Plasma metabolomic profiles of breast cancer patients after short-term limonene intervention.
Limonene is a lipophilic monoterpene found in high levels in citrus peel. Limonene demonstrates anticancer properties in preclinical models with effects on multiple cellular targets at varying potency. While of interest as a cancer chemopreventive, the biologic activity of limonene in humans is poorly understood. We conducted metabolite profiling in 39 paired (pre/postintervention) plasma samples from early-stage breast cancer patients receiving limonene treatment (2 g QD) before surgical resection of their tumor. Metabolite profiling was conducted using ultra-performance liquid chromatography coupled to a linear trap quadrupole system and gas chromatography-mass spectrometry. Metabolites were identified by comparison of ion features in samples to a standard reference library. Pathway-based interpretation was conducted using the human metabolome database and the MetaCyc database. Of the 397 named metabolites identified, 72 changed significantly with limonene intervention. Class-based changes included significant decreases in adrenal steroids (P < 0.01), and significant increases in bile acids (P ≤ 0.05) and multiple collagen breakdown products (P < 0.001). The pattern of changes also suggested alterations in glucose metabolism. There were 47 metabolites whose change with intervention was significantly correlated to a decrease in cyclin D1, a cell-cycle regulatory protein, in patient tumor tissues (P ≤ 0.05). Here, oral administration of limonene resulted in significant changes in several metabolic pathways. Furthermore, pathway-based changes were related to the change in tissue level cyclin D1 expression. Future controlled clinical trials with limonene are necessary to determine the potential role and mechanisms of limonene in the breast cancer prevention setting.
University of Arizona Cancer Center, Tucson, Arizona. Department of Nutritional Sciences, University of Arizona, Tucson, Arizona. jam1@email.arizona.edu.
Jessica A
JA
Miller
Metabolon, Inc., Durham, North Carolina.
Kirk
K
Pappan
Department of Pathology, Stony Brook University, Stony Brook, New York.
Patricia A
PA
Thompson
Department of Surgery and Cancer, Imperial College, London.
Elizabeth J
EJ
Want
Department of Surgery and Cancer, Imperial College, London.
Alexandros P
AP
Siskos
Department of Surgery and Cancer, Imperial College, London.
Hector C
HC
Keun
Metabolon, Inc., Durham, North Carolina.
Jacob
J
Wulff
College of Public Health, University of Arizona, Tucson, Arizona.
Chengcheng
C
Hu
Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California.
Julie E
JE
Lang
University of Arizona Cancer Center, Tucson, Arizona.
H-H Sherry
HH
Chow
D000596:Amino Acids / Q000737:chemistry; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000737:chemistry; D001647:Bile Acids and Salts / Q000737:chemistry; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002453:Cell Cycle; D003094:Collagen / Q000737:chemistry; D019938:Cyclin D1 / Q000378:metabolism; D053138:Cyclohexenes / Q000627:therapeutic use*; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000737:chemistry; D006801:Humans; D000077222:Limonene; D055442:Metabolome; D055432:Metabolomics; D010949:Plasma / Q000378:metabolism; D013729:Terpenes / Q000627:therapeutic use*
D000596:Amino Acids; D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D001647:Bile Acids and Salts; C530104:CCND1 protein, human; D053138:Cyclohexenes; D013729:Terpenes; C116917:acylcarnitine; D019938:Cyclin D1; D003094:Collagen; D000077222:Limonene; D005947:Glucose; D002331:Carnitine