Pharmacological effects of vinorelbine in combination with lenvatinib in anaplastic thyroid cancer

Abstract

Anaplastic thyroid cancer (ATC) is a rare neoplasia with a poor prognosis. Proliferation and apoptosis assays were performed on ATC cell lines (8305C, 8505C) exposed to vinorelbine, lenvatinib, as well as to concomitant combinations. ABCB1, ABCG2 and CSF-1 mRNA expression was evaluated by real time PCR. The relative levels of pospho Akt were investigated as part of a human phospho-kinase array analysis, and CSF-1 and VEGFR-2 protein levels were measured by ELISA. The intracellular concentration of lenvatinib in ATC cells was measured by combined reversed-phase liquid chromatography-tandem mass spectrometry. An ATC subcutaneous xenograft tumor model in nude mice was treated with vinorelbine, lenvatinib, or vinorelbine plus lenvatinib. After treatment with vinorelbine, lenvatinib, a significant antiproliferative effect in ATC cell lines was observed. The concomitant treatment of vinorelbine and lenvatinib revealed synergism for all the fractions of affected cells. A decrease in ABCB1 expression was reported in both ATC cell lines treated with the lenvatinib plus vinorelbine combination, as was an increase in the intracellular concentration of lenvatinib. The combination caused a decrease in Akt, GSK3α/β, PRAS40 and Src phosphorylation, and in both CSF-1 mRNA and protein levels. In the subcutaneous tumor model, the combination reduced the tumor volume during the treatment period. Our results establish the synergistic ATC antitumor activity of a vinorelbine and lenvatinib combination.

Keywords: Anaplastic thyroid cancer; Lenvatinib; Lenvatinib - IUPAC name: 4-[3-chloro-4-(cyclopropylcarbamoylamino)phenoxy]-7-methoxyquinoline-6-carboxamide - PubChem CID: 9823820; Sorafenib; Synergism; Vinorelbine; Vinorelbine - IUPAC namemethyl (1R, 9R, 10S, 11R, 12R, 19R)-11-acetyloxy-12-ethyl-4-[(12S, 14R,)-16-ethyl-12-methoxycarbonyl-1, 10-diazatetracyclo[12.3.1.0, (3), (11).0, (4), (9),]octadeca-3(11), 4, 6, 8, 15-pentaen-12-yl]-10-hydroxy-5-methoxy-8-methyl-8, 16-diazapentacyclo[10.6.1.0, (1), (9).0, (2), (7).0, (16), (19),]nonadeca-2, 4, 6, 13-tetraene-10-carboxylate- PubChem CID 5311497.