Colon 26-L5 Carcinoma Research Articles

Synthesis and structure–activity relationships studies of brartemicin analogs as anti-invasive agents

Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to find more potent anti-invasive agents and study the structure-activity relationships, a series of 19 brartemicin analogs were prepared via two synthetic routes from α,α-D-trehalose and evaluated for their anti-invasive activities. Compound 4f, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose, was more potent than the natural brartemicin. It inhibited the invasion of murine colon 26-L5, colon carcinoma SW620, melanoma B16-BL6 and breast MDA-MB-231 cells with IC50 values of 0.15, 2.35, 4.12 and 2.61 μM, respectively. Analog 4p, 6,6'-bis(3,4-dimethoxycinnamoyl)-α,α-D-trehalose, was as potent as brartemicin against invasion of murine colon 26-L5 carcinoma cells in vitro. The structure-activity relationships of these novel trehalose-based compounds were summarized.

Cancer upregulated gene 2, a novel oncogene, confers resistance to oncolytic vesicular stomatitis virus through STAT1-OASL2 signaling

We have recently found a novel oncogene, named cancer upregulated gene 2 (CUG2), which activates Ras and mitogen-activated protein kinases (MAPKs), including ERK, JNK and p38 MAPK. Because activation of these signaling pathways has previously been shown to enhance cancer cell susceptibility to oncolysis by certain viruses, we examined whether vesicular stomatitis virus (VSV) could function as a potential therapeutic agent by efficiently inducing cytolysis in cells transformed by CUG2. Unexpectedly, NIH3T3 cells stably expressing CUG2 (NIH-CUG2) were resistant to VSV because of the activation of signal transducers and activators of transcription 1 (STAT1). The result was supported by evidence showing that suppression of STAT1 with short interference RNA (siRNA) renders cells susceptible to VSV. Furthermore, 2'-5' oligoadenylate synthetase-like (OASL) 2 was the most affected by STAT1 expression level among anti-viral proteins and furthermore suppression of OASL2 mRNA level caused NIH-CUG2 cells to succumb to VSV as seen in NIH-CUG2 cells treated with STAT1 siRNA. In addition, Colon26L5 carcinoma cells stably expressing CUG2 (Colon26L5-CUG2) exhibited resistance to VSV, whereas Colon26L5 stably expressing a control vector yielded to VSV infection. Moreover, Colon26L5-CUG2 cells stably suppressing STAT1 succumbed to VSV infection, resulting in apoptosis. Taken together, we propose that VSV treatment combined with the selective regulation of genes such as STAT1 and OASL2 will improve therapeutic outcomes for CUG2-overexpressing tumors.

Synthesis and evaluation of trehalose-based compounds as anti-invasive agents

Brartemicin is a trehalose-based inhibitor of tumor cell invasion produced by the actinomycete of the genus Nonomuraea. In order to explore the preliminary structure-activity relationship and obtain more potent inhibitors, a series of brartemicin analogs were synthesized through the Mitsunobu coupling of the secondary hydroxyls benzyl protected α,α-D-trehalose with benzoic acid derivatives, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells in vitro. Among the synthetic analogs tested, 6,6'-bis(2,3-dimethoxybenzoyl)-α,α-D-trehalose (5e) was found to be the most potent anti-invasive agent, exhibited a 2.6-fold improvement with regard to the parent natural product brartemicin, and it is considered to be a promising lead molecule for the anti-metastasis.

Cytotoxicity of Constituents from Mexican Propolis against a Panel of Six Different Cancer Cell Lines

The cytotoxicity of 39 compounds, including eighteen flavonoids (flavanones, 1-10; flavones, 11-17; flavanol, 18), sixteen phenolic acid derivatives (aromatic acids, 19-24; aldehyde, 25; esters, 26-34) and five glycerides (35-39), isolated from Mexican propolis, were evaluated against a panel of six different cancer cell lines; murine colon 26-L5 carcinoma, murine B16-BL6 melanoma, murine Lewis lung carcinoma, human lung A549 adenocarcinoma, human cervix HeLa adenocarcinoma and human HT-1080 fibrosarcoma. A phenylpropanoid-substituted flavanol, (2R,3S)-8-[4-phenylprop-2-en-1-one]-4',7-dihydroxy-3',5-dimethoxyflavan-3-ol (18), showed the most potent cytotoxicity against A549 cells (IC50, 6.2 microM) and HT-1080 cells (IC50, 3.9 microM), stronger than those of the clinically used anticancer drug, 5-fluorouracil (IC50, 7.5 microM and 5.4 microM, respectively). Based on the observed results, the structure-activity relationships are discussed.

Cytotoxic Activity of Quassinoids from Eurycoma longifolia

Twenty-four quassinoids isolated from Eurycoma longifolia Jack were investigated for their cytotoxicity against a panel of four different cancer cell lines, which includes three murine cell lines [colon 26-L5 carcinoma (colon 26-L5), B16-BL6 melanoma (B16-BL6), Lewis lung carcinoma (LLC)] and a human lung A549 adenocarcinoma (A549) cell line. Among the tested compounds, eurycomalactone (9) displayed the most potent activity against all the tested cell lines; colon 26-L5 (IC50 = 0.70 microM), B16-BL6 (IC50 = 0.59 microM), LLC (IC50 = 0.78 microM), and A549 (IC50 = 0.73 microM). These activities were comparable to clinically used anticancer agent doxorubicin (colon 26-L5, IC50 = 0.76 microM; B16-BL6, IC50 = 0.86 microM; LLC, IC50 = 0.80 microM; A549, IC50 = 0.66 microM).

ChemInform Abstract: Staminolactones A and B and Norstaminol A: Three Highly Oxygenated Staminane-Type Diterpenes from Orthosiphon stamineus.

[formula: see text] Staminolactones A (1) and B (2) and norstaminol A (3), three highly oxygenated staminane-type diterpenes having mild cytotoxic activities against highly liver-metastatic colon 26-L5 carcinoma cells, were isolated from the aerial part of the Vietnamese medicinal plant Orthosiphon stamineus (Lamiaceae). Their structures were elucidated on the basis of the extensive spectral analyses.

Cytotoxic Constituents of Soymida febrifuga from Myanmar

The 70% ethanol extract of Soymida febrifuga was found to kill PANC-1 human pancreatic cancer cells preferentially under nutrition-deprived conditions at a concentration of 10 microg/mL. Phytochemical investigation led to the isolation of 27 compounds including four new compounds [(3R)-6,4'-dihydroxy-8-methoxyhomoisoflavan (1), (2R)-7,4'-dihydroxy-5-methoxy-8-methylflavan (2), 7-hydroxy-6-methoxy-3-(4'-hydroxybenzyl)coumarin (3), and 6-hydroxy-7-methoxy-3-(4'-hydroxybenzyl)coumarin (4)]. 2',4'-Dihydroxychalcone (8) displayed the most potent preferential cytotoxicity (PC(50) 19.0 microM) against PANC-1 cells. In addition, the cytotoxic activity against colon 26-L5 carcinoma (colon 26-L5), B16-BL6 melanoma (B16-BL6), lung A549 adenocarcinoma (A549), cervix HeLa adenocarcinoma (HeLa), and HT-1080 fibrosarcoma (HT-1080) cell lines and their structure-activity relationship are discussed. The cytotoxic activity of 4'-hydroxy-3,5-dimethoxystilbene (6) against colon 26-L5 (IC(50) 2.96 microM) was found to be stronger than the positive control, doxorubicin, at IC(50) 3.12 microM.

Synthesis and evaluation of myxochelin analogues as antimetastatic agents

Myxochelin A ( 1) is an inhibitor of tumor cell invasion produced by the bacterium belonging to the genus Nonomuraea. In order to obtain more potent inhibitors, a series of myxochelin analogues [ 2 and ( S)- 3– 17] were synthesized through the coupling of lysine or diaminoalkane derivatives and appropriately protected hydroxybenzoate, followed by modification of functional groups and deprotection. These compounds were evaluated for their inhibitory activity against invasion of murine colon 26-L5 carcinoma cells. Among the synthetic analogues tested, compound ( S)- 6 which possesses carbamoyl group at C-1 was found to be the most potent antiinvasive agent and is considered to be a promising lead molecule for the antimetastasis. Compound ( S)- 6 was also shown to inhibit gelatinase activities of MMP-2 and MMP-9 and in vivo lung metastasis in mice.

Cytotoxic Constituents of Propolis from Myanmar and Their Structure-Activity Relationship

Thirteen cycloartane-type tritepenes (1-13) and four prenylated flavanones (14-17) isolated from propolis collected in Myanmar, were evaluated for their cytotoxic activity against a panel of six different cancer cell lines; three murine cancer cell lines (colon 26-L5 carcinoma, B16-BL6 melanoma, and Lewis lung carcinoma) and three human cancer cell lines (lung A549 adenocarcinoma, cervix HeLa adenocarcinoma and HT-1080 fibrosarcoma). Among them, a cycloartane-type triterpene, 3alpha,27-dihydroxycycloart-24E-en-26-oic acid (3), showed the most potent cytotoxicity against B16-BL6 cells with an IC(50) value of 5.91 microM, comparable to those of positive controls, doxorubicin (IC(50), 5.66 microM) and 5-fluorouracil (IC(50), 4.88 microM). In addition, (2S)-5,7-dihydroxy-4'-methoxy-8,3'-diprenylflavanone (14) exhibited strong cytotoxicity against all the tested cancer cell lines with the IC(50) values ranging from 14.0 to 26.4 microM. Based on the observed results, the structure-activity relationships are discussed.

Antitumor Anthraquinones from an Endophytic Actinomycete Micromonospora lupini sp. nov.

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Antitumor anthraquinones from an endophytic actinomycete Micromonospora lupini sp. nov.

Two novel anthraquinones, lupinacidins A ( 1) and B ( 2), have been isolated from the culture broth of a new endophytic actinomycete belonging to the genus Micromonospora. Lupinacidins were found to show significant inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells without inhibiting cell growth.

Differential Effects of Antioxidants on the In Vitro Invasion, Growth and Lung Metastasis of Murine Colon Cancer Cells

We conducted a comparative study of 20 antioxidants including antioxidative vitamins and polyphenols to examine their inhibitory activities against the in vitro invasion, growth and experimental lung metastasis of murine colon 26-L5 carcinoma cells. Among the compounds tested, epigallocatechin gallate (EGCG), gallocatechin gallate and genistein exhibited significant reductions at 77%, 46% and 44% in tumor metastasis by an intraperitoneal administration for 5 d beginning at 3 d before tumor inoculation, respectively. Quercetin also showed a slight but not statistically significant inhibition. Alpha-tocopherol, beta-carotene, ascorbic acid and 2 EGCG-related compounds of epicatechin gallate and epigallocatechin had no effect. EGCG also inhibited tumor metastasis dose-dependently with 98% suppression at 2 micromol; and an almost equivalent inhibition was also produced by only pre-administration of EGCG at the same dose before tumor inoculation. EGCG significantly inhibited tumor cell invasion and proliferation, but its inhibition of these activities was much less effective than that of other compounds which did not show any antimetastatic effect. No statistically significant relationship was observed between the radical scavenging activities of the test compounds and their rates of inhibition of tumor metastasis. The antimetastatic mechanism of EGCG thus seems to be independent of its inhibition of tumor invasion and growth, as well as its radical scavenging activity. Our results suggest that EGCG is potentially beneficial for tumor metastasis inhibition.

Absolute Configuration and Antitumor Activity of Myxochelin A Produced by Nonomuraea pusilla TP-A0861†

In the screening of antitumor compounds from microbial secondary metabolites, myxochelin A was isolated from a culture broth of Nonomuraea pusilla TP-A0861. The absolute configuration was determined to be S by synthesizing both enantiomers from an L- or D-lysine derivative and comparing their specific rotations. Both enantiomers of myxochelin A showed remarkable inhibitory effects on the invasion of murine colon 26-L5 carcinoma cells at non-cytotoxic concentrations.

Colon26-L5 대장암 세포를 이용한 간전이 모델에 산삼약침 처치가 혈중 cytokine에 미치는 영향

Objective : This experiment was conducted to evaluate inhibitory effects against hepatic metastasis by cultivated wild ginseng Herbal Acupuncture. Methods : Colon26-L5 carcinoma cells were injected through hepatic portal vein to induce hepatic metastatic cancer. After treated cultivated wild ginseng Herbal Acupuncture and investigated various kinds of cytokine level using cytokine chip. Results : 1. Mice treated with cultivated wild ginseng Herbal Acupuncture reduced the level of , , and compared to the control group. 2. Mice treated with cultivated wild ginseng Herbal Acupuncture was not showed significant change in the level of IL-4, IL-l0, IL-12 and compared to the control group. 3. Observing the level of various kinds of cytokine, cultivated wild ginseng Herbal Acupuncture was suppressed pro-inflammatory cytokine. These findings indicate cultivated wild ginseng Herbal Acupuncture is possible to use the inflammatory disease and futher studies carry out for the explanation of anticancer mechanism.

Increased surgical stress promotes tumor metastasis

Background. Although it is well-known that excessive surgical stress augments the growth of residual cancer and metastasis, whether surgical stress is increased according to the degree of surgical manipulation and can consequently lead to the enhancement of cancer metastasis has not been thoroughly examined. Moreover, the molecules associated with response for stress-enhanced metastasis have not been well-analyzed. The aim of this study was to examine whether cancer metastasis is enhanced with an increase of surgical stress with an experimental lung metastasis model and to analyze the related molecules responsible for stress-enhanced metastasis. Methods. Colon 26-L5 carcinoma cells (1.5 × 104/mouse) were injected intravenously into 6-week-old female BALB/c mice (Japan SLC, Hamamatsu, Japan). Two hours later, the mice were divided into 5 groups: untreated controls (the C group); mice given anesthesia only (the A group); mice given anesthesia and laparotomy (the AL group); mice given anesthesia, laparotomy, and appendectomy (the ALAp group); and mice given anesthesia, laparotomy, appendectomy, and left hepatic lobectomy (the ALApH group). The anesthesia procedures were the same in all groups (intraperitoneal administration of 0.8 mg/mouse sodium pentobarbital). In the AL, ALAp, and ALApH groups, a 3-cm long laparotomy was performed, and the time of the whole operation was just 5 minutes. All mice were killed 14 days after the procedures, and the number of lung metastases on the lung surface was counted manually. At the same time, BALB/c mice without tumor burden were given the same 5 kinds of surgical stress, and the messenger RNA expression of various metastasis-related molecules in the lung was measured with reverse transcriptase-polymerase chain reaction at 6, 24, and 48 hours after surgical stress. We also examined the effect of ONO-4817 (an inhibitor of matrix metalloproteinases ([MPs]) on lung metastasis in the mice with the 5 kinds of surgical stress. Results. The numbers of lung metastases on the lung surface and the messenger RNA expression of MMP-9, membrane type IBMMP, and urokinase-type plasminogen activator at 24 hours after surgery were enhanced in proportion to the degree of surgical stress. Moreover, ONO-4817 significantly inhibited lung metastasis. Conclusion. These results strongly suggest that increased surgical stress augments cancer metastasis via surgical stress-induced expression of proteinases in the target organ of metastasis. (Surgery 2003;133:547-55.)

Antiproliferative activity of cardenolides isolated from Streptocaulon juventas.

Sixteen cardenolides, two hemiterpenoids, two phenylpropanoids and a phenylethanoid isolated from the roots of Streptocaulon juventas (LOUR.) MERR. were examined for their antiproliferative activity toward three human-derived (HT-1080 fibrosarcoma, lung A549 adenocarcinoma, cervix HeLa adenocarcinoma) and three murine-derived (colon 26-L5 carcinoma, Lewis lung carcinoma, B16-BL6 melanoma) cell lines. The cardenolides selectively and strongly inhibited proliferation of the HT-1080 (IC(50) values, 0.054-1.6 microM) and A549 (IC(50), 0.016-0.65 microM) cell lines. The characteristic morphological changes and ladder-like DNA fragmentation in those cells treated with the cardenolides indicated the antiproliferative activity was due to the induction of apoptosis.

Inhibitory effects of caffeic acid phenethyl ester analogues on experimental lung metastasis of murine colon 26-L5 carcinoma cells.

We have previously examined the antiproliferative activity of caffeic acid phenethyl ester (CAPE) and its 20 analogues against six tumor cell lines, and found that CAPE analogues possess selective antiproliferative activity toward the murine colon 26-L5 carcinoma cell line. To extend our study, the effects of CAPE analogues on the metastatic development of murine colon 26-L5 carcinoma cells in the lung were examined. The oral administration of CAPE (5 mg/mice/d) for 7 d after tumor inoculation decreased the tumor weight and the number of tumor nodules in the lung by 50% and 50%, respectively, compared to the control, while CAPE (5 mg/mice/d) administered for 7 d before tumor inoculation showed no significant effect. Besides CAPE, 4-phenylbutyl caffeate, 8-phenyl-7-octenyl caffeate, 2-cyclohexylethyl caffeate and n-octyl caffeate at an oral dose of 2 mg/mice/d caused a 55%, 43%, 55% and 35% reduction of the tumor nodules in their lung metastasis formation, respectively. These results further elaborate the possibility of CAPE and its analogues to become a new class of chemopreventive agents for the treatment of colon cancer metastasis.

Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells

Morphine is frequently used for cancer patient's terminal medical care to relieve cancer pain. In the present study, we examined the inhibitory effect of morphine on experimental lung metastasis and invasion of colon 26-L5 cells. Morphine was found to significantly reduce the number of tumor colonies and the weight of the tumor-containing lung. Morphine inhibited the adhesion and migration of colon 26-L5 cells to extracellular matrix components and invasion into reconstituted basement membrane Matrigel, without affecting the cell proliferation in vitro. Notably, naloxone, an antagonist of morphine, abrogated morphine-induced inhibition of tumor cell adhesion, but did not affect the inhibitory effect on the production of matrix metalloproteinases (MMPs) from tumor cells. These results suggest that morphine inhibited the adhesive and invasive properties of tumor cells by different inhibitory mechanisms that involved the mediation of an opioid receptor.

Three new C-14 oxygenated taxanes from the wood of Taxus yunnanensis.

Three new C-14 oxygenated taxane-type diterpenes, hongdoushans A-C (1-3), were isolated from the wood of Taxus yunnanensis together with four known diterpenes and two lignans. The absolute stereochemistry of the 2-methylbutyryloxy group attached at C-14 of the taxane skeleton was determined to be S by GC analysis of the methyl ester of 2-methylbutyric acid obtained after alkaline hydrolysis of 1 and 4 followed by treatment with CH(2)N(2). The complete stereostructure of the known compound 2alpha,5alpha,10beta-triacetoxy-14beta-[(S)-2-methylbutyryloxy]-4(20),11-taxadiene (4) was established for the first time. The isolates obtained were evaluated for their antiproliferative activity toward murine colon 26-L5 carcinoma and human HT-1080 fibrosarcoma cell lines.

Antimetastatic and immunomodulating properties of a new herbal prescription, Bojung-bangam-tang

We investigated the antimetastatic effect of Bojung-bangam-tang, a new herbal prescription, on liver metastasis by the inoculation of colon 26-L5 carcinoma cells into the portal vein. Oral administration of Bojung-bangam-tang for 15 days from day 7 before tumor inoculation significantly inhibited liver metastasis in a dose-dependent manner. Bojung-bangam-tang enhanced the mitogenic activity of BALB/c whole splenocytes induced by various mitogenic stimuli. Oral administration of Bojung-bangam-tang, by itself, could not induce the production of interleukin (IL)-12 or IFN-γ by macrophages, but enhanced the potential of macrophages to produce cytokines in response to lipopolysaccharide (LPS). Experiments using macrophage- or natural killer (NK) cell-deficient mice revealed that the antimetastatic effect of Bojung-bangam-tang is mediated by macrophages rather than NK cells. Bojung-bangam-tang caused a marked increase of production of Th1 cytokine (IFN-γ) and decrease of production of Th2 cytokine (IL-4) by splenocytes stimulated with concanavalin A (Con A). These results indicated that oral administration of Bojung-bangam-tang inhibited the liver metastasis of colon 26-L5 cells through a mechanism leading to a Th1 dominant immune state and activation of macrophages. Thus, Bojung-bangam-tang may be useful for the prevention of cancer metastasis.