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Pharmaceuticals (Basel). 2014 Jan 9;7(1):46-57. doi: 10.3390/ph7010046.

Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways.

Author information

1
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. rbatchu@med.wayne.edu.
2
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. ovgruzdy@med.wayne.edu.
3
NEA Baptist Clinic, Jonesboro, AR 72401, USA. Chris.Bryant@NEABC.com.
4
Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. aamer.qazi@oicr.on.ca.
5
Baptist Memorial Medical Group, Memphis, TN 38120, USA. Sanjeev.kuman@bmg.md.
6
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. sreedharchamala94@yahoo.co.in.
7
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. skung@med.wayne.edu.
8
Virocan Therapeutics R&D division, Yashaswi Hospital, Guntur 522007, India. sramaraoson@gmail.com.
9
Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India,. pudayasri@gmail.com.
10
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. dweaver@med.wayne.edu.
11
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. scott.gruber@va.gov.

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.

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