ABSTRACT
The deficiency in available targeted agents and frequency of chemoresistance are primary challenges in clinical management of triple-negative breast cancer (TNBC). The aberrant expression of USP21 and JAK2 represents a characterized mechanism of TNBC progression and resistance to paclitaxel (PTX). Despite its clear that high expression of USP21-mediated de-ubiquitination leads to increased levels of JAK2 protein, we lack regulator molecules to dissect the mechanisms that the interaction between USP21 and JAK2 contributes to the phenotype and resistance of TNBC. Here, we report a USP21/JAK2/STAT3 axis-targeting regulator 13c featuring a N-anthraniloyl tryptamine scaffold that showed excellent anti-TNBC potency and promising safety profile. Importantly, the therapeutic potential of using 13c in combination with PTX in PTX-resistant TNBC was demonstrated. This study showcases N-anthraniloyl tryptamine derivatives as a novel anti-TNBC chemotype with a pharmacological mode of action targeting the USP21/JAK2/STAT3 axis and provides a potential therapeutic target for the treatment of TNBC.
Subject(s)
Antineoplastic Agents , Janus Kinase 2 , STAT3 Transcription Factor , Triple Negative Breast Neoplasms , Ubiquitin Thiolesterase , Humans , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , STAT3 Transcription Factor/metabolism , STAT3 Transcription Factor/antagonists & inhibitors , Janus Kinase 2/metabolism , Janus Kinase 2/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Ubiquitin Thiolesterase/antagonists & inhibitors , Ubiquitin Thiolesterase/metabolism , Structure-Activity Relationship , Cell Proliferation/drug effects , Animals , Drug Discovery , Molecular Structure , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Small Molecule Libraries/chemical synthesis , Female , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Cell Line, Tumor , Mice , Paclitaxel/pharmacology , Paclitaxel/chemistryABSTRACT
Taking the drought-sensitive Dactylis glomerata line "01998" and drought-tolerant cultivar "Baoxing" as test materials, a pot experiment was conducted to study the effects of drought stress on the seedlings root growth, physiological characteristics, and leaf photosynthesis, aimed to approach the differences in the drought-tolerance mechanism of different D. glomerata lines (cultivars). Under drought stress, the root vitality and root number of "01998" and "Baoxing" presented a trend of increased first and decreased then. When the soil relative moisture content decreased to 30%, the root vitality and root number of "01998" and "Baoxing" increased significantly and reached the maximum. Drought stress decreased the relative water content, leaf chlorophyll content, net photosynthesis, transpiration, and stomatal conductance, but increased the electric conductivity and intercellular CO2 concentration of "01998" and "Baoxing". Under drought stress, the leaf area per plant of both "01998" and "Baoxing" decreased, and the underground and aboveground plant biomass of "01998" decreased while that of "Baoxing" had less change.
Subject(s)
Dactylis/physiology , Droughts , Photosynthesis/physiology , Plant Roots/growth & development , Stress, Physiological , China , Dactylis/growth & development , Ecosystem , Seedlings/physiologyABSTRACT
OBJECTIVE: To establish the HPLC profile of Ciwujia Injection. METHODS: HPLC profile of Ciwujia Injection from two different sources was developed. RESULTS: The methodological evaluation showed that this method had a good repeatability, and the ratio of common peak's area of different samples were different. CONCLUSION: This method can be used to differentiate Ciwujia Injection from different sources conveniently.