Search Results (17)

Prostate cancer (PCa) is among the highest incidence malignancies in men, with high rates of inevitable resistance development, relapse, and mortality. Castration-resistant prostate cancer (CRPC) continued to pose substantial therapeutic challenges, highlighting the urgent need for effective treatment options. This study assessed the marine cembranoid sarcophine activity against the progression and recurrence of the metastatic CRPC (mCRPC) in mouse xenograft models. Protein and phosphorylation levels were assessed by immunoblotting and mRNA expression by qPCR and RNA sequencing. The in vivo efficacy was evaluated through tumor progression over 3 weeks followed by primary tumor excision and recurrence monitoring over an 8-week course. Sarcophine significantly reduced the mCRPC CWR-R1ca tumor volume by 74.1% and suppressed the epigenetic regulators EZH2 and SMYD2; lineage plasticity factors ASCL1 and BRN2; Wnt/stemness signaling markers β-catenin and LGR6; AKT total expression and activation; and invasion-associated proteins TRPC4 and MMP2 in primary tumors. Sarcophine effectively prevented the mCRPC locoregional recurrence, as well as lung and spleen distant recurrences, and effectively reduced recurrence in other organs. Transcriptomics-RNA-Seq analysis of primary tumors identified 2697 downregulated and 3534 upregulated genes, indicating broad transcriptional reprogramming following sarcophine treatments. These findings demonstrate coordinated suppression of multi-oncogenic pathways and validate the therapeutic potential of sarcophine to control mCRPC. Full article

The ubiquitin-proteasome system (UPS) is a major proteolytic pathway that safeguards protein homeostasis. The main 26S proteasome consists of a 20S catalytic core proteasome and a 19S substrate recognition proteasome. UPS dysfunction underlies many important clinical diseases involving inflammation, tumors, and neurodegeneration. Currently, three 20S proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, have been approved for the treatment of multiple myeloma. We aim to screen UPS inhibitors for biomedical purposes. The protein interaction network of human cytomegalovirus UL76 targets UPS, resulting in aggregations of ubiquitinated proteins termed aggresomes. In this study, we demonstrated that cell-based high-content measurements of EGFP-UL76 aggresomes responded to bortezomib and MG132 treatment in a dose-dependent manner. Employing this high-content screening (HCS) assay, we screened natural compounds purified from Formosan soft corals. Four cembrane-based compounds, sarcophytonin A (1), sarcophytoxide (2), sarcophine (3), and laevigatol A (4), were found to enhance the high-content profiles of EGFP-UL76 aggresomes with relative ratios of 0.2. By comparison to the mechanistic action of proteasome inhibitors, compounds 1 and 3 modulated the accumulation of ubiquitinated proteins, with a unique pattern likely targeting 19S proteasome. We confirmed that the EGFP-UL76 aggresome-based HCS system greatly improves the efficacy and sensitivity of the identification of proteasome inhibitors. Full article

Sarcophyton sp. soft corals are rich in cembranoid diterpenes, which represent the main chemical defense of corals against their natural predators in addition to their myriad biological effects in humans. Quantitative NMR (qNMR) was applied for assessing the diterpene variation in 16 soft coral specimens in the context of their genotype, origin, and growing habitat. qNMR revealed high diterpene levels in Sarcophyton sp. compared to Sinularia and Lobophyton, with (ent)sarcophines as major components (17–100 µg/mg) of the coral tissues. Multivariate data analysis was employed to classify samples based on the quantified level of diterpenes, and compared to the untargeted NMR approach. Results revealed that qNMR provided a stronger classification model of Sarcophyton sp. than untargeted NMR fingerprinting. Additionally, cytotoxicity of soft coral crude extracts was assessed against androgen-dependent prostate cancer cell lines (PC3) and androgen-independent colon cancer cell lines (HT-29), with IC₅₀ values ranging from 10–60 µg/mL. No obvious correlation between the extracts’ IC₅₀ values and their diterpene levels was found using either Spearman or Pearson correlations. This suggests that this type of bioactivity may not be easily predicted by NMR metabolomics in soft corals, or is not strongly correlated to measured diterpene levels. Full article

Five new isoprenoids, 3,4,8,16-tetra-epi-lobocrasol (1), 1,15β-epoxy-deoxysarcophine (2), 3,4-dihydro-4α,7β,8α-trihydroxy-Δ²-sarcophine (3), ent-sarcophyolide E (4), and 16-deacetyl- halicrasterol B (5) and ten known compounds 6‒15, were characterized from the marine soft coral Sarcophyton glaucum, collected off Taitung coastline. Their structures were defined by analyzing spectra data, especially 2D NMR and electronic circular dichroism (ECD). The structure of the known compound lobocrasol (7) was revised. Cytotoxicity potential of the isolated compounds was reported, too. Full article

Three new cembrene diterpenoids, sarcoehrenbergilid A–C (1–3), along with four known diterpenoids, sarcophine (4), (+)-7α,8β-dihydroxydeepoxysarcophine (5), sinulolide A (6), and sinulolide B (7), and one steroid, sardisterol (8), were isolated and characterized from a solvent extract of the Red Sea soft coral Sarcophyton ehrenbergi. Chemical structures were elucidated by NMR and MS analyses with absolute stereochemistry determined by X-ray analysis. Since these isolated cembrene diterpenes contained 10 or more carbons in a large flexible ring, conformer stabilities were examined based on density functional theory calculations. Anti-proliferative activities for 1–8 were evaluated against three human tumor cell lines of different origins including the: lung (A549), colon (Caco-2), and liver (HepG2). Sardisterol (8) was the most potent of the metabolites isolated with an IC₅₀ of 27.3 µM against the A549 cell line. Since an elevated human-cancer occurrence is associated with an aberrant receptor function for the epidermal growth factor receptor (EGFR), molecular docking studies were used to examine preferential metabolite interactions/binding and probe the mode-of-action for metabolite-anti tumor activity. Full article

Five new polyoxygenated cembranoids, named (+)-1,15-epoxy-2-methoxy-12-methoxycarbonyl-11E-sarcophytoxide (1), (+)-2-epi-12-methoxycarbonyl-11E-sarcophine (2), 3,4-epoxyehrenberoxide A (3), ehrenbergol D (4) and ehrenbergol E (5), were obtained from the soft coral Sarcophyton ehrenbergi. The structures of 1–5 were established on the basis of comprehensive NMR and HR-ESI-MS analyses and by comparison with reported data in the literature. Compounds 4 and 5 showed moderate cytotoxicity against P-388 (mouse lymphocytic leukemia) cancer cell line with EC₅₀ values of 2.0 and 3.0 μM, respectively. Compound 2 exhibited slight antiviral activity against HCMV (human cytomegalovirus) with IC₅₀ values of 25.0 μg/mL. Full article

Chemical investigations of the Egyptian soft coral Sarcophyton ehrenbergi have led to the isolation of compounds 1–3 as well as the previously reported marine cembranoid diterpene sarcophine (4). Structures were elucidated by comprehensive NMR and HRMS experimentation. Isolated compounds were in vitro assayed for cytotoxic activity against human hepatocarcinoma (HepG2) and breast adenocarcinoma (MCF-7) cell lines. Full article

Sarcophine-diol (SD) is a semi-synthetic derivative of sarcophine with a significant chemopreventive effect against non-melanoma skin cancer both in vitro and in vivo. Recently, we have studied the effect of SD on melanoma development using the mouse melanoma B₁₆F₁₀ cell line. In this study, our findings show that SD suppresses cell multiplication and diminishes membrane permeability for ethidium bromide (EB), a model marker used to measure cell permeability for Ca²⁺ ions. SD also decreases protein levels of COX-2, and increases degradation of phospholipases PLA₂ and PLC_γ1 and diminishes enzymatic activity of the Ca²⁺-dependent cPLA₂. This lower membrane permeability for Ca²⁺-ions, associated with SD, is most likely due to the diminished content of lysophosphosphatidylcholine (lysoPC) within cell membranes caused by the effect of SD on PLA₂. The decrease in diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP₃) due to inhibition of PLC_γ1, leads to the downregulation of Ca²⁺-dependent processes within the cell and also inhibits the formation of tumors. These findings support our previous data suggesting that SD may have significant potential in the treatment of melanoma. Full article

Sarcophine-diol (SD) is a lactone ring-opened analogue of sarcophine. It has shown chemopreventive effects on chemically-induced skin tumor development in female CD-1 mice, as well as in a UVB-induced skin tumor development model in hairless SKH-1 mice at a dose of 30 μg SD applied topically and 180 mJ/cm² UVB. The objective of this study was to determine the dose-response on the chemopreventive effects of SD on SKH-1 hairless mice when exposed to a UVB radiation dose of 30 mJ/cm². This UVB dose better represents chronic human skin exposure to sunlight leading to skin cancer than previous studies applying much higher UVB doses. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into five groups. The control group was topically treated with 200 μL of acetone (vehicle), and the SD treatment groups were topically treated with SD (30 μg, 45 μg, and 60 μg dissolved in 200 μL of acetone) 1 h before UVB radiation (30 mJ/cm²). The last group of animals received 60 μg SD/200 μL acetone without UVB exposure. These treatments were continued for 27 weeks. Tumor multiplicity and tumor volumes were recorded on a weekly basis for 27 weeks. Weight gain and any signs of toxicity were also closely monitored. Histological characteristics and the proliferating cell nuclear antigen (PCNA) were evaluated in the mice skin collected at the end of the experiment. The dose-response study proved a modest increase in chemopreventive effects with the increase in SD dose. SD reduced the number of cells positively stained with PCNA proliferation marker in mice skin. The study also showed that SD application without UVB exposure has no effect on the structure of skin. The results from this study suggest that broader range doses of SD are necessary to improve the chemopreventive effects. Full article

In order to search for new bioactive substances from marine organisms, we have investigated the acetone extracts of the soft coral Sarcophyton ehrenbergi collected at San-Hsian-Tai, Taitong County, Taiwan. Chromatographic fractionation of the extracts of the octocoral S. ehrenbergi led to the isolation of three new cembranoids, (+)-12-ethoxycarbonyl-11Z-sarcophine (1), ehrenbergol A and B (2 and 3). The structures of these isolated metabolites were elucidated through extensive spectroscopic analyses. Moreover, metabolites 1–3 were evaluated in vitro for their cytotoxicity towards selected cancer cell lines and antiviral activity against human cytomegalovirus (HCMV). Full article

A chemical investigation of an ethyl acetate extract of the Red Sea soft coral Sarcophyton glaucum has led to the isolation of two peroxide diterpenes, 11(S) hydroperoxylsarcoph-12(20)-ene (1), and 12(S)-hydroperoxylsarcoph-10-ene (2), as well as 8-epi-sarcophinone (3). In addition to these three new compounds, two known structures were identified including: ent-sarcophine (4) and sarcophine (5). Structures were elucidated by spectroscopic analysis, with the relative configuration of 1 and 2 confirmed by X-ray diffraction. Isolated compounds were found to be inhibitors of cytochrome P₄₅₀ 1A activity as well as inducers of glutathione S-transferases (GST), quinone reductase (QR), and epoxide hydrolase (mEH) establishing chemo-preventive and tumor anti-initiating activity for these characterized metabolites. Full article

Sarcodiol (SD) is a semi-synthetic derivative of sarcophine, a marine natural product. In our previous work, we reported the significant chemopreventive effects of SD against non-melanoma skin cancer both in vitro and in vivo mouse models. In this investigation, we extended this work to study the effect of sarcodiol on melanoma development, the more deadly form of skin cancer, using the mouse melanoma B₁₆F₁₀ cell line. In this study we report that SD inhibits the de novo DNA synthesis and enhances fragmentation of DNA. We also evaluated the antitumor effect of SD on melanoma cell viability using several biomarkers for cell proliferation and apoptosis. SD inhibits the expression levels of signal transducers and activators of transcription protein (STAT-3) and cyclin D1, an activator of cyclin-dependent kinase 4 (Cdk4). SD treatment also enhances cellular level of tumor suppressor protein 53 (p53) and stimulates cleavage of the nuclear poly (ADP-ribose) polymerase (cleaved-PARP). SD also enhances cellular levels of cleaved Caspase-3, -8, -9 and stimulates enzymatic activities of Caspase-3, -8 and -9. These results, in addition to inhibition of cell viability, suggest that SD inhibits melanoma cell proliferation by arresting the cell-division cycle in a Go quiescent phase and activates programmed cell death (apoptosis) via extrinsic and intrinsic pathways. Finally, these studies demonstrate that SD shows a very promising chemopreventive effect in melanoma B₁₆F₁₀ tumor cells. Full article

Sarcophine-diol (SD), one of the structural modifications of sarcophine, has shown chemopreventive effects on 12-dimethylbenz(a)anthracene-initiated and 12-O- tetradecanoylphorbol-13-acetate-promoted skin tumor development in female CD-1 mice. The objective of this study was to determine the chemopreventive effects of SD on UVB-induced skin tumor development in hairless SKH-1 mice, a model more relevant to human skin cancer, and to determine the possible mechanisms of action. Carcinogenesis was initiated and promoted by UVB radiation. Female hairless SKH-1 mice were divided into two groups having 27 mice in each group: control and SD treatment. The control group was topically treated with 100 μL acetone and SD treatment group was topically treated with SD (30 μg/100 μL in acetone) 1 hour before each UVB radiation for 32 weeks. Tumor counts were recorded on a weekly basis for 30 weeks. Effects of SD on the expression of caspases were investigated to elucidate the possible mechanism of action. The proteins from epidermal homogenates of experimental mice were used for SDS-PAGE and Western blotting using specific antibodies against caspase-3, caspase-8 and caspase-9 respectively. TUNEL assay was used for determining DNA fragmented apoptotic cells in situ. Results showed that at the end of experiment, tumor multiplicity in control and SD treatment groups was 25.8 and 16.5 tumors per mouse respectively. Furthermore, Topical treatment of SD induced DNA fragmented apoptotic cells by upgrading the expressions of cleaved caspase-3 and caspase-8. This study clearly suggested that SD could be an effective chemopreventive agent for UVB-induced skin cancer by inducing caspase dependent apoptosis. Full article

Sarcotriol (ST) has been shown to be chemopreventive on 7,12-dimethylbenz( a)anthracene (DMBA) initiated and 12-O-tetradecanoylphorbol-13-acetate (TPA)- promoted skin tumor development in CD-1 mice in recent studies from our laboratory. The objective of this study was to determine the chemopreventive effects of ST on ultraviolet B (UVB)-induced skin tumor development in female SKH-1 hairless mice, an experimental model relevant to human skin cancer development, and its possible mechanisms of action. Female SKH-1 mice were divided into two groups: Control and ST treated. Control was topically treated with 100 μL acetone and ST treated group administered with 30 μg ST in 100 μL acetone one hour before UVB exposure. For UVB-induced tumorigenesis, carcinogenesis was initiated and promoted by UVB (180 mJ/cm2). Group weights and tumor counts were taken once every week. After 30 weeks, mice were sacrificed and dorsal skin samples were collected. The proteins from the skin sample were further used for SDSPAGE and Western blotting using specific antibodies against caspase-3, caspase-8, caspase-9 and p53. Tumor multiplicity was found 19.6, 5.2 in the control and ST treated groups respectively. Caspase-3, -8, -9 and p53 were significantly (P < 0.05) upregulated in ST treated group compared to Control group. Together, this study for the first time identifies the chemopreventive effects of ST in UVB-induced carcinogenesis possibly by inducing apoptosis and upregulating p53. Full article

Sarcophine derivatives have been suggested to be chemopreventive in nature. One of its derivatives, Sarcotriol (ST), was investigated to study the skin cancer chemopreventive effects in female CD-1 mice. Three groups (control, promotion, initiation) of 30 female CD-1 mice each were taken. Carcinogenesis was initiated with 7, 12-dimethylbenz (a) anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA). One hour before treating with DMBA (200 nmol/100 μl acetone), control and promotion groups were treated with acetone (100 μl) and initiation group with ST (30μg/100μl of acetone). Beginning one week after initiation with DMBA, control and initiation groups were treated with acetone and promotion group with ST (30μg/100μl of acetone), one hour before treating with TPA (5 nmol/100 μl acetone). This was carried out twice a week for the next 20 weeks. The effects of ST on ³H-thymidine incorporation in epidermal DNA, the possible role of apoptotic proteins and COX-2 involved in the prevention of skin tumor development of CD-1 mice were investigated. Tumor incidence and multiplicity was found to be 100%, 73%, 100% and 8.2, 4.8, 9.7 in control, promotion and initiation groups respectively. ST treatment resulted in a significant (P < 0.05) inhibition in the incorporation of ³H-thymidine in epidermal DNA. The promotion group showed higher levels of caspase-3, -8 and –9 compared to the control. COX-2 expression was significantly lower (P < 0.05) in the promotion group as compared to the control. No significant difference in caspase-3, -8, -9 and COX-2 levels were observed in the initiation group compared to control. Together, this study confirms the chemopreventive effects of ST, and for the first time identifies the stage of carcinogenesis at which ST exerts its chemopreventive effect, and elucidates the mechanism possibly by inducing apoptosis and decreasing the COX-2 levels, contributing to its overall cancer chemopreventive effects in the mouse skin cancer model. Full article