ArticleClinical cancer research : an official journal of the American Association for Cancer Research2006
Effects of HIV protease inhibitor ritonavir on Akt-regulated cell proliferation in breast cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 121 citations in OpenAlex.
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- Darunavir analog precursors target mitochondrial metabolism in multiple myeloma and CLL.Cancer cell international · 2025Article
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- Rational Identification of Ritonavir as IL-20 Receptor A Ligand Endowed with Antiproliferative Properties in Breast Cancer Cells.International journal of molecular sciences · 2025Article
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- Ritonavir's Evolving Role: A Journey from Antiretroviral Therapy to Broader Medical Applications.Current oncology (Toronto, Ont.) · 2024Review
- Structural Characterization of Heat Shock Protein 90β and Molecular Interactions with Geldanamycin and Ritonavir: A Computational Study.International journal of molecular sciences · 2024Article
- Antiretroviral Drug Repositioning for Glioblastoma.Cancers · 2024Article
- Ritonavir Has Reproductive Toxicity Depending on Disrupting PI3K/PDK1/AKT Signaling Pathway.Toxics · 2024Article
- Case report: Complete response after transcatheter arterial chemoembolization combined with donafenib plus tislelizumab therapy for hepatocellular carcinoma with main trunk portal vein tumor thrombus in a patient coinfected with HIV and HBV.Frontiers in immunology · 2024Article
- A Strategy Utilizing Protein-Protein Interaction Hubs for the Treatment of Cancer Diseases.International journal of molecular sciences · 2023Review
- PEGylated Liposomes Loaded with Carbamate Inhibitor ANP0903 Trigger Apoptosis by Enhancing ER Stress in HepG2 Cancer Cells.International journal of molecular sciences · 2023Article
- Reproductive toxicity of ritonavir in male: Insight into mouse sperm capacitation.Reproductive toxicology (Elmsford, N.Y.) · 2022Article
- Mechanisms behind context-dependent role of glucocorticoids in breast cancer progression.Cancer metastasis reviews · 2022Review
- Drug repurposing: re-inventing therapies for cancer without re-entering the development pipeline-a review.Journal of the Egyptian National Cancer Institute · 2022Review
- Aspartyl Protease Inhibitors as Anti-Filarial Drugs.Pathogens (Basel, Switzerland) · 2022Article
- Molecular Mechanisms of HIV Protease Inhibitors Against HPV-Associated Cervical Cancer: Restoration ofFrontiers in molecular biosciences · 2022Review
- Review
6 more citing papers are in PubMed but not listed here.
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Authors and funding
17 authors at 7 institutions in 4 countries.
Funding
Abstract
purposeThese studies were designed to determine whether ritonavir inhibits breast cancer in vitro and in vivo and, if so, how. EXPERIMENTAL
designRitonavir effects on breast cancer cell growth were studied in the estrogen receptor (ER)-positive lines MCF7 and T47D and in the ER-negative lines MDA-MB-436 and MDA-MB-231. Effects of ritonavir on Rb-regulated and Akt-mediated cell proliferation were studied. Ritonavir was tested for inhibition of a mammary carcinoma xenograft.
resultsER-positive estradiol-dependent lines (IC50, 12-24 micromol/L) and ER-negative (IC50, 45 micromol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-alpha levels notably in ER-positive lines. Ritonavir causes G1 arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D1 but not cyclin E, and depletes phosphorylated Rb and Ser473 Akt. Ritonavir induces apoptosis independent of G1 arrest, inhibiting growth of cells that have passed the G1 checkpoint. Myristoyl-Akt, but not activated K-Ras, rescues ritonavir inhibition. Ritonavir inhibited a MDA-MB-231 xenograft and intratumoral Akt activity at a clinically attainable serum Cmax of 22 +/- 8 micromol/L. Because heat shock protein 90 (Hsp90) substrates are depleted by ritonavir, ritonavir effects on Hsp90 were tested. Ritonavir binds Hsp90 (K(D), 7.8 micromol/L) and partially inhibits its chaperone function. Ritonavir blocks association of Hsp90 with Akt and, with sustained exposure, notably depletes Hsp90. Stably expressed Hsp90alpha short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations.
conclusionsRitonavir inhibits breast cancer growth in part by inhibiting Hsp90 substrates, including Akt. Ritonavir may be of interest for breast cancer therapeutics and its efficacy may be increased by sustained exposure or Hsp90 RNA interference.
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