| Autor: |
Hastings RH; VA San Diego Healthcare System, CA, USA. rhhastings@ucsd.edu, Burton DW, Nefzi A, Montgrain PR, Quintana R, Deftos LJ |
| Jazyk: |
angličtina |
| Zdroj: |
Cancer biology & therapy [Cancer Biol Ther] 2010 Nov 15; Vol. 10 (10), pp. 1067-75. Date of Electronic Publication: 2010 Nov 15. |
| DOI: |
10.4161/cbt.10.10.13374 |
| Abstrakt: |
PTHrP (parathyroid hormone-related protein) is abnormally expressed in a substantial majority of lung cancers, especially non-small cell lung cancers, and plays a key role in tumor progression. Thus, this oncoprotein could be a target for treating patients with lung cancer. This study screened combinatorial libraries of heterocyclic amines for inhibitory effects on PTHrP expression and cell proliferation. Two libraries of over 780,000 bis-cyclic thiourea and guanidine compounds each were tested in BEN lung carcinoma cells. The number of PTHrP inhibitors and the magnitude of the reduction in PTHrP were greater for thioureas. Selected lead thiourea compounds decreased cell PTHrP protein content in dose-dependent fashion, reduced relative abundance of PTHrP mRNA, decreased transcripts derived from the PTHrP P3 promoter and reduced activity of a full length PTHrP promoter luciferase construct. Similar effects on PTHrP mRNA were observed in A549 and H441 lung adenocarcinoma cells and in H727 lung carcinoid cells. However, the compounds only inhibited PTHrP protein levels in BEN cells and H727 cells. The compounds reduced the rate of cell proliferation in BEN cells and H727 cells, but not in lines that showed no inhibition of PTHrP protein. These results suggest that cyclic thiourea compounds inhibit PTHrP expression mediated by the P3 promoter, which is widely used in the majority of PTHrP-expressing cells, and that they may inhibit growth of lung cancer cells through the same mechanism. Further work will be necessary to investigate their mechanism for effects on growth of PTHrP-positive tumors in vivo. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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