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.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer death, and more than 80% of patients present with distant metastases at the time of diagnosis, thereby precluding surgical resection
Exposure to 5–30 μM ritonavir for 72 h resulted in dose-dependent inhibition of cell proliferation and cell death in all three cell lines tested (Figure 1A–C) with negligible effects on normal human fibroblasts
PANC-1 cell death as observed by phase contract microscopy at 48 h increased as a function of ritonavir dose (Figure 1D)
Summary
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer death, and more than 80% of patients present with distant metastases at the time of diagnosis, thereby precluding surgical resection. Systemic chemotherapy still relies on only a few drugs and has not significantly increased overall patient survival [1], underscoring the need for development of novel therapies [2]. Recent observations point to a decreasing incidence of some cancers in patients on protease inhibitors [4], with our previous work demonstrating inhibition of cell growth and induction of apoptosis in ovarian cancer [5]. Along these lines, phase I clinical trials with nelfinavir showed partial remission with acceptable toxicity when used along with radiation and chemotherapy in patients with locally-advanced pancreatic cancer [6].
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