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

Speyer, Cecilia L.; Bukhsh, Miriam A.; Jafry, Waris S.; Sexton, Rachael E.; Bandyopadhyay, Sudeshna; Gorski, David H.

doi:10.1007/s10549-017-4435-x

Cited by 19 publications

(39 citation statements)

References 33 publications

(48 reference statements)

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“…Our data demonstrate that riluzole can display synergistic anti-GBM effects with mTOR inhibitors (see Figure 5C) and recent data have demonstrated that riluzole synergizes with the chemotherapeutic paclitaxel in triple-negative breast cancers [53]. It is well known that chemotherapeutically induced cellular stress can activate IRES-mediated protein synthesis of various transcripts, including the aryl hydrocarbon receptor, ATF2, ribosome binding protein 1, c-myc and β-catenin [54][55][56][57][58].…”

Section: Discussionsupporting

confidence: 74%

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

Benavides-Serrato

Saunders

Holmes

et al. 2020

IJMS

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Internal ribosome entry site (IRES)-mediated protein synthesis has been demonstrated to play an important role in resistance to mechanistic target of rapamycin (mTOR) targeted therapies. Previously, we have demonstrated that the IRES trans-acting factor (ITAF), hnRNP A1 is required to promote IRES activity and small molecule inhibitors which bind specifically to this ITAF and curtail IRES activity, leading to mTOR inhibitor sensitivity. Here we report the identification of riluzole (Rilutek®), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), via an in silico docking analysis of FDA-approved compounds, as an inhibitor of hnRNP A1. In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (GBM) affects with mTOR inhibitors in vitro and in GBM xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in glioblastoma.

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Section: Discussionsupporting

confidence: 74%

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

Benavides-Serrato

Saunders

Holmes

et al. 2020

IJMS

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“…Interestingly, the response of xenograft to riluzole monotherapy was minimal. To add, our observations do not agree with another report which proposed that breast cancer xenografts treated with riluzole had a significant decrease in tumor volume [14]. However, several differences exist between this report and our work.…”

Section: Discussioncontrasting

confidence: 99%

“…International Publisher response of cancer to different anti-tumor treatments, including chemotherapy and radiotherapy [13][14][15][16].…”

Section: Ivyspringmentioning

confidence: 99%

Riluzole Enhances the Response of Human Nasopharyngeal Carcinoma Cells to Ionizing Radiation via ATM/P53 Signalling Pathway

Sun

Jun

et al. 2020

J. Cancer

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Riluzole is approved by the FDA as an amyotrophic lateral sclerosis (ALS) drug. Previous studies showed that treatment with riluzole suppressed the proliferation of many cancer cells. However, little is known about its effects on nasopharyngeal carcinoma (NPC) and its molecular mode of action. In this study, we determined the effect of riluzole on apoptosis, cell cycle, migration, and invasion in NPC cell lines and investigated its mechanism at the molecular level. By using the human NPC cell lines CNE1, CNE2, and HNE1, we revealed that riluzole effectively inhibited viability of the NPC cell lines in dose-and time-dependent manners. Furthermore, riluzole dose-dependently induced apoptosis and G2/M cell cycle arrest in the NPC cell lines. After combination with radiotherapy (RT), greater cytotoxicity was achieved than with riluzole or RT alone in vitro and vivo. This was associated with the activation of ataxia telangiectasia mutated (ATM) and phosphoinositide p53 pathways. P53 silencing reduced cell reactiveness to riluzole therapy. These observations demonstrate that the riluzole-activated ATM/P53 pathway is directly involved in radiation-induced apoptosis of NPC cells. Given the acceptable side effect, combining of riluzole and radiotherapy is promising in NPC treatment.

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“…After 24 hours, riluzole had no significant effect on CXCL1 levels in any cell line. This is consistent with microarray analysis performed previously with riluzole-treated MDA-MB-231 cells 24 . By 48 hours, a dose-dependent increase in CXCL1 was observed in all 3 cell lines with a significant increase of over 3-fold in SUM159 and BT549 cells after treatment with the highest dose (50 μM).…”

Section: Resultssupporting

confidence: 92%

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

Sexton

Hachem

Assi

et al. 2018

Sci Rep

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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.

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

Abstract: 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.

Cited by 19 publications

References 33 publications

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

Riluzole Enhances the Response of Human Nasopharyngeal Carcinoma Cells to Ionizing Radiation via ATM/P53 Signalling Pathway

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

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