ABSTRACT
Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were designed with the inspiration of Loureirin, a DHC extracted from Resina Draconis, and synthesized by classical Claisen-Schmidt reactions. Afterwards the reduction reactions were carried out to obtain the corresponding DHCs. Cytotoxicity assay indicated chalcones and DHCs possessed selective cytotoxicity against colorectal cancer (CRC) cells. The preliminary structure-activity relationships (SAR) of these compounds suggested the α, ß-unsaturated ketone of the chalcones were crucial for the anticancer activity. Interestingly, compounds 3d and 4c exhibited selective anticancer activity against CRC cell line HCT116 with IC50s of 8.4 and 17.9 µM but not normal cell. Moreover, 4c could also inhibit the migration and invasion of CRC cells. Mechanism investigations showed 4c could induce cell cycle G2/M arrest by regulating cell cycle-associated proteins and could also up-regulate Fas cell surface death receptor. The virtual docking further pointed out that compounds 3d and 4c could nicely bind to the Fas/FADD death domain complex (ID: 3EZQ). Furthermore, silencing of Fas significantly enhanced the proliferation of CRC cells and attenuated the cytotoxicity induced by 4c. These results suggested 4c exerted its anticancer activity possibly regulating cell cycle and Fas death receptor. In summary, this study investigated the anticancer activity and mechanism of Loureirin analogues in CRC, suggesting these compounds may warrant further investigation as promising anticancer drug candidates for the treatment of CRC.
Subject(s)
Antineoplastic Agents , Chalcones , Colorectal Neoplasms , fas Receptor , Humans , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Chalcones/pharmacology , Chalcones/chemistry , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , fas Receptor/metabolism , Structure-Activity Relationship , HCT116 Cells , Molecular Docking Simulation , Cell Movement/drug effects , Cell Cycle/drug effects , Cell Line, TumorABSTRACT
BACKGROUND: The importance of multiple genes-environment interaction (G × E) has been highlighted in studies on depressive symptoms. 5-HTTLPR and BDNF Val66Met polymorphisms, with functional interconnection, have been implicated in the pathophysiology of depressive symptoms. However, little is understood about whether the interaction of 5-HTTLPR, BDNF Val66Met and parenting fits better with the epistatic or cumulative manner. METHODS: 865 adolescents (T1: Mage = 12.32, 50.2% girls) were included in a three-year interval longitudinal design. Standardized questionares about parenting and depressive symptoms were collected. Saliva samples were collected for genotyping. RESULTS: Neither the concurrent nor longitudinal interaction of 5-HTTLPR, BDNF Val66Met and parenting (G × G × E) showed significant effects on depressive symptoms. The interaction between cumulative genotypes and positive parenting (CG × E) was significant, with the strong differential susceptibility model, for depressive symptoms concurrently but not longitudinally after statistical correction. Adolescents who carried 3 (i.e. SS and Val/Met, L allele and Val/Val) and 4 (i.e. SS and Val/Val), not 1 (i.e. L allele and Met/Met) or 2 cumulative susceptibility alleles (i.e. SS and Met/Met, L allele and Val/Met), reported fewer depressive symptoms if they had experienced higher levels of positive parenting, and more symptoms under lower levels of positive parenting. LIMITATIONS: This study did not examine the 5-HTTLPR triallelic (rs25531) marker and did not include an external sample. CONCLUSIONS: The combined effects of 5-HTTLPR and BDNF Val66Met polymorphisms functioned in a manner of cumulative rather than epistatic in response to positive parenting on early adolescent depressive symptoms.