title: Induction of apoptotic cell death by betulin in multidrug-resistant human renal carcinoma cells.
abstract: Betulin, a triterpene from the bark of various species of birch tree, has various biological effects, including antiviral, antifungal and anticancer activities. The aim of the present study was to elucidate the mechanisms underlying the apoptotic effect of betulin in RCC4 multidrug-resistant human renal carcinoma cells. To evaluate anticancer activity, we performed cell viability and caspase activity assays, a proteome profiler array and western blot analysis in RCC4 cells. Betulin significantly decreased RCC4 cell viability in a time- and concentration-dependent manner. Betulin activated caspase family proteins, including caspase-3, -7, -8 and -9, and increased the expression of apoptosis-related proteins, including PARP and Bcl-2 family members. In an apoptosis array, betulin activated the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors TRAIL R1/DR4 and R2/DR5, and tumour necrosis factor receptor 1 (TNFR1), suggesting that betulin treatment leads to induction of apoptosis through both intrinsic and extrinsic apoptosis pathways in RCC4 cells. Notably, betulin significantly enhanced cytotoxicity and PARP cleavage in etoposide-treated RCC4 cells, and downregulated the expression of multidrug resistance protein 1 (MDR1). Taken together, our findings suggest that the anticancer effects of betulin involve induction of apoptosis and sensitisation of RCC4 cells, providing potentially useful information applicable to the use of betulin in renal cancer treatment.
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Nam-Hui
authors.initials: NH
authors.lastname: Yim
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Young Pil
authors.initials: YP
authors.lastname: Jung
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Aeyung
authors.initials: A
authors.lastname: Kim
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Taesoo
authors.initials: T
authors.lastname: Kim
authors.affiliation: Korean Medicine (KM)-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine (KIOM), Yuseong-gu, Daejeon 305-811, Republic of Korea.
authors.forename: Jin Yeul
authors.initials: JY
authors.lastname: Ma
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D040901:Proteomics; D014315:Triterpenes / Q000494:pharmacology*; D000094062:Betulinic Acid
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D020169:Caspases; D014315:Triterpenes; C513055:ABCB1 protein, human; C002503:betulin; D000094062:Betulinic Acid