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Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA
John D. Dingell VA Medical Center, Lab 4242, 4646 John R Street, Detroit, MI 48201, USA
NEA Baptist Clinic, Jonesboro, AR 72401, USA
Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada
Baptist Memorial Medical Group, Memphis, TN 38120, USA
Virocan Therapeutics R&D division, Yashaswi Hospital, Guntur 522007, India
Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India,
* Author to whom correspondence should be addressed.
Received: 15 November 2013; in revised form: 20 December 2013 / Accepted: 2 January 2014 / Published: 9 January 2014
Abstract: 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.
Keywords: ritonavir; pancreatic adenocarcinoma; AKT; retinoblastoma; 2F-1
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Batchu, R.B.; Gruzdyn, O.V.; Bryant, C.S.; Qazi, A.M.; Kumar, S.; Chamala, S.; Kung, S.T.; Sanka, R.S.; Puttagunta, U.S.; Weaver, D.W.; Gruber, S.A. Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways. Pharmaceuticals 2014, 7, 46-57.
Batchu RB, Gruzdyn OV, Bryant CS, Qazi AM, Kumar S, Chamala S, Kung ST, Sanka RS, Puttagunta US, Weaver DW, Gruber SA. Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways. Pharmaceuticals. 2014; 7(1):46-57.
Batchu, Ramesh B.; Gruzdyn, Oksana V.; Bryant, Christopher S.; Qazi, Aamer M.; Kumar, Sanjeev; Chamala, Sreedhar; Kung, Shu T.; Sanka, Ramana S.; Puttagunta, Udaya S.; Weaver, Donald W.; Gruber, Scott A. 2014. "Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways." Pharmaceuticals 7, no. 1: 46-57.