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

International Journal of Molecular Sciences

Matthias Bache¹  Christin Münch¹  Antje Güttler¹  Henri Wichmann¹  Katharina Theuerkorn¹  Daniel Emmerich²  Reinhard Paschke²  Dirk Vordermark¹ 

[1] Department of Radiotherapy, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, D-06120 Halle, Germany;Biozentrum, Martin Luther Universität Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany;

关键词: betulinic acid derivatives;    carbonic anhydrase inhibitors;    breast cancer;    cytotoxicity;    irradiation;    normoxia;    hypoxia;   

DOI  :  10.3390/ijms161125953

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.