Selective Antitumor Activity of Datelliptium toward Medullary Thyroid Carcinoma by Downregulating RET Transcriptional Activity

Abstract

Medullary thyroid carcinoma (MTC) is a rare aggressive form of thyroid cancer with high rates of metastasis. Sporadic and hereditary MTC are strongly driven by somatic and germline mutations, respectively, in the transmembrane REarranged during Transfection (RET) proto-oncogene, which encodes a receptor tyrosine kinase. Our previous study identified datelliptium as a novel RET transcription inhibitor, which stabilizes the RET G-quadruplex structures and suppresses RET oncogene transcription. The present study aimed to elucidate the effect of datelliptium on the suppression of epithelial-to-mesenchymal transition (EMT) and metastasis-related behaviors of MTC cells, including cell migration and formation of cancer stem cells (CSCs). Our results demonstrated that datelliptium downregulated the expression of the mesenchymal markers, including N-cadherin, vimentin, slug, snail, and claudin-1. Compared to untreated cells, datelliptium significantly decreased the migration of TT cells in a dose-dependent manner in a wound healing assay. Additionally, datelliptium significantly reduced the size of preformed spheroids from TT cells over the time course. Finally, datelliptium inhibited approximately 75% of MTC xenograft growth with minimal systemic toxicity. In conclusion, datelliptium exerts its antitumor activity against MTC cells by reducing the EMT program, migratory ability, and self-renewal capacity of TT cells, thus preventing invasive and metastatic behavior of MTC.

Adefovir Dipivoxil as a Therapeutic Candidate for Medullary Thyroid Carcinoma: Targeting RET and STAT3 Proto-Oncogenes

“…We investigated the influence of adefovir dipivoxil on the three dimensions of growth of TT spheroids in non-adherent, serum-free culture conditions. Adefovir dipivoxil notably diminished the spheroid size over time, with cell death progressing from the periphery inwards to the spheroid core [ 51 ] ( Figure 11 ).…”

“…Although MZ-CRC1, an MTC cell line with the M918T mutation, appears to be more resistant to adefovir dipivoxil treatment compared to TT cells carrying the C634W mutation ( Figure S1 ), it can be hypothesized that specific genes might be highly overexpressed in the RET M918T mutant but not in the C634W mutant. This overexpression could contribute to the increased resistance of MZ-CRC1 to the treatment [ 11 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Notably, we also found that normal thyroid cells, Nthy-ori-3-1, and hepatocytes cell lines showed significant resistance to adefovir dipivoxil, indicating that this compound is more selective for MTC.…”

Microwave-assisted Cu(i)-catalyzed one-pot tandem synthesis of pyridoimidazole-fused quinolines as new antimycobacterial agents: DFT and ESI-HRMS study

“…The imidazo[1,2-a]pyridine moiety coupled with a quinoline framework has attracted a great deal of interest recently in medicinal chemistry because it has structural similarity to antiproliferative compounds such as Ellipticine and Datelliptium. 23,24 It is therefore important to develop new methods of synthesis of imidazopyridines coupled quinolines. Pyrido[2 0 ,1 0 :2,3]imidazo [4,5-c]quinoline has been synthesized using a variety of approaches (Scheme 1).…”