Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling.
Sho NakaiHironari TamiyaYoshinori ImuraTakaaki NakaiNaohiro YasudaToru WakamatsuTakaaki TanakaHidetatsu OutaniSatoshi TakenakaKenichiro HamadaAkira MyouiNobuhito ArakiTakafumi UedaHideki YoshikawaNorifumi NakaPublished in: Molecular cancer therapeutics (2019)
Clear cell sarcoma (CCS) is a rare but chemotherapy-resistant and often fatal high-grade soft-tissue sarcoma (STS) characterized by melanocytic differentiation under control of microphthalmia-associated transcription factor (MITF). Eribulin mesilate (eribulin) is a mechanistically unique microtubule inhibitor commonly used for STS treatment, particularly liposarcoma and leiomyosarcoma. In this study, we examined the antitumor efficacy of eribulin on four human CCS cell lines and two mouse xenograft models. Eribulin inhibited CCS cell proliferation by inducing cell-cycle arrest and apoptosis, shrunk CCS xenograft tumors, and increased tumor vessel density. Eribulin induced MITF protein upregulation and stimulated tumor cell melanocytic differentiation through ERK1/2 inactivation (a MITF negative regulator) in vitro and in vivo Moreover, tumor reoxygenation, probably caused by eribulin-induced vascular remodeling, attenuated cell growth and inhibited ERK1/2 activity, thereby upregulating MITF expression and promoting melanocytic differentiation. Finally, downregulation of MITF protein levels modestly debilitated the antiproliferative effect of eribulin on CCS cells. Taken together, eribulin suppresses CCS through inhibition of cell proliferation and promotion of tumor differentiation by acting both directly on tumor cells and indirectly through tumor reoxygenation.
Keyphrases
- metastatic breast cancer
- cell proliferation
- cell cycle arrest
- pi k akt
- signaling pathway
- phase ii
- induced apoptosis
- transcription factor
- cell death
- high grade
- cell cycle
- poor prognosis
- clear cell
- endothelial cells
- high glucose
- binding protein
- diabetic rats
- open label
- squamous cell carcinoma
- protein protein
- small molecule
- bone marrow
- drug induced
- amino acid
- low grade
- phase iii
- rectal cancer