Simultaneous determination of cytotoxic bufadienolides in the Chinese medicine ChanSu by high-performance liquid chromatography coupled with photodiode array and mass spectrometry detections

Ye, Min; Guo, Hui; Guo, Hongzhu; Han, Jian; Guo, Dan

doi:10.1016/j.jchromb.2006.04.042

Cited by 90 publications

(59 citation statements)

References 19 publications

(24 reference statements)

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“…The 13 C NMR spectrum of M-2 showed that the carbon signal of C-5 shifted downfield to ␦ 73.5. Furthermore, the NMR data of M-2 agreed well with the spectral data of cinobufotalin reported in previous studies (Ye et al, 2006;Ma et al, 2008). Taken together, these data indicated that M-2 was 5␤-hydroxylcinobufagin (5-HCB).…”

Section: Resultssupporting

confidence: 88%

“…ϩ that can be used for molecular mass determination (Table 1). Most metabolites can be assigned by comparison of retention times, UV spectra, and mass spectra with authentic standards (Ye et al, 2006;Ma et al, 2007), whereas peaks 1 (5.28 min) and 3 (5.61 min) were tentatively assigned as monohydroxylated deacetylcinobufagin and peak 2 (5.40 min) was tentatively assigned as 3-ketohydroxylated deacetylcinobufagin by UFLC-ESI-MS. It is evident from Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Cinobufagin (CB) (Fig. 1), the principal constituent of Chansu (Ye et al, 2006;Zhao et al, 2006), is one of the most intensively investigated bufadienolides because of its natural abundance (approximately 4 -6% dry weight) and potent biological activities, such as its cardiotonic, blood pressure-stimulating, local anesthetic, antimicrobial, and anticancer activities (Hong et al, 1992;Kamano et al, 1998;Ma et al, 2009). In recent years, more attention has been paid to the antitumor activity of CB.…”

Section: Introductionmentioning

confidence: 99%

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Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Minipig, Monkey, and Human

Ma¹,

Ning²,

Ge³

et al. 2011

Drug Metab Dispos

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ABSTRACT:Cinobufagin (CB), a major bioactive component of the traditional Chinese medicine Chansu, has been reported to have potent antitumor activity. In this study, in vitro metabolism of CB among species was compared with respect to metabolic profiles, enzymes involved, and catalytic efficiency by using liver microsomes from human (HLM), mouse (MLM), rat (RLM), dog (DLM), minipig (PLM), and monkey (CyLM). Significant species differences in CB metabolism were revealed. In particular, species-specific deacetylation and epimerization combined with hydroxylation existed in RLM, whereas hydroxylation was a major pathway in HLM, MLM, DLM, PLM, and CyLM. Two monohydroxylated metabolites of CB in human and animal species were identified as 1␣-hydroxylcinobufagin and 5␤-hydroxylcinobufagin by using liquid chromatography-mass spectrometry and two-dimensional NMR techniques. CYP3A4 was identified as the main isoform involved in CB hydroxylation in HLM on the basis of the chemical inhibition studies and screen assays with recombinant human cytochrome P450s. Furthermore, ketoconazole, a specific inhibitor of CYP3A, strongly inhibited CB hydroxylation in MLM, DLM, PLM, and CyLM, indicating that CYP3A was responsible for CB hydroxylation in these animal species. The apparent substrate affinity and catalytic efficiency for 1␣-and 5␤-hydroxylation of CB in liver microsomes from various species were also determined. PLM appears to have K m and total intrinsic clearance value (V max /K m ) similar to those for HLM, and the total microsomal intrinsic clearance values for CB obeyed the following order: mouse > dog > monkey > human > minipig. These findings provide vital information to better understand the metabolic behaviors of CB among various species.

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Section: Resultssupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Minipig, Monkey, and Human

Ma¹,

Ning²,

Ge³

et al. 2011

Drug Metab Dispos

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“…Some studies demonstrated that huachansu injection can improve the QOL of patients and has been used as a treatment of cancer in China [26][27][28] . It was reported that digitalis-like cinobufagin can protect prostate cancer cells from proliferation.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of gemcitabine-oxaliplatin combined with huachansu in patients with advanced gallbladder carcinoma

Qin¹,

Zhao²,

Yun³

et al. 2008

WJG

105

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A I M :To e v a l u a t e t h e e f f i c a c y a n d s a f e t y o f gemcitabine-oxaliplatin (GEMOX) combined with huachansu (cinobufagin) injection treatment in patients with locally advanced or metastatic gallbladder carcinoma (GBC), and to assess the quality of life (QOL) of such patients. METHODS: Twenty-five patients with locally advanced or metastatic GBC were treated with intravenous gemcitabine (1000 mg/m 2 ) over 30 min on days 1 and 8, 2 h infusion of oxaliplatin (120 mg/m 2 ) on day 1, and 2-3 h infusion of huachansu (20 mL/m 2 ) on days -3-11, every 3-4 wk. Treatment was continued until occurrence of unacceptable toxicity or disease progression. QOL of patients was assessed by the EORTC QLQ-C30 at baseline, at the end of the first, third and sixth chemotherapy cycles, and 1 mo after the treatment. RESULTS: Among the 25 patients with a median age of 64 years (range 42-78 years), 23 were evaluable in the study. A total of 137 cycles of therapy were performed and the median cycle was 5 (range 1-8) per patient. Out of the 23 patients whose response could be evaluated, 8 partial responses (PR) were observed (34.8%), while 7 patients (30.4%) demonstrated a stable disease (SD). The disease control rate was 65.2%. Progression of cancer was observed in 8 (34.8%) patients. The median progression-free and overall survival time was 5.8 mo (95% CI: 4.5-7.1 mo) and 10.5 mo, respectively. The therapy was well tolerated, with moderate myelosuppression as the main toxicity. Anemia grade 2 was seen in 16.0%, neutropenia grade 3 in 8.0% and thrombocytopenia grade 3 in 24.0% of patients, respectively. Nonhematologic toxicity ranged from mild to moderate. No death occurred due to toxicity. The QOL of patients was improved after chemotherapy, and the scores of QOL were increased by 10 to 20 points. CONCLUSION: GEMOX combined with huachansu (cinobufagin) injection is well tolerated, effective, thus improving the QOL of patients with advanced GBC.

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“…Acetonitrile and methanol used for HPLC were of chromatographic grade (Merck, Darmstadt, Germany), and water was distilled. Cinobufagin (1) was isolated from ChanSu with the purity of over 98% by the authors and identified by NMR and MS techniques [22]. C. militaris was purchased from China General Microbiological Culture Collection Center (Beijing, China).…”

Section: Reagents and Materialsmentioning

confidence: 99%

Efficient isolation and purification of five products from microbial biotransformation of cinobufagin by high‐speed counter‐current chromatography

Xin

Zhang

et al. 2010

J of Separation Science

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An efficient separation method of using high-speed counter-current chromatography was successfully established to directly purify cytotoxic transformed products of cinobufagin by Cordyceps militaris. The two-phase solvent system composed of n-hexane-ethyl acetate-methanol-water (4:6:3:4, v/v) was used in high-speed counter-current chromatography. A total of 9 mg of 4beta,12alpha-dihydroxyl-cinobufagin (1), 15 mg of 12beta-hydroxyl-cinobufagin (2), 8 mg of 5beta-hydroxyl-cinobufagin (3), 12 mg of deacetylcinobufagin (4) and 6 mg of 3-keto-cinobufagin (5) were obtained in a one-step separation from 400 mg of the crude extract with purity of 98.7, 97.2, 90.6, 99.1 and 99.4%, respectively, as determined by HPLC. Their chemical structures were identified on the basis of (1)H-NMR and (13)C-NMR technology. All products (1-5) showed the potent activities against human carcinoma cervicis (Hela) and malignant melanoma (A375) cells in vitro.

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Simultaneous determination of cytotoxic bufadienolides in the Chinese medicine ChanSu by high-performance liquid chromatography coupled with photodiode array and mass spectrometry detections

Cited by 90 publications

References 19 publications

Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Minipig, Monkey, and Human

Comparative Metabolism of Cinobufagin in Liver Microsomes from Mouse, Rat, Dog, Minipig, Monkey, and Human

Efficacy and safety of gemcitabine-oxaliplatin combined with huachansu in patients with advanced gallbladder carcinoma

Efficient isolation and purification of five products from microbial biotransformation of cinobufagin by high‐speed counter‐current chromatography

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