The human immunodeficiency virus protease inhibitor ritonavir inhibits lung cancer cells, in part, by inhibition of survivin

Anjaiah Srirangam, Monica Milani, Ranjana Mitra, Zhijun Guo, Mariangellys Rodriguez, Hitesh Kathuria, Seiji Fukuda, Anthony Rizzardi, Stephen Schmechel, David G. Skalnik, Louis M. Pelus, David A Potter

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Introduction: Ritonavir is a potential therapeutic agent in lung cancer, but its targets in lung adenocarcinoma are unknown, as are candidate biomarkers for its activity. Methods: RNAi was used to identify genes whose expression affects ritonavir sensitivity. Synergy between ritonavir, gemcitabine, and cisplatin was tested by isobologram analysis. Results: Ritonavir inhibits growth of K-ras mutant lung adenocarcinoma lines A549, H522, H23, and K-ras wild-type line H838. Ritonavir causes G0/G1 arrest and apoptosis. Associated with G0/G1 arrest, ritonavir down-regulates cyclin-dependent kinases, cyclin D1, and retinoblastoma protein phosphorylation. Associated with induction of apoptosis, ritonavir reduces survivin messenger RNA and protein levels more than twofold. Ritonavir inhibits phosphorylation of c-Src and signal transducer and activator of transcription protein 3, which are important events for survivin gene expression and cell growth, and induces cleavage of PARP1. Although knock down of survivin, c-Src, or signal transducer and activator of transcription protein 3 inhibits cell growth, only survivin knock down enhances ritonavir inhibition of growth and survivin overexpression promotes ritonavir resistance. Ritonavir was tested in combination with gemcitabine or cisplatin, exhibiting synergistic and additive effects, respectively. The combination of ritonavir/gemcitabine/ cisplatin is synergistic in the A549 line and additive in the H522 line, at clinically feasible ritonavir concentrations (<10 μM). Conclusions: Ritonavir is of interest for lung adenocarcinoma therapeutics, and survivin is an important target and potential biomarker for its sensitivity. Ritonavir cooperation with gemcitabine/cisplatin might be explained by involvement of PARP1 in repair of cisplatin-mediated DNA damage and survivin in repair of gemcitabine-mediated double-stranded DNA breaks.

Original languageEnglish (US)
Pages (from-to)661-670
Number of pages10
JournalJournal of Thoracic Oncology
Volume6
Issue number4
DOIs
StatePublished - Apr 2011

Bibliographical note

Funding Information:
Supported by the National Institute of Health (grants R01 CA113570 [to D.A.P.] and HL-079654 to [L.M.P.]). D.A.P. acknowledges a Walther Cancer Research Prize, the Flight Attendant's Medical Research Institute Clinical Innovator Award 042257, and support from the Walther Oncology Center at Indiana University, the Thoracic Oncology Program at Indiana University, a Clarian Values Foundation grant, and equipment grant from the Indiana Elks. The authors also acknowledge the Masonic Cancer Center Experimental Therapeutics Initiative.

Keywords

  • Chemotherapy
  • Non-small cell lung cancer
  • Ritonavir
  • Survivin

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