%0 Journal Article
%T Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways
%A Ramesh B. Batchu
%A Oksana V. Gruzdyn
%A Christopher S. Bryant
%A Aamer M. Qazi
%A Sanjeev Kumar
%A Sreedhar Chamala
%A Shu T. Kung
%A Ramana S. Sanka
%A Udaya S. Puttagunta
%A Donald W. Weaver
%A Scott A. Gruber
%J Pharmaceuticals
%D 2014
%I MDPI AG
%R 10.3390/ph7010046
%X 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.
%K ritonavir
%K pancreatic adenocarcinoma
%K AKT
%K retinoblastoma
%K 2F-1
%U http://www.mdpi.com/1424-8247/7/1/46