in expression of inflammatory genes regulated by mGluR1. Results were confirmed by ELISA using GRM1-silenced and overexpressed cells and mGluR1 inhibitors. A functional role for these differentially expressed genes was determined in vitro and in vivo. 131 genes were differentially expressed in GRM1-silenced MDA-MB-231 cells, with some of these falling into four major canonical pathways associated with acute inflammation, specifically leukocyte migration/chemotaxis. Upregulation of three of these genes (CXCL1, IL6, IL8) and their corresponding protein was confirmed by qPCR analysis and ELISA in GRM1-manipulated TNBC cells. Upregulation of these cytokines enhanced endothelial adhesion and transmigration of neutrophils in co-culture assays and in 4T1 mouse tumors. Our results suggest mGluR1 may serve as a novel endogenous regulator of inflammation in TNBC.