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Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer

Authors' Affiliations: Departments of ¹ Medicine, ² Biochemistry and Molecular Biology, ³ Pathology, ⁴ Surgery, and ⁵ Microbiology and Immunology, ⁶ Walther Oncology Center, ⁷ Walther Cancer Institute, and ⁸ Indiana University Cancer Center, Indiana University, Indianapolis, Indiana; ⁹ Department of Chemistry and Biology, Miami University, Oxford, Ohio; and ¹⁰ Department of Surgery, University of California, San Francisco, California

Requests for reprints: David A. Potter, Indiana University School of Medicine, 1044 West Walnut Street, R4-202, Indianapolis, IN 46202. Phone: 317-274-3589; Fax: 317-274-0396; E-mail: dapotter{at}iupui.edu.

Purpose: These studies were designed to determine whether ritonavir inhibits breast cancer in vitro and in vivo and, if so, how.

Experimental Design: Ritonavir 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.

Results: ER-positive estradiol-dependent lines (IC₅₀, 12-24 µmol/L) and ER-negative (IC₅₀, 45 µmol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER- 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 C_max of 22 ± 8 µmol/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 µmol/L) and partially inhibits its chaperone function. Ritonavir blocks association of Hsp90 with Akt and, with sustained exposure, notably depletes Hsp90. Stably expressed Hsp90 short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations.

Conclusions: Ritonavir 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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