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Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic

Sho Nakai1, Hironari Tamiya2, Yoshinori Imura2

  • 1Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Molecular Cancer Therapeutics
|December 5, 2019
PubMed

Insights

Eribulin effectively treats clear cell sarcoma (CCS) by inhibiting cancer cell growth and promoting differentiation. This microtubule inhibitor works directly on tumor cells and indirectly via tumor reoxygenation, offering a new therapeutic avenue for this rare soft-tissue sarcoma.

Area of Science:

  • Oncology
  • Pharmacology
  • Cell Biology

Background:

  • Clear cell sarcoma (CCS) is a rare, aggressive soft-tissue sarcoma (STS) with poor prognosis and chemotherapy resistance.
  • Microphthalmia-associated transcription factor (MITF) regulates melanocytic differentiation in CCS.
  • Eribulin mesilate (eribulin) is a microtubule inhibitor used for STS, but its efficacy in CCS is not well-established.

Purpose of the Study:

  • To investigate the antitumor efficacy of eribulin in human clear cell sarcoma (CCS) cell lines and xenograft models.
  • To elucidate the mechanisms underlying eribulin's action in CCS, including its effects on cell proliferation, differentiation, and the MITF pathway.

Main Methods:

  • Treatment of four human CCS cell lines and two mouse xenograft models with eribulin.
  • Assessment of cell proliferation, cell-cycle arrest, apoptosis, and melanocytic differentiation markers.
  • Analysis of MITF protein levels and ERK1/2 pathway activity.
  • Evaluation of tumor volume, vessel density, and tumor reoxygenation in xenograft models.

Main Results:

  • Eribulin inhibited CCS cell proliferation, induced cell-cycle arrest and apoptosis, and reduced tumor volume in xenografts.
  • Eribulin treatment led to MITF protein upregulation and promoted melanocytic differentiation via ERK1/2 inactivation.
  • Tumor reoxygenation, potentially due to eribulin-induced vascular remodeling, further enhanced MITF expression and differentiation.
  • Downregulation of MITF partially reduced eribulin's antiproliferative effect.

Conclusions:

  • Eribulin demonstrates significant antitumor activity against clear cell sarcoma (CCS) through direct antiproliferative and differentiation-promoting effects.
  • The drug's efficacy is mediated, in part, by MITF upregulation and subsequent melanocytic differentiation.
  • Indirect mechanisms involving tumor reoxygenation contribute to eribulin's therapeutic action in CCS.
  • Eribulin represents a promising therapeutic agent for clear cell sarcoma, acting via combined direct and indirect pathways.

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