Ritonavir-Mediated Induction of Apoptosis in Pancreatic Cancer Occurs via the RB/E2F-1 and AKT Pathways.
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.
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. rbatchu@med.wayne.edu.
Ramesh B
RB
Batchu
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. ovgruzdy@med.wayne.edu.
Oksana V
OV
Gruzdyn
NEA Baptist Clinic, Jonesboro, AR 72401, USA. Chris.Bryant@NEABC.com.
Christopher S
CS
Bryant
Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. aamer.qazi@oicr.on.ca.
Aamer M
AM
Qazi
Baptist Memorial Medical Group, Memphis, TN 38120, USA. Sanjeev.kuman@bmg.md.
Sanjeev
S
Kumar
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. sreedharchamala94@yahoo.co.in.
Sreedhar
S
Chamala
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. skung@med.wayne.edu.
Shu T
ST
Kung
Virocan Therapeutics R&D division, Yashaswi Hospital, Guntur 522007, India. sramaraoson@gmail.com.
Ramana S
RS
Sanka
Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India,. pudayasri@gmail.com.
Udaya S
US
Puttagunta
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. dweaver@med.wayne.edu.
Donald W
DW
Weaver
Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA. scott.gruber@va.gov.
Scott A
SA
Gruber