期刊
ARCHIV DER PHARMAZIE
卷 352, 期 5, 页码 -出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/ardp.201800315
关键词
analogue; calcitriol; cancer; oxolane; vitamin D receptor
资金
- Fondo para la Investigacion Cientifica y Tecnologica [PICT 2012-0966]
- CITACA Strategic Partnership [ED431E 2018/07]
- Xunta de Galicia [ED431C2017/70]
- Secretaria de Ciencia y Tecnica de la Universidad Nacional del Sur
- Consejo Nacional de Investigaciones Cientificas y Tecnicas [PIP PIP 112-201101-00556]
- National Council of Scientific and Technical Research (CONICET)
- National Agency for Scientific and Technological Promotion [PICT 2012-1595]
- Universidad Nacional del Sur
The active form of vitamin D-3, calcitriol, is a potent antiproliferative compound. However, when effective antitumor doses of calcitriol are used, hypercalcemic effects are observed, thus blocking its therapeutic application. To overcome this problem, structural analogues have been designed with the aim of retaining or even increasing the antitumor effects while decreasing its calcemic activity. This report aims at gaining insights into the structure-activity relationships of the novel oxolane-containing analogue, AM-27, recently synthesized. We herein demonstrate that this compound has antiproliferative and antimigratory effects in squamous cell carcinoma, glioblastoma, and breast cancer cell lines. Analyses of the mechanisms underlying the AM-27 effects on cell viability revealed induction of apoptosis by the analogue. Importantly, nonmalignant cell lines were little or not affected by the compound. In addition, the analogue did not produce hypercalcemia in mice. Also, in silico studies involving docking and molecular dynamics techniques showed that AM-27 is able to bind to the human vitamin D receptor with a higher affinity than the natural ligand calcitriol, a feature that is mostly derived from an electrostatic interaction pattern. Altogether, the proapoptotic effect observed in cancer cells, the lack of calcemic activity in mice, and the differential effects in normal cells suggest the potential of AM-27 as a therapeutic compound for cancer treatment.
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