Ursolic acid sensitized colon cancer cells to chemotherapy under hypoxia by inhibiting MDR1 through HIF-1α.
OBJECTIVE
To explore the efficacy of ursolic acid in sensitizing colon cancer cells to chemotherapy under hypoxia and its underlying mechanisms.


METHODS
Three colon cancer cell lines (RKO, LoVo, and SW480) were used as in vitro models. 5-Fluorouracil (5-FU) and oxaliplatin were used as chemotherapeutic drugs. Cell viability and apoptosis were tested to evaluate the sensitivity of colon cancer cells to chemotherapy. The transcription and expression levels of hypoxia-inducible factor-1α (HIF-1α), multidrug resistance gene 1 (MDR1), and vascular endothelial growth factors (VEGF) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting. Cycloheximide and MG132 were used to inhibit protein synthesis and degradation, respectively. In vitro tube formation assay was used to evaluate angiogenesis.


RESULTS
We demonstrated the chemosensitizing effects of ursolic acid with 5-FU and oxaliplatin in three colon cancer cell lines under hypoxia. This effect was correlated to its inhibition of MDR1 through HIF-1α. Moreover, ursolic acid was capable of inhibiting HIF-1α accumulation with little effects on its constitutional expression in normoxia. In addition, ursolic acid also down-regulated VEGF and inhibited tumor angiogenesis.


CONCLUSIONS
Ursolic acid exerted chemosensitizing effects in colon cancer cells under hypoxia by inhibiting HIF-1α accumulation and the subsequent expression of the MDR1 and VEGF.
Department of Medical Oncology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Jian-Zhen
JZ
Shan
Cancer Institute of Zhejiang University, Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou 310009, China.
Yan-Yan
YY
Xuan
Department of General Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Qi
Q
Zhang
Department of Medical Oncology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Jian-Jin
JJ
Huang
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003513:Cycloheximide / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005472:Fluorouracil / Q000008:administration & dosage; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014315:Triterpenes / Q000737:chemistry*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000097245:Ursolic Acid
D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D003513:Cycloheximide; D005472:Fluorouracil; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D034741:RNA, Small Interfering; D014315:Triterpenes; D042461:Vascular Endothelial Growth Factor A; D000097245:Ursolic Acid; C513055:ABCB1 protein, human; C497442:HIF1A protein, human; C467484:VEGFA protein, human
Colon cancer; Drug resistance; Hypoxia-inducible factor-1α (HIF-1α); Multidrug resistance gene 1 (MDR1); Ursolic acid