ABSTRACT
Chemotherapy treatment against pancreatic ductal adenocarcinoma (PDAC) is thwarted by tumoral activation of multiple therapy resistance pathways. The growth hormone (GH)-GH receptor (GHR) pair is a covert driver of multimodal therapy resistance in cancer and is overexpressed in PDAC tumors, yet the therapeutic potential of targeting the same has not been explored. Here, we report that GHR expression is a negative prognostic factor in patients with PDAC. Combinations of gemcitabine with different GHR antagonists (GHRAs) markedly improve therapeutic outcomes in nude mice xenografts. Employing cultured cells, mouse xenografts, and analyses of the human PDAC transcriptome, we identified that attenuation of the multidrug transporter and epithelial-to-mesenchymal transition programs in the tumors underlie the observed augmentation of chemotherapy efficacy by GHRAs. Moreover, in human PDAC patients, GHR expression strongly correlates with a gene signature of tumor promotion and immune evasion, which corroborate with that in syngeneic tumors in wild-type vs. GH transgenic mice. Overall, we found that GH action in PDAC promoted a therapy-refractory gene signature in vivo, which can be effectively attenuated by GHR antagonism. Our results collectively present a proof of concept toward considering GHR antagonists to improve chemotherapeutic outcomes in the highly chemoresistant PDAC.
Subject(s)
Carcinoma, Pancreatic Ductal , Deoxycytidine , Gemcitabine , Pancreatic Neoplasms , Receptors, Somatotropin , Xenograft Model Antitumor Assays , Animals , Humans , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Deoxycytidine/therapeutic use , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Pancreatic Neoplasms/genetics , Mice , Receptors, Somatotropin/metabolism , Receptors, Somatotropin/antagonists & inhibitors , Receptors, Somatotropin/genetics , Carcinoma, Pancreatic Ductal/drug therapy , Carcinoma, Pancreatic Ductal/metabolism , Carcinoma, Pancreatic Ductal/pathology , Carcinoma, Pancreatic Ductal/genetics , Cell Line, Tumor , Mice, Nude , Drug Resistance, Neoplasm/drug effects , Gene Expression Regulation, Neoplastic/drug effects , FemaleABSTRACT
Human growth hormone (hGH) is a pituitary-derived endocrine protein that regulates several critical postnatal physiologic processes including growth, organ development, and metabolism. Following adulthood, GH is also a regulator of multiple pathologies like fibrosis, cancer, and diabetes. Therefore, there is a significant pharmaceutical interest in developing antagonists of hGH action. Currently, there is a single FDA-approved antagonist of the hGH receptor (hGHR) prescribed for treating patients with acromegaly and discovered in our laboratory almost 3 decades ago. Here, we present the first data on the structure and function of a new set of protein antagonists with the full range of hGH actions-dual antagonists of hGH binding to the GHR as well as that of hGH binding to the prolactin receptor. We describe the site-specific PEG conjugation, purification, and subsequent characterization using MALDI-TOF, size-exclusion chromatography, thermostability, and biochemical activity in terms of ELISA-based binding affinities with GHR and prolactin receptor. Moreover, these novel hGHR antagonists display distinct antagonism of GH-induced GHR intracellular signaling in vitro and marked reduction in hepatic insulin-like growth factor 1 output in vivo. Lastly, we observed potent anticancer biological efficacies of these novel hGHR antagonists against human cancer cell lines. In conclusion, we propose that these new GHR antagonists have potential for development towards multiple clinical applications related to GH-associated pathologies.
Subject(s)
Human Growth Hormone , Receptors, Prolactin , Humans , Carrier Proteins/chemistry , Cell Line , Human Growth Hormone/antagonists & inhibitors , Human Growth Hormone/chemistry , Prolactin/chemistry , Receptors, Prolactin/antagonists & inhibitors , Receptors, Prolactin/chemistry , Receptors, Somatotropin/chemistry , Polyethylene Glycols/chemistryABSTRACT
A novel mixed-ligand Cu(II) complex of ciprofloxacin (cfH) and phenanthroline, is found to crystallize as a dimeric moiety containing monocationic and dicationic species. Two such dimeric moieties are found in the same unit cell leading to a dicationic cluster. The higher negative redox potential for this cluster dampens its antimycobacterial activity against M. smegmatis.
Subject(s)
Anti-Bacterial Agents/chemistry , Ciprofloxacin/chemistry , Copper/chemistry , Phenanthrolines/chemistry , Anti-Bacterial Agents/pharmacology , Ciprofloxacin/pharmacology , Copper/pharmacology , Ligands , Mycobacterium smegmatis/drug effects , Mycobacterium smegmatis/growth & development , Phenanthrolines/pharmacologyABSTRACT
The copper complexes of 5-amino-imidazole ligands were prepared and characterized by various spectroscopic techniques. The ligand geometry around the copper(II) centre is square pyramidal based on N2O2 donor atoms and a coordinated water molecule at the apex. Single crystal X-ray structures were determined for both ligands. Ligands and copper complexes exhibited dose-dependent antiproliferative effects on the growth of B16F10 melanoma cells line but lower IC50 values were observed for the copper complexes.
Subject(s)
Antineoplastic Agents/chemical synthesis , Melanoma/drug therapy , Organometallic Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Copper , Dose-Response Relationship, Drug , Imidazoles/chemical synthesis , Imidazoles/chemistry , Imidazoles/pharmacology , Inhibitory Concentration 50 , Ligands , Melanoma/pathology , Mice , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Spectrum Analysis , Structure-Activity RelationshipABSTRACT
Acetylpyridine benzoyl hydrazone (APBH) 1 and its copper complex [[(APBH)CuCl](2)].(EtOH) 2 were structurally characterized by elemental analysis, magnetic measurements, spectroscopy, electrochemistry and single crystal X-ray diffraction studies. The ligand assumes Z-isomeric form and planar geometry in solid state, coordinating through pyridyl nitrogen, azomethine nitrogen and the carbonyl oxygen of the benzoyl group. The copper complex is dimeric and has a distorted octahedral geometry in which the two copper atoms are bridged by two chloride atoms. Antimycobacterial screening of ligand and its copper compound against Mycobacterium smegmatis shows clear enhancement in the antitubercular activity upon copper complexation.
Subject(s)
Antitubercular Agents/chemistry , Copper/pharmacology , Hydrazines/pharmacology , Mycobacterium smegmatis/drug effects , Pyridines/pharmacology , Antitubercular Agents/pharmacology , Copper/chemistry , Crystallography, X-Ray , Dimerization , Electrochemistry , Hydrazines/chemistry , Ligands , Microbial Sensitivity Tests , Molecular Structure , Pyridines/chemistry , Spectrum Analysis , StereoisomerismABSTRACT
N(1)-Benzylidene-pyridine carboxamidrazones and their metal conjugates have emerged as a new class of potential antimycobacterial agents. Nine such carboxamidrazone analogs (L(1)-L(9)) along with their Cu(II) (MC(1)-MC(9)) and Fe(III) (MC(10)-MC(18)) complexes were synthesized. Single crystal X-ray structures of copper complexes MC(1) and MC(5) were determined which suggest slightly distorted square planer geometries for copper complexes and octahedral geometries for ferric compounds. All compounds were evaluated for their in vitro antimycobacterial activity against Mycobacterium tuberculosis H(37)Rv. The results show 32-64-fold enhancement in antitubercular activity upon copper complexation.
