Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells

Hayasaka, Naotaka; Takada, Kohichi; Nakamura, Hajime; Arihara, Yohei; Kawano, Yutaka; Osuga, Takahiro; Murase, Kazuyuki; Kikuchi, Shohei; Iyama, Satoshi; Emori, Makoto; Sugita, Shintaro; Hasegawa, Tadashi; Takasawa, Akira; Miyanishi, Koji; Kobune, Masayoshi; Kato, Junji

doi:10.1038/s41598-019-42300-z

Cited by 19 publications

(14 citation statements)

References 35 publications

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“…An effect on cell growth in cell lines corresponding to LMS (SK-L-MS1) and FS (HT1080) has also been observed. Similarly, in our study eribulin also produced an inhibitory effect on cell growth in LPS, LMS and FS cell lines [30][31][32].…”

Section: Discussionsupporting

confidence: 83%

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Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: Could the combination with other drugs improve its antitumoral effect?

Escudero

Heredia-Soto

Wang

et al. 2021

Preprint

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Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D spheroid) cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest for the first time a synergistic effect with ifosfamide in all models and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

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Section: Discussionsupporting

confidence: 83%

“…Few combinations have been previously explored in STS cell line models [32,39]. Regarding eribulin combinations, a recent study was published suggesting activity with an AKT inhibitor (MK-2206) in FS and LMS cell lines [31].…”

Section: Discussionmentioning

confidence: 99%

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: Could the combination with other drugs improve its antitumoral effect?

Escudero

Heredia-Soto

Wang

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Few combinations have been previously explored in STS cell line models [ 32 , 43 ]. Regarding eribulin combinations, a recent study was published suggesting activity with an AKT inhibitor (MK-2206) in FS and LMS cell lines [ 31 ].…”

Section: Discussionmentioning

confidence: 99%

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

Escudero¹,

Heredia-Soto²,

Wang³

et al. 2021

Cancer Cell Int

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Background Eribulin has shown antitumour activity in some soft tissue sarcomas (STSs), but it has only been approved for advanced liposarcoma (LPS). Methods In this study, we evaluated the effect of eribulin on proliferation, migration and invasion capabilities in LPS, leiomyosarcoma (LMS) and fibrosarcoma (FS) models, using both monolayer (2D) and three-dimensional (3D) spheroid cell cultures. Additionally, we explored combinations of eribulin with other drugs commonly used in the treatment of STS with the aim of increasing its antitumour activity. Results Eribulin showed activity inhibiting proliferation, 2D and 3D migration and invasion in most of the cell line models. Furthermore, we provide data that suggest, for the first time, a synergistic effect with ifosfamide in all models, and with pazopanib in LMS as well as in myxoid and pleomorphic LPS. Conclusions Our results support the effect of eribulin on LPS, LMS and FS cell line models. The combination of eribulin with ifosfamide or pazopanib has shown in vitro synergy, which warrants further clinical research.

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“…MK-2206, an allosteric AKT inhibitor, binds to the AKT protein in the pleckstrin homology domain resulting in a conformational change of AKT that inhibits the AKT activation by preventing its localization to the plasma membrane (Lindsley et al, 2007). As an anticancer drug, MK-2206 has been proved to be effective both in adult tumors (Djuzenova et al, 2019;Hayasaka et al, 2019) and in a spectrum of pediatric tumors (Gorlick et al, 2012). Phase I studies showed that an oral dose of MK-2206 ranging from 0.25 to 100 mg was well-tolerated (Trucksis et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

et al. 2020

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Neuroblastoma (NB) is the most common pediatric malignant extracranial solid tumor. Despite multi-modality therapies, the emergence of drug resistance is an obstacle in the treatment of high-risk NB patients (with MYCN amplification). In our previous study, we found that rapamycin and MK-2206 synergistically induced cell death in MYCN-amplified cell lines but the mechanisms remained unclear. In our present study, either 3-MA or necroatatin-1 blocked the cell death induced by rapamycin and MK-2206, but z-VAD-fmk did not block this cell death. The expressions of autophagy markers (ATG5, ATG7, Beclin-1, LC3 B) and the necroptosis marker RIPK3 increased and another necroptosis marker RIPK1 decreased after the combination treatment of rapamycin and MK-2206, and were accompanied by the morphological characteristics of autophagy and necroptosis. In NB xenograft tumor tissues, the expressions of autophagy and necroptosis markers were consistent with observations in vitro. These data suggested that autophagy and necroptosis contributed to the cell death induced by rapamycin and MK-2206 in NB cells. To understand the role of MYCN in this process, MYCN expression was downregulated in MYCN-amplified cell lines (NGP, BE2) using siRNAs and was upregulated in MYCN non-amplified cell lines (AS, SY5Y) using plasmid. We found the cell death induced by rapamycin and MK-2206 was MYCN-dependent. We also found that the metabolic activity in NB cells was correlated with the expression level of MYCN. This study delineates the role of MYCN in the cell death induced by combination treatment of rapamycin and MK-2206 in MYCN-amplified NB cells.

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Combination of eribulin plus AKT inhibitor evokes synergistic cytotoxicity in soft tissue sarcoma cells

Cited by 19 publications

References 35 publications

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: Could the combination with other drugs improve its antitumoral effect?

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: Could the combination with other drugs improve its antitumoral effect?

Eribulin activity in soft tissue sarcoma monolayer and three-dimensional cell line models: could the combination with other drugs improve its antitumoral effect?

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

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