ABSTRACT
Significant evidence has accumulated suggesting that the inducible form of cyclooxygenase (COX-2), a central enzyme in the prostaglandin biosynthetic pathway, plays an important role in tumor development. To better understand the role of COX-2 in tumorigenesis, we generated transgenic mice that overexpress COX-2 under control of the human keratin 14 promoter, which allows for expression in the epidermis and some other epithelia. Transgenic mice, referred to as K14.COX2 mice, were readily distinguished from their nontransgenic littermates by the appearance of significant alopecia. Administration of a specific COX-2 inhibitor restored hair growth, indicating that the alopecia was attributable to elevated COX-2 enzymatic activity. Unexpectedly, COX-2 overexpression was found to protect, rather than sensitize, K14.COX2 mice to skin tumor development induced by an initiation/promotion protocol. K14.COX2 transgenics developed tumors at a much lower frequency than did their littermate controls (3.3% versus 93%, respectively, on a FVB background and approximately 25% versus 100%, respectively, on an ICR background) and presented with significantly reduced tumor burdens (average, 0.03 versus 12.7 tumors/mouse, respectively, on a FVB background and 0.5 versus 7.1 tumors/mouse, respectively, on an ICR background). Mice fed a COX-2 inhibitor in utero and as weanlings up to the time of promotion also showed a significant resistance to tumor development. These results clearly raise questions regarding the role of COX-2 and elevated prostaglandin levels in skin tumor development.
Subject(s)
Isoenzymes/biosynthesis , Prostaglandin-Endoperoxide Synthases/biosynthesis , Skin Neoplasms/enzymology , Skin Neoplasms/prevention & control , Skin/enzymology , 9,10-Dimethyl-1,2-benzanthracene , Alopecia/drug therapy , Alopecia/enzymology , Animals , Carcinogens , Celecoxib , Cyclooxygenase 2 , Cyclooxygenase 2 Inhibitors , Cyclooxygenase Inhibitors/pharmacology , Dinoprostone/metabolism , Female , Hair Follicle/drug effects , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/genetics , Male , Membrane Proteins , Mice , Mice, Inbred ICR , Mice, Transgenic , Phenotype , Prostaglandin-Endoperoxide Synthases/genetics , Pyrazoles , Skin/drug effects , Skin/metabolism , Skin Neoplasms/chemically induced , Sulfonamides/pharmacology , Tetradecanoylphorbol AcetateABSTRACT
The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kß. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described.