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

Pharmaceuticals

Ramesh B. Batchu³  Oksana V. Gruzdyn³  Christopher S. Bryant²  Aamer M. Qazi¹  Sanjeev Kumar⁶  Sreedhar Chamala³  Shu T. Kung³  Ramana S. Sanka⁵  Udaya S. Puttagunta⁴  Donald W. Weaver³ 

[1] Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; E-Mail:;NEA Baptist Clinic, Jonesboro, AR 72401, USA; E-Mail:;Laboratory of Surgical Oncology & Developmental Therapeutics, Department of Surgery, Wayne State University, Detroit, MI 48201, USA; E-Mails:;Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India, E-Mail:;Virocan Therapeutics R&D division, Yashaswi Hospital, Guntur 522007, India; E-Mail:;Baptist Memorial Medical Group, Memphis, TN 38120, USA; E-Mail:

关键词: ritonavir;    pancreatic adenocarcinoma;    AKT;    retinoblastoma;    2F-1;   

DOI  :  10.3390/ph7010046

来源: mdpi

【 摘 要 】

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.

【 授权许可】

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