Han-Dong Sun

Diterpenoids from Isodon species and their biological activities

Isodon species (Labiatae) are widely distributed plants, many of which are used in folk medicine. Over the past twenty years, they have received considerable phytochemical and biological attention. Thestructures of their many diterpenoids constituents, especially those with an ent-kaurane skeleton, have been elucidated. The significant phytochemical and pharmacological diterpenoids form the subject of this review. There are 290 references.

Adenanthin targets peroxiredoxin I and II to induce differentiation of leukemic cells

Peroxiredoxins (Prxs) are potential therapeutic targets for major diseases such as cancers. However, isotype-specific inhibitors remain to be developed. We report that adenanthin, a diterpenoid isolated from the leaves of Rabdosia adenantha, induces differentiation of acute promyelocytic leukemia (APL) cells. We show that adenanthin directly targets the conserved resolving cysteines of Prx I and Prx II and inhibits their peroxidase activities. Consequently, cellular H(2)O(2) is elevated, leading to the activation of extracellular signal-regulated kinases and increased transcription of CCAAT/enhancer-binding protein β, which contributes to adenanthin-induced differentiation. Adenanthin induces APL-like cell differentiation, represses tumor growth in vivo and prolongs the survival of mouse APL models that are sensitive and resistant to retinoic acid. Thus, adenanthin can serve as what is to our knowledge the first lead natural compound for the development of Prx I- and Prx II-targeted therapeutic agents, which may represent a promising approach to inducing differentiation of APL cells.

Eriocalyxin B induces apoptosis of t(8;21) leukemia cells through NF-|[kappa]|B and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner

Diterpenoids isolated from Labiatae family herbs have strong antitumor activities with low toxicity. In this study, Eriocalyxin B (EriB), a diterpenoid extracted from Isodon eriocalyx, was tested on human leukemia/lymphoma cells and murine leukemia models. Acute myeloid leukemia cell line Kasumi-1 was most sensitive to EriB. Significant apoptosis was observed, concomitant with Bcl-2/Bcl-XL downregulation, mitochondrial instability and caspase-3 activation. AML1-ETO oncoprotein was degraded in parallel to caspase-3 activation. EriB-mediated apoptosis was associated with NF-κB inactivation by preventing NF-κB nuclear translocation and inducing IκBα cleavage, and disturbance of MAPK pathway by downregulating ERK1/2 phosphorylation and activating AP-1. Without affecting normal hematopoietic progenitor cells proliferation, EriB was effective on primary t(8;21) leukemia blasts and caused AML1-ETO degradation. In murine t(8;21) leukemia models, EriB remarkably prolonged the survival time or decreased the xenograft tumor size. Together, EriB might be a potential treatment for t(8;21) leukemia by targeting AML1-ETO oncoprotein and activating apoptosis pathways.

Study on solid phase extraction and graphite furnace atomic absorption spectrometry for the determination of nickel, silver, cobalt, copper, cadmium and lead with MCI GEL CHP 20Y as sorbent.

A solid phase extraction and graphite furnace atomic absorption spectrometry (GFAAS) for the determination of nickel, silver, cobalt, copper, cadmium and lead with MCI GEL CHP 20Y as sorbent was studied. Trace amounts of chromium, nickel, silver, cobalt, copper, cadmium and lead were reacted with 2-(2-quinolinil-azo)-4-methyl-1,3-dihydroxidobenzene (QAMDHB) followed by adsorption onto MCI GEL CHP 20Y solid phase extraction column, and 1.0molL(-1) HNO(3) was used as eluent. The metal ions in 300mL solution can be concentrated to 1.0mL, representing an enrichment factor of 300 was achieved. The recoveries of analytes at pH 8.0 with 1.0g of resin were greater than 95% without interference from alkaline, earth alkaline and some metal ions. When detected with graphite furnace atomic absorption spectrometry, the detection limits in the original samples were 1.4ngL(-1) for Cr(III), 1.0ngL(-1) for Ni(II), 0.85ngL(-1) for Ag(I), 1.2ngL(-1) for Co(II), 1.0ngL(-1) for Cu(II), 1.2ngL(-1) for Cd(II) and 1.3ngL(-1) for Pb(II). The validation of the procedure was performed by the analysis of the certified standard reference materials, and the presented procedure was applied to the determination of analytes in biological, water and soil samples with good results (recoveries range from 89 to 104%, and R.S.D.% lower than 3.2%. The results agreed with the standard value or reference method).

Sterols from the fungus Lactarium volemus

Seven ergostane-type sterols and two mono-glucosides were isolated from the ethyl acetate soluble fraction of Lactarium rolemus. Three are previously unknown, i.e. 3-O-beta-D-glucopyranosyl-22E,24R-5alpha,8alpha-epidioxyergosta-6,22-diene, 3-O-beta-D-glucopyranosyl-22E,24R-5beta,8beta-epidioxyergosta-6,22-diene and 22E,24R-ergosta-7,22-diene-3beta,5alpha,6beta,9alpha-tetraol. The structural elucidation of these compounds was mainly achieved by spectroscopic methods.

Smac mimetics increase cancer cell response to chemotherapeutics in a TNF-α-dependent manner.

Second mitochondria-derived activator of caspase (Smac) is a mitochondrial protein released into the cytosol during apoptosis. Smac mimetics have recently been touted as a novel therapeutic to induce apoptosis in cancer cells. The ability of Smac mimetics to induce apoptosis in vitro has been shown to be dependent upon both XIAP neutralization and cancer cell autocrine tumor necrosis factor-α (TNF-α) production. In this study we provide new evidence for the utility of Smac mimetics in combination with conventional chemotherapy agents to exacerbate caspase activation and induce cancer cell death. Furthermore, we find that the combination effect is because of a multifaceted mechanism involving both inhibition of cell proliferation by the chemotherapy agents and an enhanced autocrine TNF-α feedback loop by the Smac mimetic/chemotherapy agent combination. Surprisingly, although genotoxic agents typically induce apoptosis through the mitochondrial intrinsic pathway, we show that this synergism is mediated through a TNF-α/RIP1-dependent pathway, leading to activation of the extrinsic apoptotic pathway. Finally, we report that autocrine TNF-α contributes to Smac mimetic-induced tumor regression as a single agent or in combination with chemotherapeutics in xenograft mouse models. Collectively, we provide mechanistic and applicable data to support translational studies in the use of a Smac mimetic/chemotherapy antineoplasm modality.

Overexpression and Small Molecule-Triggered Downregulation of CIP2A in Lung Cancer

Background Lung cancer is the leading cause of cancer deaths worldwide, with a five-year overall survival rate of only 15%. Cancerous inhibitor of PP2A (CIP2A) is a human oncoprotein inhibiting PP2A in many human malignancies. However, whether CIP2A can be a new drug target for lung cancer is largely unclear. Methodology/Principal Findings Normal and malignant lung tissues were derived from 60 lung cancer patients from southern China. RT-PCR, Western blotting and immunohistochemistry were used to evaluate the expression of CIP2A. We found that among the 60 patients, CIP2A was undetectable or very low in paratumor normal tissues, but was dramatically elevated in tumor samples in 38 (63.3%) patients. CIP2A overexpression was associated with cigarette smoking. Silencing CIP2A by siRNA inhibited the proliferation and clonogenic activity of lung cancer cells. Intriguingly, we found a natural compound, rabdocoetsin B which is extracted from a Traditional Chinese Medicinal herb Rabdosia coetsa, could induce down-regulation of CIP2A and inactivation of Akt pathway, and inhibit proliferation and induce apoptosis in a variety of lung cancer cells. Conclusions/Significance Our findings strongly indicate that CIP2A could be an effective target for lung cancer drug development, and the therapeutic potentials of CIP2A-targeting agents warrant further investigation.

Megastigmane glucosides from Stachys byzantina

From the aerial parts of Stachys byzantina, two new megastigmane glucosides, byzantionosides A and B, were isolated, together with the known glycosides, icariside B2, blumeol C glucoside, (6R, 9R)- and (6R, 9S)-3-oxo-α-ionol glucosides and verbascoside. The structures of the new compounds have been elucidated by spectroscopic means.

DITERPENOIDS FROM ISODON-WIKSTROEMIOIDES

Abstract Four new diterpenoids wikstroemioidin A–D, together with eight known compounds, isodonal, longikaurin D, adenolin B, effusanin A, effusanin E, 5,3′,4′-trihydroxy-6,7,8-trimethoxy flavone, ursolic acid and sitosterol were isolated from the leaves of Isodon wikstroemioides . The structures of new compounds were determined by detailed spectroscopic analysis and some chemical evidence.

Diterpenoids from Isodon japonica.

A new ent-kaurane diterpenoid maoyecrystal F (1) and its acetonide derivative (2), together with seven known compounds, lasiodonin, maoyerabdosin, odonicin, enmenin, oridonin, beta-sitosterol and daucosterol, were isolated from the leaves of Isodon japonica.