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Mar. Drugs 2013, 11(11), 4570-4584; doi:10.3390/md11114570

Ophiobolin-O Reverses Adriamycin Resistance via Cell Cycle Arrest and Apoptosis Sensitization in Adriamycin-Resistant Human Breast Carcinoma (MCF-7/ADR) Cells

2,*  and 1,*
1 Department of Biochemistry and Molecular Biology, College of Basic Medical, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China 2 The Key Laboratory of Marine Drugs, Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China 3 Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China These authors contributed equally to this work.
* Authors to whom correspondence should be addressed.
Received: 30 August 2013 / Revised: 20 October 2013 / Accepted: 24 October 2013 / Published: 14 November 2013
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Multidrug-resistance is a major obstacle facing cancer chemotherapy. This paper demonstrates that novel compound Ophiobolin-O reverses MCF-7/ADR resistance to adriamycin (ADM). The IC50 of ADM treated MCF-7 cells was 2.02 ± 0.05 µM and 74.00 ± 0.18 µM treated MCF-7/ADR cells, about 37-fold, compared to the former. However, 0.1 µM Ophiobolin-O (less than 20% inhibition concentration) combined with ADM caused the decreased IC50 of ADM to 6.67 ± 0.98 µM, indicating it reversed ADM resistance of MCF-7/ADR cells (11-fold). Furthermore, Ophiobolin-O increased ADM-induced mitochondrial pathway apoptosis and G2/M phase arrest, which is partly due to the elevation level of ROS in MCF-7/ADR cells. As we described in this paper, the reversal effect of Ophiobolin-O may be due to the reduction of resistance-related protein P-Glycoprotein (P-gp, also known as MDR1) through inhibiting the activity of the multidrug resistance 1 (MDR1) gene promoter, which makes MCF-7/ADR cells more sensitive to ADM treatment. Assays in nude mice also showed that the combination of ADM and Ophiobolin-O significantly improved the effect of ADM.
Keywords: Ophiobolin-O; adriamycin (ADM); drug resistance reversal Ophiobolin-O; adriamycin (ADM); drug resistance reversal
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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Sun, W.; Lv, C.; Zhu, T.; Yang, X.; Wei, S.; Sun, J.; Hong, K.; Zhu, W.; Huang, C. Ophiobolin-O Reverses Adriamycin Resistance via Cell Cycle Arrest and Apoptosis Sensitization in Adriamycin-Resistant Human Breast Carcinoma (MCF-7/ADR) Cells. Mar. Drugs 2013, 11, 4570-4584.

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