Discovery of new chalone adamantyl arotinoids having RXRα-modulating and anticancer activities.

In the present study, a new series of chalcone adamantly arotinoids (chalcone AdArs) derived from RAR antagonist MX781, are synthesized, characterized, and evaluated for the biological activities in vitro. The studies of antiproliferative activity and RXRα-binding affinity of target compounds result in the discovery of a lead candidate (WA15), which is a good RXRα binder (Kd = 2.89 × 10-6 M) with potent antiproliferative activity against human cancer cell lines (IC50 ≈ 10 µM) and low toxic to normal LO2 and MRC-5 cells (IC50 > 50 µM). Different from MX781, WA15 eliminates RARα antagonist activity but inhibits 9-cis-RA-induced RXRα transactivation activity in a dose-dependent manner. Compound WA15 is found to be a good apoptosis inducer in various cancer cells and promotes cell apoptosis in an RXRα-independent manner. Besides, WA15 shows the induction of proteasome-dependent RXRα degradation which might enhance the WA15-induced apoptosis. Finally, the immunoblotting indicates that WA15 can inhibit the TNFα-induced IKK activation and IκBα degradation, suggesting that the anticancer activity of WA15 might be related to the inhibition of IKK/NF-κB signal pathway.

Phenols displaying tyrosinase inhibition from Humulus lupulus.

Tyrosinase is the rate-limiting enzyme for the production of melanin and other pigments via the oxidation of l-tyrosine. The methanol extract from Humulus lupulus showed potent inhibition against mushroom tyrosinase. The bioactivity-guided fractionation of this methanol extract resulted in the isolation of seven flavonoids (1-7), identified as xanthohumol (1), 4'-O-methylxanthohumol (2), xanthohumol C (3), flavokawain C (4), xanthoumol B (5), 6-prenylnaringenin (6) and isoxanthohumol (7). All isolated flavonoids (1-7) effectively inhibited the monophenolase (IC50s = 15.4-58.4 µM) and diphenolase (IC50s = 27.1-117.4 µM) activities of tyrosinase. Kinetic studies using Lineweaver-Burk and Dixon-plots revealed that chalcones (1-5) were competitive inhibitors, whereas flavanones (6 and 7) exhibited both mixed and non-competitive inhibitory characteristics. In conclusion, this study is the first to demonstrate that the phenolic phytochemicals of H. lupulus display potent inhibitory activities against tyrosinase.

A retinoblastoma orthologue is required for the sensing of a chalone in Dictyostelium discoideum.

Retinoblastoma-like proteins regulate cell differentiation and inhibit cell proliferation. The Dictyostelium discoideum retinoblastoma orthologue RblA affects the differentiation of cells during multicellular development, but it is unclear whether RblA has a significant effect on Dictyostelium cell proliferation, which is inhibited by the secreted proteins AprA and CfaD. We found that rblA⁻ cells in shaking culture proliferate to a higher density, die faster after reaching stationary density, and, after starvation, have a lower spore viability than wild-type cells, possibly because in shaking culture, rblA⁻ cells have both increased cytokinesis and lower extracellular accumulation of CfaD. However, rblA⁻ cells have abnormally slow proliferation on bacterial lawns. Recombinant AprA inhibits the proliferation of wild-type cells but not that of rblA⁻ cells, whereas CfaD inhibits the proliferation of both wild-type cells and rblA⁻ cells. Similar to aprA⁻ cells, rblA⁻ cells have a normal mass and protein accumulation rate on a per-nucleus basis, indicating that RblA affects cell proliferation but not cell growth. AprA also functions as a chemorepellent, and RblA is required for proper AprA chemorepellent activity despite the fact that RblA does not affect cell speed. Together, our data indicate that an autocrine proliferation-inhibiting factor acts through RblA to regulate cell density in Dictyostelium, suggesting that such factors may signal through retinoblastoma-like proteins to control the sizes of structures such as developing organs or tumors.

Synthesis and biological evaluation of novel pyranochalcone derivatives as a new class of microtubule stabilizing agents.

Twenty-five novel pyranochalcone derivatives were synthesized and evaluated for their in vitro and in vivo antiproliferative activities. Among them, compound 10i exhibited superior potent activity against 21 tumor cell lines including multidrug resistant phenotype with the IC50 values ranged from 0.09 to 1.30 µM. In addition, 10i significantly induced cell cycle arrest in G2/M phase, promoted tubulin polymerization into microtubules and caused microtubule stabilization. Further studies confirmed that 10i significantly suppressed the growth of tumor volume in HepG2 xenograft tumor model. Our study demonstrated that 10i could have beneficial antitumor activity as a novel microtubule stabilizing agent.

Design, synthesis, and structure-activity relationship studies of novel millepachine derivatives as potent antiproliferative agents.

In this paper, 38 millepachine derivatives have been designed, synthesized and evaluated for their in vitro and in vivo antiproliferative activity. Among these novel derivatives, 15 displayed more potent antiproliferative activity than millepachine against HepG2, K562, SK-OV-3, HCT116, HT29, and SW620 tumor cells (mean IC(50) = 0.64 vs. 2.86 µM, respectively). Furthermore, 15 could effectively inhibit tubulin polymerization in HepG2 cells, and induce the HepG2 cell cycle arrest at the G2/M phase in a concentration-dependant manner. Further studies confirmed that 15 significantly suppressed the growth of tumor volume and exerted more potent anticancer potency than millepachine and anticancer drug cisplatin in A549 lung xenograft tumor model.

A comparative study of tumor-suppression effects of enterotoxin B and Chalone 19-peptide on experimental gastric carcinoma.

BACKGROUND/AIMS: In this paper, the in vivo tumor suppression effects of Staphyococal enterotoxin B (SEB) and Chalone 19-peptide, a form of Tumstain with modified coding sequence, on poorly differentiated human gastric carcinoma cells were compared. METHODOLOGY: Animal model for studying human gastric carcinoma was established by injecting tumor cells (Human poorly differentiated gastric carcinoma cell line, SGC-7901) underneath the gastric serosa of BALB/c nude mice. RESULTS: Results demonstrated that SEB induced tumor cell death on a large scale and destroyed surrounding normal tissue at the same time, leading to tumor cluster breaking down and seeding. SEB had no effect on lymphovascular metastasis. The administration of 19-peptide on gastric carcinoma resulted in sheets-like tumor central necrosis, decreased angiogenesis and a moderate tumor infiltration into surrounding tissue without distant metastasis. Therefore, both SEB and 19-peptide could suppress the local growth, distant metastasis and invasion of poorly differentiated gastric carcinoma cells into surrounding tissues. CONCLUSIONS: Data suggested that this model could effectively simulate the microenvironment of human gastric carcinoma, hence providing a platform for study on this cancer.

Chalcone based aryloxypropanolamines as potential antihyperglycemic agents.

A series of chalcone based aryloxypropanolamines were synthesized and evaluated for their antihyperglycemic activity in SLM and STZ rat models. Most of the compounds exhibited moderate to good activity ranging from 6.5% to 31.1% in SLM and 8.3% to 22.6% in STZ models, respectively. The most potent compound 5 g exhibited glucose lowering of 26.7% in SLM and 22.6% in STZ models. A definite structure-activity relationship was observed while varying the nature as well as the position of the amine in ring B.

Effect of chalone system on proliferation of Ehrlich ascitic tumor cells under conditions of modified photoregimen.

We studied the influence of different photoregimens (light/darkness alternation and constant darkness) on the effect of saline and chalone regulation of cell proliferation in Ehrlich ascitic tumor was studied. Saline slightly inhibited proliferation of tumor cells. Chalone-containing preparations from animals exposed to light/darkness alternation and to constant darkness were characterized by different effects on cell proliferation in this tumor. Cell kinetics attested to possible mechanisms of the effect of the chalone system on the status of Ehrlich ascitic tumor; these mechanisms were independent on each other.

Anticancer activities of novel chalcone and bis-chalcone derivatives.

A series of novel chalcones and bis-chalcones containing boronic acid moieties has been synthesized and evaluated for antitumor activity against the human breast cancer MDA-MB-231 (estrogen receptor-negative) and MCF7 (estrogen receptor-positive) cell lines and against two normal breast epithelial cell lines, MCF-10A and MCF-12A. These molecules inhibited the growth of the human breast cancer cell lines at low micromolar to nanomolar concentrations, with five of them (1-4, 9) showing preferential inhibition of the human breast cancer cell lines. Furthermore, bis-chalcone 8 exhibited a more potent inhibition of colon cancer cells expressing wild-type p53 than of an isogenic cell line that was p53-null.

Chalones: from aqueous extracts to oligopeptides.

The term "chalone" was coined about 40 years ago to describe endogenous growth-inhibiting factors with a tissue-specific and reversible effect. A large number of "chalones" were reported in the 1970's and early 80's. The term was, however, used rather indiscriminately and attempts at purification of the active component(s) were without success. As a result, most laboratories lost interest. Then, in the early 1980's, two different research teams demonstrated that the active growth-inhibiting constituents were N-substituted oligopeptides. In the following years, similar oligopeptides were characterized in extracts of liver, the large bowel, melanocytes, lymphocytes, and neuroblastoma, in addition to the two first ones from monomyelopoietic cells and epidermis, respectively. All peptides have a bell-shaped dose response pattern and optimal effect at very low concentrations. Several of them inhibit growth even in tumors derived from the respective organs. Preliminary studies have revealed that two of the oligopeptides alter the expression of growth- and differentiation-related genes. Quite recently, some papers are again using the term "chalone" and a short review therefore seems appropriate.