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

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.

Costunolide induces G1/S phase arrest and activates mitochondrial-mediated apoptotic pathways in SK-MES 1 human lung squamous carcinoma cells

“…Sesquiterpene lactones are phytochemicals derived from Chinese medicinal herbs, and have been demonstrated previously to have anti-neoplastic and anti-inflammatory activities (8). Costunolide is a well-known sesquiterpene lactone and a number of previous studies have shown that it has a broad spectrum of cytotoxicity against human cancer cell lines of different origins (6,18,(20)(21)(22)26,27).…”

Sesquiterpene lactones derived from Saussurea lappa induce apoptosis and inhibit invasion and migration in neuroblastoma cells

“…Costunolide has been shown to inhibit capillary-like tube formation in TR-LE cells (9). Moreover, these compounds have been shown to induce cell cycle arrest (10,13,18,27) in cancer cell lines; the phase of cell cycle arrest differed among the cell lines. Taken together, sesquiterpene lactones derived from S. lappa have anticancer effects against neuroblastoma cells via multiple mechanisms.…”

Dehydrocostus lactone inhibits in vitro gastrinoma cancer cell growth through apoptosis induction, sub-G1 cell cycle arrest, DNA damage and loss of mitochondrial membrane potential

“…Dehydrocostus lactone caused sub-G1 cell cycle arrest, as evident from the increased number of sub-G1 cells in the treated cells. A previous study reported that a similar type of compound causes G2/M cell cycle arrest [17,18]. Moreover, the current study used a different and rare cancer cell line, viz.…”