Recent observations suggest a lower incidence of malignancies in patients infected with HIV during treatment with Highly Active Anti-Retroviral Therapy (HAART) utilizing protease inhibitors. We investigated the effects of ritonavir, a FDA approved HIV protease inhibitor, on proliferation of pancreatic ductal adeno-carcinoma (PDAC) cell lines. Human PDAC cell lines BxPC-3, MIA PaCa-2, and PANC-1 were propagated under standard conditions and treated with serial dilutions of ritonavir. Ritonavir inhibited cell growth in a dose-dependent manner as well as activated the intrinsic apoptotic pathway in human pancreatic ductal adenocarcinoma (PDAC) cell lines. We observed down-modulation of cell-cycle promoting and up-regulation of cell-cycle inhibitory genes; enhanced interaction of retinoblastoma protein (RB) with E2F-1 transcription factor; inhibition of phosphorylation of RB, resulting in sequestration of E2F-1 and subsequent down-regulation of S phase genes; decreased interaction of E2F-1 with its consensus binding sites; inhibition of cell motility and invasiveness; and inhibition of the AKT pathway. Our results demonstrate a potential use of ritonavir as part of combination chemotherapy for PDAC. Since ritonavir is FDA approved for HIV, drug repositioning for PDAC would limit the costs and reduce risks.

Background: Herbicides are classified either by toxicity or by mechanism of action, based on the chemical nature of the compound. Herbicides fall into two categories. Contact the herbicide and the transferred herbicide. Herbicides have been selected because they are highly toxic to plants and less toxic to animals and humans, but the main concern is the direct toxic effects of herbicides on animals. Since ketol acid reductoisomerase (KARI) is considered an acceptable target for most amide herbicides, this study conducted an in-silico analysis of KARI from Staphylococcus aureus against eight amide herbicides, obsessed with investigating by performing virtual molgro molecule docking. Materials and Methods: The ilvC gene encoding KARI from Staphylococcus aureus was amplified and its sequence and chimera were checked using the GenBank project`s CHIMERA CHECK program. It uses the BLAST algorithm and the GenBank database to compare the environment sequence with the GenBank sequence to find evolutionary relatives. Homology modeling of Staphylococcus aureus ketol acid reductoisomerase (KARI) was performed because its threedimensional structure revealed by either X-ray crystallography or NMR studies was not available. The generated model was used to repeat the energy minimization cycle many times using SPDBV software, and the final model was also used to perform docking analysis against the amide herbicide used in the inhibitor study. Results: The amplified DNA fragment containing 1005 base sequence BLAST hit, shows an absolute open reading frame encoding the Staphylococcus aureus protein KARI. PROSITE method shows active site residues Gln28,