An Unusual Michael-Induced Skeletal Rearrangement of a Bicyclo[3.3.1]nonane Framework of Phloroglucinols to a Novel Bioactive Bicyclo[3.3.0]octane

A novel skeletal rearrangement of bicyclo[3.3.1]nonane-2,4,9-trione (16) to an unprecedented highly functionalized bicyclo[3.3.0]octane system (17), induced by an intramolecular Michael addition, is presented. This novel framework was found to be similarly active to hyperforin (1), against PC-3 cell lines. A mechanistic study was examined in detail, proposing a number of cascade transformations. Also, reactivity of the Δ7,10-double bond was examined under several conditions to explain the above results

Synthesis of novel vitamin E-selenium antioxidants and study of their antiproliferative and apoptotic properties

Selenium and vitamin E are two antioxidants that have attracted great attention due to a strong synergism resulting in anti-cancer activity. Further, accumulated evidence supports the chemical form of selenium as an important factor in eliciting defined cellular responses. There is ample evidence that TNF-family-mediated mitochondrial apoptosis involves the production of reactive oxygen species (ROS). In order to elicit the apoptotic effect of both vitamin E and selenium it has been essential to counterbalance the reduction of ROS through structural modifications of these compounds. Herein, we report the synthesis and assessment of the antioxidant activity as well as the cancer cell growth inhibitory and apoptotic properties of novel vitamin E-selenium esters (such as α-tocopheryl selenyl diacetate). These compounds were designed to (a) provide a better understanding of vitamin E synergism with selenium, (b) enable the synthesis of antioxidants combining both selenium and vitamin E apoptotic activity, and (c) elucidate the mechanisms underlying the potent apoptotic effects of succinate esters. Antioxidant activity and free radical scavenging capacity were assessed by the glutathione peroxidase (GPx) catalytic activity assay and 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, respectively. Reactions of organic peroxides with the antioxidants were evaluated by NMR spectroscopy. Redox potentials were determined using cyclic voltammetry. While the novel esters retained the antioxidant activity of both selenium and vitamin E, they had significant antiproliferative and growth inhibitory effects on three prostate cancer cell lines (PC-3, DU-145, LNCaP) as measured by the trypan blue exclusion test and the crystal violet proliferation assay. These properties were tested against their thionyl analogues, succinate and phenylselenyl succinate vitamin E esters. DAPI staining of nuclei revealed features of apoptotic cell death such as apoptotic bodies, apoptotic rings and condensed chromatin in diacetate and succinated esters of vitamin E, an effect not observed in cells treated with the natural vitamin E derivatives or the selenodiacetic acid. Apoptotic cell death was further assessed by caspase-3 activation, as detected by the cleavage of the fluorogenic caspace-3 substrate, z-DEVD-AFC. The presence of selenium further enhanced the pro-apoptotic effect of these compounds, as reveled by both DNA fragmentation and caspase-3 activation. Generally these novel selenium esters have cell growth inhibitory and pro-apoptotic properties superior to those of succinate, thionyl diacetic and phenylselenyl succinate esters. These differences in the biological properties imply that the higher stability of novel vitamin E-selenium esters play a key role in the improvement of the bioavailability of selenium at cellular level

Role of Constitutive Behavior and Tumor-Host Mechanical Interactions in the State of Stress and Growth of Solid Tumors

<div><p>Mechanical forces play a crucial role in tumor patho-physiology. Compression of cancer cells inhibits their proliferation rate, induces apoptosis and enhances their invasive and metastatic potential. Additionally, compression of intratumor blood vessels reduces the supply of oxygen, nutrients and drugs, affecting tumor progression and treatment. Despite the great importance of the mechanical microenvironment to the pathology of cancer, there are limited studies for the constitutive modeling and the mechanical properties of tumors and on how these parameters affect tumor growth. Also, the contribution of the host tissue to the growth and state of stress of the tumor remains unclear. To this end, we performed unconfined compression experiments in two tumor types and found that the experimental stress-strain response is better fitted to an exponential constitutive equation compared to the widely used neo-Hookean and Blatz-Ko models. Subsequently, we incorporated the constitutive equations along with the corresponding values of the mechanical properties - calculated by the fit - to a biomechanical model of tumor growth. Interestingly, we found that the evolution of stress and the growth rate of the tumor are independent from the selection of the constitutive equation, but depend strongly on the mechanical interactions with the surrounding host tissue. Particularly, model predictions - in agreement with experimental studies - suggest that the stiffness of solid tumors should exceed a critical value compared with that of the surrounding tissue in order to be able to displace the tissue and grow in size. With the use of the model, we estimated this critical value to be on the order of 1.5. Our results suggest that the direct effect of solid stress on tumor growth involves not only the inhibitory effect of stress on cancer cell proliferation and the induction of apoptosis, but also the resistance of the surrounding tissue to tumor expansion.</p></div

Effect of tumor constitutive behavior on tumor growth and state of stress.

<p>A) Model fit to the experimentally measured growth curve of SW620 tumors using the neo-Hookean and the exponential equation. B) Evolution of bulk solid stress in the tumor interior does not depend on the selection of the constitutive equation. Results using the Blatz-Ko material are omitted for clarity.</p

Values of the mechanical properties of the two tumor types derived by fitting the model to the experimental stress-strain curves.

<p>Standard errors are shown in parenthesis.</p>a<p>The Poisson’s ratio was taken to be 0.2 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0104717#pone.0104717-Roose1" target="_blank">[22]</a>.</p

Effect of tumor-host mechanical interactions on tumor state of stress and growth.

<p>Dependence of A) state of stress and B) growth rate of tumors on the mechanical properties of the host tissue. The host tissue was modeled as a compressible neo-Hookean material with Poisson’s ratio of 0.2 and three values of the shear modulus were used, <i>µ</i> = 10, 15 and 30 kPa. The stiffer the host tissue is, the higher the stress in the tumor and the lower its growth rate becomes.</p

Experimental measurements for the elastic modulus and tan(<i>δ</i>) of the two tumor types.

<p>Experimental measurements for the elastic modulus and tan(<i>δ</i>) of the two tumor types.</p

Effect of relative stiffness of the tumor compared to the host tissue on solid stress and tumor growth.

<p>Dependence of A) the state of stress and B) tumor volume on the relative stiffness of the tumor compared to the normal tissue, <i>µ</i>*. Relative stiffness is the ratio of the tumor shear modulus to that of the host. Results correspond to day 5 of the simulations. Tumor solid stress increases with stiffening of the surrounding host tissue and reaches a plateau when the stiffness of the tumor becomes the same as or lower than the stiffness of the host (panel A). The tumor has to reach a critical stiffness compared with that of the normal tissue to be able to displace the tissue and grow (panel B).</p