Novel cytotoxic bufadienolides derived from bufalin by microbial hydroxylation and their structure–activity relationships

Ye, Min; Qu, Guiqin; Guo, Hongzhu; Guo, Dan

doi:10.1016/j.jsbmb.2004.01.010

Cited by 84 publications

(61 citation statements)

References 32 publications

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“…Consistently, recent in vitro and in vivo studies have identified several new CTS compounds that exhibit anti-cancer activities (30 -32). Oleandrin, for example, is in clinical trials in the United States as an anti-cancer remedy for human cancers (31,33). Although ouabain inhibits the pumping function of the Na/K-ATPase, it is important to note that the growth inhibitory effect of ouabain can occur at doses that neither cause significant changes in intracellular Na ϩ and K ϩ nor affect cell viability.…”

mentioning

confidence: 99%

Changes in Sodium Pump Expression Dictate the Effects of Ouabain on Cell Growth

Tian

Liang

et al. 2009

Journal of Biological Chemistry

113

115

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Here we show that ouabain-induced cell growth regulation is intrinsically coupled to changes in the cellular amount of Na/KATPase via the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Ouabain increases the endocytosis and degradation of Na/K-ATPase in LLC-PK1, human breast (BT20), and prostate (DU145) cancer cells. However, ouabain stimulates the PI3K/Akt/mTOR pathway and consequently up-regulates the expression of Na/K-ATPase in LLC-PK1 but not BT20 and DU145 cells. This up-regulation is sufficient to replete the plasma membrane pool of Na/K-ATPase and to stimulate cell proliferation in LLC-PK1 cells. On the other hand, ouabain causes a gradual depletion of Na/K-ATPase and an increased expression of cell cycle inhibitor p21 cip , which consequently inhibits cell proliferation in BT20 and DU145 cells. Consistently, we observe that small interfering RNA-mediated knockdown of Na/K-ATPase is sufficient to induce the expression of p21 cip and slow the proliferation of LLC-PK1 cells. Moreover, this knockdown converts the growth stimulatory effect of ouabain to growth inhibition in LLC-PK1 cells. Mechanistically, both Src and caveolin-1 are required for ouabaininduced activation of Akt and up-regulation of Na/K-ATPase. Furthermore, inhibition of the PI3K/Akt/mTOR pathway by rapamycin completely blocks ouabain-induced expression of Na/K-ATPase and converts ouabain-induced growth stimulation to growth inhibition in LLC-PK1 cells. Taken together, we conclude that changes in the expression of Na/K-ATPase dictate the growth regulatory effects of ouabain on cells.The Na/K-ATPase, a member of P-type ATPase family, was discovered as an energy transducing ion pump. It transports Na ϩ and K ϩ across the cell membrane and maintains ion homeostasis in animal cells (1, 2). Recent studies indicate that the Na/K-ATPase is also an important receptor that can transduce ligand binding into the activation of protein kinase cascades (3). Specifically, the Na/K-ATPase interacts with Src, which provides at least two important cellular regulations (4, 5). First, association with Na/K-ATPase keeps Src in an inactive state. Thus, the Na/K-ATPase serves as a native negative Src regulator (4). Second, this interaction forms a functional receptor complex for cardiotonic steroids (CTS) 3 (3), a group of well characterized ligands of the Na/K-ATPase. Cardiotonic steroids include cardenolides (e.g. ouabain) and bufadienolides (e.g. marinobufagenin) (6). Although CTS are known cardiac drugs, some of them have now been identified as endogenous steroid hormones (6 -8). Binding of CTS to the receptor complex activates the Na/K-ATPase-associated Src. Subsequently, the activated Src transactivates other tyrosine kinases, and together they recruit and further phosphorylate multiple membrane and soluble proteins, which results in the activation of protein kinase cascades and the generation of second messengers (3, 4, 6). Ultimately, this chain of signaling events would alter cellular functions and cell growth in a cell-...

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mentioning

confidence: 99%

Changes in Sodium Pump Expression Dictate the Effects of Ouabain on Cell Growth

Tian

Liang

et al. 2009

Journal of Biological Chemistry

113

115

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“…Comparison the NMR data of 1 with those of known compound telicinobufagin (18) revealed the signals of the two compounds for rings C, D and E were very similar, 14 suggesting that 1 had the same substructure as telicinobufagin.…”

Section: Resultsmentioning

confidence: 88%

“…

Twelve new bufadienolides (1-12), along with fourteen known analogues (13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26) were isolated from the skins of Bufo bufo gargarizans CANTOR. Their chemical structures were elucidated on the basis of NMR, HRESIMS and X-ray diffraction analysis.

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confidence: 99%

Bufadienolides with cytotoxic activity from the skins of Bufo bufo gargarizans

Tian

Zhang

et al. 2015

Fitoterapia

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“…Cinobufagin exhibited significant inhibitory activities against different kinds of human cancer cells such as myeloid leukemia and prostate cells [5,6]. Due to its significant bioactivity, the various modifications of cinobufagin derivatives [7] and structureactivity relation (SAR) [8][9] caused more attention in recent years.…”

Section: Introductionmentioning

confidence: 99%

“…So far, more than 50 products of cinobufagin have been obtained by a microbial transformation approach, including many novel bufadienolide analogues, to improve cytotoxicities and increase water solubilities for development of new drugs [10][11][12][13][14]. Furthermore, these bioactive products of cinobufagin obtained by microbial transformation approach have been widely applied to investigate the SAR and in vivo metabolism of bufadienolides for development of new drugs [7,15]. Because these transformed products usually have similar steroidal structures, the various chromatographic methods such as HPLC and column chromatography were applied jointly to separate and purify these transformed products, which would be time-consuming, using large amounts of reagent and resulting in a great loss of target compounds [11,12].…”

Section: Introductionmentioning

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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Novel cytotoxic bufadienolides derived from bufalin by microbial hydroxylation and their structure–activity relationships

Cited by 84 publications

References 32 publications

Changes in Sodium Pump Expression Dictate the Effects of Ouabain on Cell Growth

Changes in Sodium Pump Expression Dictate the Effects of Ouabain on Cell Growth

Bufadienolides with cytotoxic activity from the skins of Bufo bufo gargarizans

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

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