Dehydrocostuslactone disrupts signal transducers and activators of transcription 3 through up-regulation of suppressor of cytokine signaling in breast cancer cells

Abstract

This study investigates the anticancer effect of dehydrocostuslactone (DHE), a plant-derived sesquiterpene lactone, on human breast cancer cells. DHE inhibits cell proliferation by inducing cells to undergo cell cycle arrest and apoptosis. DHE suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G 0 /G 1 -S phase arrest in MCF-7 cells. In contrast, DHE caused S-G 2 /M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. DHE induces up-regulation of Bax and Bad, down-regulation of Bcl-2 and Bcl-XL, and nuclear relocation of the mitochondrial factors apoptosis-inducing factor and endonuclease G. We also found that DHE inhibits survival signaling through the Janus tyrosine kinase-signal transducer and activator of transcription-3 signaling by increasing the expression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell cycle progression and cell death through SOCS-1 and SOCS-3. Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer.

Evaluation of anticancer activity of dehydrocostuslactone in vitro

“…under the same conditions, exposure to dehydrocostuslactone resulted in significant apoptosis in all the cell lines examined. This is consistent with reports that dehydrocostuslactone is an effective anticancer agent capable of inducing apoptosis (14)(15)(16)(17). apoptosis is an important series of events that lead to programmed cell death, and is essential for development and tissue homeostasis.…”

“…a similar pattern was observed for breast cancer cells, although the effect was weaker than that observed in the ovarian cancer cells (~1.3 to 2.3-fold increase compared to the respective controls). dehydrocostuslactone has been shown to induce cell cycle arrest at the G2/M phase in several cancer cell lines in vitro (14,15). This is consistent with our results, which indicated that exposure to dehydrocostuslactone induces significant cell cycle arrest.…”

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

“…Costunolide and dehydrocostus lactone, major sesquiterpene lactones derived from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 S. lappa, are reported to induce cell death in some cancer cells (9e11). Dehydrocostus lactone has been shown to induce apoptosis in lung cancer (12), breast cancer (13), hepatocellular carcinoma (14), prostate cancer (15) and leukemia (16). Costunolide has also been shown to induce apoptosis in bladder cancer (17), breast cancer (18), ovarian cancer (19), and leukemia (20,21).…”

Hepatoprotective Effect of Costus Roots Extract against Carbon Tetrachloride (CCl4)-Induced Liver Injury in Guinea Pigs

“…Saussurea costus is considered to be one of the antioxidant-rich medicinal plants. Many authors have reported that the roots of this plant possess various biological activities, including cortisol lowering effect [38], anti-infammatory [39,40], anticancer [41,42], antiviral [23], antimicrobial [43,44], antifungal [15], antioxidant [45,46], antidiabetic [47], antiulcer [20] and hepatoprotective effects [38]. Liv-52 is widely used in treatment of liver diseases of varying origins.…”