Planta Med 2012; 78(16): 1749-1756
DOI: 10.1055/s-0032-1315385
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Effect of Costunolide and Dehydrocostus Lactone on Cell Cycle, Apoptosis, and ABC Transporter Expression in Human Soft Tissue Sarcoma Cells

Nadine Kretschmer
1   Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens-University, Graz, Austria
,
Beate Rinner
2   Center for Medical Research, Medical University of Graz, Graz, Austria
,
Nicole Stuendl
3   Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria
,
Heike Kaltenegger
3   Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria
,
Elisabeth Wolf
3   Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria
,
Olaf Kunert
4   Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Karl-Franzens-University, Graz, Austria
,
Herbert Boechzelt
5   Department of Plant Materials Sciences and Utilisation, Joanneum Research Forschungsgesellschaft mbH, Graz, Austria
,
Andreas Leithner
3   Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria
,
Rudolf Bauer
1   Institute of Pharmaceutical Sciences, Department of Pharmacognosy, Karl-Franzens-University, Graz, Austria
,
Birgit Lohberger
3   Department of Orthopaedic Surgery, Medical University of Graz, Graz, Austria
› Author Affiliations
Further Information

Publication History

received 21 February 2012
revised 13 August 2012

accepted 22 August 2012

Publication Date:
09 October 2012 (online)

Abstract

Human soft tissue sarcomas represent a rare group of malignant tumours that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment. In this study, we investigated the effects of costunolide and dehydrocostus lactone, which have been isolated from Saussurea lappa using activity-guided isolation, on three soft tissue sarcoma cell lines of various origins. The effects on cell proliferation, cell cycle distribution, apoptosis induction, and ABC transporter expression were analysed.

Both compounds inhibited cell viability dose- and time-dependently. IC50 values ranged from 6.2 µg/mL to 9.8 µg/mL. Cells treated with costunolide showed no changes in cell cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 h. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction. In addition, the influence of costunolide and dehydrocostus lactone on the expression of ATP binding cassette transporters related to multidrug resistance (ABCB1/MDR1, ABCC1/MRP1, and ABCG2/BCRP1) was examined using real-time RT-PCR. The expressions of ABCB1/MDR1 and ABCG2/BCRP1 in liposarcoma and synovial sarcoma cells were significantly downregulated by dehydrocostus lactone.

Our data demonstrate for the first time that dehydrocostus lactone affects cell viability, cell cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumours.

 
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