ABSTRACT
Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.
Subject(s)
Diterpenes/pharmacology , Neoplasms/drug therapy , Neovascularization, Pathologic/drug therapy , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor Receptor-2/genetics , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/genetics , Andrographis paniculata , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Blood Vessels/drug effects , Blood Vessels/metabolism , Carrier Proteins/drug effects , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Collagen/pharmacology , Diterpenes/chemistry , Drug Combinations , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Laminin/pharmacology , Neoplasms/genetics , Neoplasms/pathology , Neovascularization, Pathologic/genetics , Neovascularization, Pathologic/pathology , Plant Extracts/chemistry , Protein Conformation/drug effects , Proteoglycans/pharmacology , Signal Transduction/drug effects , Vascular Endothelial Growth Factor A/chemistry , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
Curcumin, the bioactive component of turmeric also known as "Indian Yellow Gold," exhibits therapeutic efficacy against several chronic inflammatory and infectious diseases. Even though considered as a wonder drug pertaining to a myriad of reported benefits, the translational potential of curcumin is limited by its low systemic bioavailability due to its poor intestinal absorption, rapid metabolism, and rapid systemic elimination. Therefore, the translational potential of this compound is specifically challenged by bioavailability issues, and several laboratories are making efforts to improve its bioavailability. We developed a simple one-step process to generate curcumin nanoparticles of ~200 nm in size, which yielded a fivefold enhanced bioavailability in mice over regular curcumin. Curcumin nanoparticles drastically reduced hepatotoxicity induced by antitubercular antibiotics during treatment in mice. Most interestingly, co-treatment of nanoparticle-formulated curcumin along with antitubercular antibiotics dramatically reduced the risk for disease reactivation and reinfection, which is the major shortfall of current antibiotic treatment adopted by Directly Observed Treatment Short-course. Furthermore, nanoparticle-formulated curcumin significantly reduced the time needed for antibiotic therapy to obtain sterile immunity, thereby reducing the possibility of generating drug-resistant variants of the organisms. Therefore, adjunct therapy of nano-formulated curcumin with enhanced bioavailability may be beneficial to treatment of tuberculosis and possibly other diseases.