Lani
03-24-2006, 11:13 PM
utilizing a drug already on the market for HIV (ie,potentially available to be used off-label)
not yet tried in a her2+ cell line, but most her2+ tumors growth are very AKT dependent
works in petri dish and in mice with human breast cancer cells implanted--not yet tried in humans:
Clin Cancer Res. 2006 Mar 15;12(6):1883-1896. Related Articles, Links
Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer.
Srirangam A, Mitra R, Wang M, Gorski JC, Badve S, Baldridge L, Hamilton J, Kishimoto H, Hawes J, Li L, Orschell CM, Srour EF, Blum JS, Donner D, Sledge GW, Nakshatri H, Potter DA.
Authors' Affiliations: Departments of Medicine, Biochemistry and Molecular Biology, Pathology, Surgery, and Microbiology and Immunology, Walther Oncology Center, Walther Cancer Institute, and Indiana University Cancer Center, Indiana University, Indianapolis, Indiana.
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 (IC(50), 12-24 mumol/L) and ER-negative (IC(50), 45 mumol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-alpha levels notably in ER-positive lines. Ritonavir causes G(1) arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D(1) but not cyclin E, and depletes phosphorylated Rb and Ser(473) Akt. Ritonavir induces apoptosis independent of G(1) arrest, inhibiting growth of cells that have passed the G(1) 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 mumol/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 mumol/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. 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.
PMID: 16551874 [PubMed - as supplied by publisher]
not yet tried in a her2+ cell line, but most her2+ tumors growth are very AKT dependent
works in petri dish and in mice with human breast cancer cells implanted--not yet tried in humans:
Clin Cancer Res. 2006 Mar 15;12(6):1883-1896. Related Articles, Links
Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer.
Srirangam A, Mitra R, Wang M, Gorski JC, Badve S, Baldridge L, Hamilton J, Kishimoto H, Hawes J, Li L, Orschell CM, Srour EF, Blum JS, Donner D, Sledge GW, Nakshatri H, Potter DA.
Authors' Affiliations: Departments of Medicine, Biochemistry and Molecular Biology, Pathology, Surgery, and Microbiology and Immunology, Walther Oncology Center, Walther Cancer Institute, and Indiana University Cancer Center, Indiana University, Indianapolis, Indiana.
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 (IC(50), 12-24 mumol/L) and ER-negative (IC(50), 45 mumol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-alpha levels notably in ER-positive lines. Ritonavir causes G(1) arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D(1) but not cyclin E, and depletes phosphorylated Rb and Ser(473) Akt. Ritonavir induces apoptosis independent of G(1) arrest, inhibiting growth of cells that have passed the G(1) 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 mumol/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 mumol/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. 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.
PMID: 16551874 [PubMed - as supplied by publisher]