Metabolic transformation of breast cancer in a MCF-7 xenograft mouse model and inhibitory effect of volatile oil from Saussurea lappa Decne treatment

Abstract

Breast cancer results from multi-step carcinogenesis, and the transforming process from normal to malignant cells is associated with profound metabolic disturbances. The metabolic transformation due to interplay between tumor and host during the development of breast cancer and its implications for breast cancer therapy have not been extensively investigated. Here, we report a metabonomic study on MCF-7 xenograft mice to delineate characteristic metabolic transformation during the development of breast cancer using a comprehensive twodimensional gas chromatography-time-of-flight mass spectrometry (GC9GC-TOF/MS) and an ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry. Volatile oil extracted from Saussurea lappa Decne (VOSL), and Costunolide and Dehydrocostus lactone (Cos-Dehy), isolated from VOSL, were used to treat the MCF-7 xenograft mice to evaluate their efficiency and to investigate their pharmacological mechanism on inhibiting the growth of tumor. The dynamic changes of serum and urine metabolic profiles indicated that both VOSL and Cos-Dehy were able to attenuate metabolic perturbation MCF-7 xenograft mice, which is consistent with their efficiency that VOSL and Cos-Dehy significantly inhibit the growth of MCF-7 xenograft tumor.Significant alterations of key metabolic pathways, including elevated glycolysis and steroid hormone metabolism, and decreased unsaturated fatty acids metabolism, were observed in MCF-7 xenograft mice, which were attenuated or normalized by VOSL and Cos-Dehy treatment. Arachidonate, docosahexaenoic acid, eicosapentaenoic acid, linoleate, dihomo-c-linolenate, 20a-hydroxyprogesterone, and cortisone were selected as a panel of candidate pathological biomarkers of MCF-7 xenografts, which may be further developed to be valuable diagnostic markers for the early detection of breast cancer.

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

“…3C). These results are consistent with our previous report that is VOSL or CD treatment was able to attenuate the metabolic perturbation in energy metabolism, lipid metabolism, glycolysis, and tyrosine metabolism of MCF-7 xenograft mice3.…”

“…Our previous study demonstrated that VOSL and its main active ingredients can suppress the growth of estrogen receptor positive breast cancer MCF-7 xenografts3. In this study, we used the estrogen receptor negative breast cancer MDA-MB-231 xenograft model to evaluate further the anti-breast cancer efficiency of VOSL in vivo .…”

“…of which, the anti-cancer activities and associated molecular mechanisms of Cos or Dehy have been reported in recent years, including inhibiting cancer cell proliferation6, accelerating apoptosis7, inducing cancer cell differentiation8, inhibiting metastasis and invasion9, reversing multidrug resistance10, restraining angiogenesis11. Our previous studies had demonstrated that VOSL has better anti-breast cancer efficacy and lower side effects than Cos or Dehy in vivo 3, however, to the best of our knowledge, the synergistic anti-cancer molecular mechanism of Cos and Dehy (CD) in VOSL has not yet been studied.…”

“…Dried 4- to 5-year-old roots of Saussurea lappa , known as Mu-xiang, are commonly used as medicine to treat breast cancer and breast hyperplasia in China, Japan and India2. Our previous study demonstrated that volatile oil from Saussurea lappa root (VOSL), sesquiterpene lactones-rich fraction, is responsible for the anti-breast cancer activity of Mu-xiang3. Gas chromatography-mass spectrometer (GC-MS) and liquid chromatography-mass spectrometer (LC-MS) analyses revealed that Costunolide (Cos) and Dehydrocostuslactone (Dehy), two natural sesquiterpene lactones, are the main ingredients of VOSL.…”

“…Gas chromatography-mass spectrometer (GC-MS) and liquid chromatography-mass spectrometer (LC-MS) analyses revealed that Costunolide (Cos) and Dehydrocostuslactone (Dehy), two natural sesquiterpene lactones, are the main ingredients of VOSL. Moreover, the combination treatment of Cos and Dehy (CD) showed synergistic anti-breast cancer efficiency both in vitro and in vivo 34.…”