Costunolide and dehydrocostuslactone combination treatment inhibit breast cancer by inducing cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 pathway

Abstract

Our previous studies demonstrated that volatile oil from saussurea lappa root (VOSL), rich in two natural sesquiterpene lactones, costunolide (Cos) and dehydrocostuslactone (Dehy), exerts better anti-breast cancer efficacy and lower side effects than Cos or Dehy alone in vivo, however, their anti-cancer molecular mechanisms were still unknown. In this study, we investigated the underlying mechanisms of Cos and Dehy combination treatment (CD) on breast cancer cells through proteomics technology coupled with Western blot validation. Ingenuity Pathways Analysis (IPA) results based on the differentially expressed proteins revealed that both VOSL and CD affect the 14-3-3-mediated signaling, c-Myc mediated apoptosis signaling and protein kinase A (PKA) signaling. Western blot coupled with cell cycle and apoptosis analysis validated the results of proteomics analysis. Cell cycle arrest and apoptosis were induced in a dose-dependent manner, and the expressions of p53 and p-14-3-3 were significantly up-regulated, whereas the expressions of c-Myc, p-AKT, p-BID were significantly down-regulated, furthermore, the ratio of BAX/BCL-2 were significantly increased in breast cancer cells after CD and VOSL treatment. The findings indicated that VOSL and CD could induce breast cancer cell cycle arrest and apoptosis through c-Myc/p53 and AKT/14-3-3 signaling pathways and may be novel effective candidates for breast cancer treatment.

Dehydrocostus Lactone Enhances Chemotherapeutic Potential of Doxorubicin in Lung Cancer by Inducing Cell Death and Limiting Metastasis

“…DHC was found to induce mitochondrial intrinsic apoptosis with enhanced pro-apoptotic effects of DOX in both cell lines. DHC was shown to induce apoptosis in liver [ 9 , 10 ], breast [ 11 , 12 ], leukemia [ 13 ], prostate [ 14 ], ovary [ 15 ], colon [ 16 ], and bladder cancer [ 17 ]. DHC caused reduction in HIF-1α levels in A549 and H460 cells followed by suppression of the levels of Akt and pAkt, GSK-3β and pGSK-3β, and mTOR and p-mTOR.…”

“…Dehydrocostus lactone (DHC) is a sesquiterpene lactone isolated from Chinese herbs like Saussurea lappa and Laurus nobilis . DHC has been used to treat various diseases, including prevention of various types of cancers, such as liver cancer [ 9 , 10 ], breast cancer [ 11 , 12 ], leukemias [ 13 ], prostatic cancer [ 14 ], ovarian cancer [ 15 ], colorectal cancer [ 16 ], and bladder cancer [ 17 ]. DHC mediates anti-cancer effects by interacting mechanisms like inhibition of telomerase activity, induction of cellular apoptosis pathways (mitochondrial intrinsic and death-receptor dependent extrinsic), induced endoplasmic reticulum (ER) stress [ 18 ], and limiting migration-invasion and metastasis [ 8 , 16 , 19 ].…”

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“…Due to various biotic and therapeutic applications of active ingredients, herbal medicine is gaining importance these days and is foundation for revolution in drug discovery. Bioactive agents obtained from various herbal drugs are irreplaceable in the management of many intractable diseases and one such drug is Saussurea lappa (Qust), one of the best-known species of Asteraceae family, is a tall perennial herb possessing antihepatitis B [1,2] antioxidant [3,4] hepatoprotective [5] and anticancerous [6,7] activity. Morphologically its stem is stout and fibrous, root is long, firm with characteristics odor, leaves are lobate and stalked, flowers are dark purple, stalkless and are arranged at periphery.…”

Costunolide promotes imatinib‐induced apoptosis in chronic myeloid leukemia cells via the Bcr/Abl–Stat5 pathway

“…Costunolide, a sesquiterpene lactone isolated from the roots of Inula helenium L , exerts a wide spectrum of biological effects, including antimicrobial, anti‐inflammatory, and anti‐proliferative effects, on several cancer cell lines (Y. K. Choi et al, ; Peng et al, ). Many previous studies have reported that costunolide can inhibit cancer cell growth by inducing caspase‐dependent apoptosis and/or cell cycle arrest (Butturini et al, ; J. H. Choi & Lee, ).…”

“…Costunolide, a sesquiterpene lactone isolated from the roots of Inula helenium L, exerts a wide spectrum of biological effects, including antimicrobial, anti-inflammatory, and anti-proliferative effects, on Abbreviations: BCA, bicinchoninic acid; RIPA, radio immunoprecipitation assay; RPMI, roswell park memorial institute; PVDF, polyvinylidene fluoride; SDS, sodium dodecyl sulfate; V-FITC, V-fluorescein isothiocyanate † Hong Cai and Xiaolin He contributed equally to this work. several cancer cell lines (Y. K. Choi et al, 2012;Peng et al, 2017).…”