Eribulin inhibits the growth of small cell lung cancer cell lines alone and with radiotherapy

Abstract

Objectives Small cell lung cancer (SCLC) patients of all stages are treated with etoposide and cisplatin or carboplatin with or without surgery or chest radiotherapy. Initial response rates are ≥70% however the majority of patients relapse and are resistant to additional therapies due to pan-resistance to these salvage therapies. Therefore, new treatments are urgently needed. The non-taxane microtubule inhibitor eribulin has produced responses in heavily pretreated breast cancer patients. We evaluated the efficacy of eribulin alone and in combination with radiation in a panel of SCLC cell lines established from patients prior to or after receiving chemotherapy and or radiation. Material and methods Growth inhibition by eribulin alone, radiation alone and the combination was assessed by MTS assay and clonogenic survival. Eribulin induced cell cycle arrest was evaluated by FACS. Apoptosis was evaluated by using the Caspase-GLO 3/7 luminescent plate assay and by the Vybrant apoptosis assay with analysis by FACS. Results Eribulin mesylate inhibited the growth of all 17-SCLC lines at concentrations of ≤10 nM which is a clinically achievable dose. Growth inhibition was not significantly different between cell lines established prior to or after chemotherapy (p = .5). Concurrent eribulin + radiation induced a greater G2-M arrest, an increase in apoptotic cells and increased growth inhibition over radiation alone. Conclusions Eribulin was highly active alone and in combination with radiation in treatment naïve SCLC lines and lines established from previously treated patients. In vivo pre-clinical studies of eribulin alone and in combination with radiation should be considered in SCLC cell lines.

In vitro radiosensitization by eribulin in human cancer cell lines

“…We found a significant increase in radioinduced cell death after combined treatment with eribulin plus irradiation as compared to radiation alone ranging from 17–32% and 18–35% for HeLa and FaDu cells, respectively. Our results are in accordance with those found in two prior publications [ 24 , 27 ]. Helfrich et al [ 24 ] reported an increase of cell growth inhibition up to 29% and 37% in irradiated H446 and H841 lung cancer cell lines pretreated with 0.625 nM eribulin, respectively, compared to those treated with radiation alone.…”

“…Our results are in accordance with those found in two prior publications [ 24 , 27 ]. Helfrich et al [ 24 ] reported an increase of cell growth inhibition up to 29% and 37% in irradiated H446 and H841 lung cancer cell lines pretreated with 0.625 nM eribulin, respectively, compared to those treated with radiation alone. Miki et al [ 27 ] also showed a remarkable increase of cell death after concurrent treatment with 0.1–5 nM eribulin and 8 Gy radiation in U87MG and U251MG glioblastoma cell lines.…”

“…Previous preclinical studies have shown a significant cytotoxic activity of eribulin in the nanomolar range in several tumour cell lines [ 3 , 24 – 26 ]. In this study, IC50 ranged from 1.58 nM to 0.7 nM after 24 h exposure time which is within the values reported in the literature [ 3 , 24 – 26 ].…”

“…Our results agree with those previously published regarding the radiosensitizing potential of eribulin. Helfrich et al [ 24 ] found a remarkable enhancement of radiation response by eribulin in small cell lung cancer cell lines; clonogenic survival of H841 cells was significantly decreased by the combination of 0.31 nM eribulin with 2–4 Gy radiation as compared to radiation or eribulin alone. Miki et al [ 27 ] also showed a reduction in clonogenic survival after concurrent treatment with eribulin and radiation in respect to radiation alone in U87MG glioblastoma cells.…”

TP53 Null Mutations Identify Lung Cancer Cell Lines with Highest Sensitivity to the Nontaxane Microtubule Inhibitor Eribulin

“…Helfrich et al (Helfrich et al, 2018) screened a panel of 17 SCLC cell lines for eribulin sensitivity and observed a much narrower range of IC 50 values (~15 fold) relative to that observed by the 5 SCLC cell lines tested in this study (~171 fold), although the sensitivity range in our study is largely driven by SHP77 and DMS53 cells which highly express ABCB1 transporter mRNA and are relatively resistant to the drug (Figs. 1B and 6).…”