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Int. J. Mol. Sci. 2015, 16(11), 26249-26262; doi:10.3390/ijms161125953

Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells

1
Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany
2
Biozentrum, Martin Luther Universität Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Terrence Piva
Received: 6 May 2015 / Revised: 8 October 2015 / Accepted: 15 October 2015 / Published: 3 November 2015
(This article belongs to the Collection Radiation Toxicity in Cells)
View Full-Text   |   Download PDF [1517 KB, uploaded 3 November 2015]   |  

Abstract

Betulinic acid (BA), a natural compound of birch bark, is cytotoxic for many tumors. Recently, a betulinyl sulfamate was described that inhibits carbonic anhydrases (CA), such as CAIX, an attractive target for tumor-selective therapy strategies in hypoxic cancer cells. Data on combined CAIX inhibition with radiotherapy are rare. In the human breast cancer cell lines MDA-MB231 and MCF7, the effects of BA and betulinyl sulfamates on cellular and radiobiological behavior under normoxia and hypoxia were evaluated. The two most effective betulinyl sulfamates CAI 1 and CAI 3 demonstrated a 1.8–2.8-fold higher cytotoxicity than BA under normoxia in breast cancer cells, with IC50 values between 11.1 and 18.1 µM. BA exhibits its strongest cytotoxicity with IC50 values of 8.2 and 16.4 µM under hypoxia. All three substances show a dose-dependent increase in apoptosis, inhibition of migration, and inhibition of hypoxia-induced gene expression. In combination with irradiation, betulinyl sulfamates act as radiosensitizers, with DMF10 values of 1.47 (CAI 1) and 1.75 (CAI 3) under hypoxia in MDA-MB231 cells. BA showed additive effects in combination with irradiation. Taken together; our results suggest that BA and betulinyl sulfamates seem to be attractive substances to combine with radiotherapy; particularly for hypoxic breast cancer. View Full-Text
Keywords: betulinic acid derivatives; carbonic anhydrase inhibitors; breast cancer; cytotoxicity; irradiation; normoxia; hypoxia betulinic acid derivatives; carbonic anhydrase inhibitors; breast cancer; cytotoxicity; irradiation; normoxia; hypoxia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Bache, M.; Münch, C.; Güttler, A.; Wichmann, H.; Theuerkorn, K.; Emmerich, D.; Paschke, R.; Vordermark, D. Betulinyl Sulfamates as Anticancer Agents and Radiosensitizers in Human Breast Cancer Cells. Int. J. Mol. Sci. 2015, 16, 26249-26262.

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