Increased mucus production is a common cause of morbidity and mortality in inflammatory airway diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the precise molecular mechanisms for pathogenic mucus production are largely undetermined. Accordingly, there are no specific and effective anti-mucus therapeutics. Here, we define a signaling pathway from chloride channel calcium-activated 1 (CLCA1) to MAPK13 that is responsible for IL-13-driven mucus production in human airway epithelial cells. The same pathway was also highly activated in the lungs of humans with excess mucus production due to COPD. We further validated the pathway by using structure-based drug design to develop a series of novel MAPK13 inhibitors with nanomolar potency that effectively reduced mucus production in human airway epithelial cells. These results uncover and validate a new pathway for regulating mucus production as well as a corresponding therapeutic approach to mucus overproduction in inflammatory airway diseases.
Twenty nine Amaryllidaceae alkaloids and their derivatives belonging to five most common groups, including lycorine-, lycorenine-, tazettine-, crinine-, and narciclasine-types, were evaluated for antiproliferative, apoptosis inducing and antiinvasive activities in vitro. The antiproliferative properties of each test compound are in agreement with those reported in the literature, while the high potency of amarbellisine is reported for the first time. It was also found that with the exception of ungeremine, amarbellisine and hippeastrine, the antiproliferative effect of the potent compounds is apoptosis-mediated. Thus, apoptosis in Jurkat cells was triggered by narciclasine, narciclasine tetraacetate, C10b-R-hydroxypancratistatin, cis-dihydronarciclasine, trans-dihydronarciclasine, lycorine, 1-O-acetyllycorine, lycorine-2-one, pseudolycorine, and haemanthamine. With the exception of narciclasine, lycorine and haemanthamine, the apoptosis inducing properties of these compounds are reported for the first time. The collagen type I invasion assay revealed potent antiinvasive properties associated with N-methyllycorine iodide, hippeastrine, clivimine, buphanamine, and narciclasine tetraacetate, all of which were tested at non-toxic concentrations. The antiinvasive activity of buphanamine is particularly promising since this alkaloid is not toxic to cells even at much higher doses. This work has resulted in identification of several novel leads for anticancer drug design.
Background: CLCA proteins activate CaCCs; CLCAs have roles in cancer and inflammatory lung diseases, but their mechanism of action is unknown. Results: CLCA proteins must undergo self-cleavage via their own novel metalloprotease domain in the N terminus to activate CaCCs. Conclusion: Self-cleavage unmasks the N-terminal fragment, which alone activates CaCCs. Significance: This work identifies a unique ion channel activation mechanism defining framework to understand CLCA functions in diseases.
Abstract. Ethnotraditional use of plant-derived natural products plays a significant role in the discovery and development of potential medicinal agents. Plants of the genus Taraxacum, commonly known as dandelions, have a history of use in Chinese, Arabian and Native American traditional medicine, to treat a variety of diseases including cancer. To date, however, very few studies have been reported on the anti-carcinogenic activity of Taraxacum officinale (TO). In the present study, three aqueous extracts were prepared from the mature leaves, flowers and roots, and investigated on tumor progression related processes such as proliferation and invasion. Our results show that the crude extract of dandelion leaf (DLE) decreased the growth of MCF-7/AZ breast cancer cells in an ERK-dependent manner, whereas the aqueous extracts of dandelion flower (DFE) and root (DRE) had no effect on the growth of either cell line. Furthermore, DRE was found to block invasion of MCF-7/ AZ breast cancer cells while DLE blocked the invasion of LNCaP prostate cancer cells, into collagen type I. Inhibition of invasion was further evidenced by decreased phosphorylation levels of FAK and src as well as reduced activities of matrix metalloproteinases, MMP-2 and MMP-9. This study provides new scientific data on TO and suggests that TO extracts or individual components present in the extracts may be of value as novel anti-cancer agents. IntroductionPlants of the genus Taraxacum, also known as dandelions, are members of the Asteraceae family. These perennial plants are widespread throughout the warmer temperate zones of the Northern Hemisphere and have been used for centuries as a remedy for various ailments by several societies. Dandelions play a pivotal role in traditional Chinese medicine (TCM) and are frequently used for treatment of breast, uterine and lung tumors as well as hepatitis and digestive diseases (1,2), while Native Americans use dandelion roots and herbs to treat kidney disease, dyspepsia and heartburn. In traditional Arabian medicine, dandelions have been applied to remedy liver and spleen disorders (3), whereas European herbalists authorize the use of dandelions for fever, boils, eye problems, diabetes and diarrhea (4).The variety of health benefits associated with the use of dandelions has been attributed to specific Taraxacum species as extracts of the whole plants or specific plant parts. Anticarcinogenic activities have been reported for the aqueous root extract of Taraxacum japonicum on mouse skin tumors (5). Further study revealed that taraxasterol and taraxerol, triterpenoids isolated from T. japonicum, were responsible for the observed effect on mouse skin tumors and that taraxasterol inhibited spontaneous mammary carcinogenesis, after oral administration (6). Taraxinic acid, isolated from Taraxacum coreanum showed potent antiproliferative activity against HL-60 cells (7) and the ethanolic extracts of the Chinese dandelion root (Taraxacum mongolicum) inhibited the growth of B16 2F2 mouse melanoma cells (8). Antitumor...
An efficient synthesis of C-1 derivatives of 7-deoxypancratistatin is reported. The key steps include the following: selective opening of an epoxide with aluminum acetylide in the presence of an aziridine; solid-state silica-gel-catalyzed opening of an aziridine; oxidative cleavage of a phenanthrene core and its recyclization to phenanthridone to provide the key C-1 aldehyde 22. The conversion of this aldehyde to C-1 acetoxymethyl and C-1 hydroxymethyl derivatives is described along with the evaluation of their biological activity against several cancer cell lines and in an apoptosis study. The C-1 acetoxymethyl derivative has shown promising activity comparable to that of the natural product. In addition, a total synthesis of trans-dihydrolycoricidine and a formal total synthesis of 7-deoxypancratistatin are reported from aldehyde 22. Detailed experimental and spectral data are provided for all new compounds.thudlicky@brocku.ca .
The mechanisms of invasion and metastasis are poorly understood. Our previous studies demonstrated that cancer cell invasion may result from reorganization of membrane molecules, thereby initiating signaling pathways. To increase our understanding on how cancer cells govern metastases we studied the established LNCaP prostate cancer progression model. Herein we show that the bone metastatic derivative cell line, C4-2B, displays changes in adhesion to collagen type I and invasion into collagen type I. Moreover, we found that these changes were concomitant with activation of the FAK/src/paxillin/Rac/JNK signaling pathway and increased activity of matrix metalloproteinases (MMPs)-2 and -9. Inhibition of src and JNK resulted in inhibition of adhesion and invasion, and deactivation of the signaling molecules in the identified pathway as well as reduced activity of MMPs. Additionally, we found a pivotal role for the integrin α2 subunit since lateral redistribution and clustering were responsible for activation of the downstream signaling and function blocking of the integrin α2 subunit resulted in poor adhesion and inhibition of invasion. In conclusion, our results suggest that invasion of prostate cancer cells can be ascribed to reorganization and clustering of integrin α2 subunits, resulting in activation of associated FAK/src/paxillin/Rac/JNK, leading to increased activity of MMPs and thus invasion.
Keywords: MAPK13; p38 MAP kinases. PDB reference: MAPK13/pTpY, 4mygSupporting information: this article has supporting information at journals.iucr.org/dThe crystal structure of phosphorylated MAPK13 reveals common structural features and differences in p38 MAPK family activation The p38 MAP kinases (p38 MAPKs) represent an important family centrally involved in mediating extracellular signaling. Recent studies indicate that family members such as MAPK13 (p38) display a selective cellular and tissue expression and are therefore involved in specific diseases. Detailed structural studies of all p38 MAPK family members are crucial for the design of specific inhibitors. In order to facilitate such ventures, the structure of MAPK13 was determined in both the inactive (unphosphorylated; MAPK13) and active (dual phosphorylated; MAPK13/pTpY) forms. Here, the first preparation, crystallization and structure determination of MAPK13/pTpY are presented and the structure is compared with the previously reported structure of MAPK13 in order to facilitate studies for structure-based drug design. A comprehensive analysis of inactive versus active structures for the p38 MAPK family is also presented. It is found that MAPK13 undergoes a larger interlobe configurational rearrangement upon activation compared with MAPK14. Surprisingly, the analysis of activated p38 MAPK structures (MAP12/pTpY, MAPK13/pTpY and MAPK14/pTpY) reveals that, despite a high degree of sequence similarity, different side chains are used to coordinate the phosphorylated residues. There are also differences in the rearrangement of the hinge region that occur in MAPK14 compared with MAPK13 which would affect inhibitor binding. A thorough examination of all of the active (phosphorylated) and inactive (unphosphorylated) p38 MAPK family member structures was performed to reveal a common structural basis of activation for the p38 MAP kinase family and to identify structural differences that may be exploited for developing family member-specific inhibitors.
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