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Medientyp:
E-Artikel
Titel:
Abstract 4444: Desthiazolylmethyloxycarbonyl ritonavir is a candidate proteasome activator drug in breast cancer that down-regulates survivin and HER2
Beteiligte:
Milani, Monica;
Mitra, Ranjana;
Jha, Gautam;
Rodriguez, Mariangellys;
Guo, Zhijun;
Weller, Dennis;
Remmel, Rory P.;
Potter, David A.
Erschienen:
American Association for Cancer Research (AACR), 2010
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Purpose: Desthiazolylmethyloxycarbonyl ritonavir (M1) is a minor metabolite of ritonavir, but exhibits more potent activity against ER+, HER2+ and triple negative breast cancer lines. The mechanisms of action of M1 are unknown and may be very different from ritonavir. This study investigates M1 effects on proteasome activity and unfolded protein response (UPR), which have been identified as ritonavir targets.</jats:p>
<jats:p>Methods: Assays for cell growth, cell cycle progression and apoptosis were used to determine the mechanisms of M1 action in ER+ (T47D), HER2+ (SKBR3) and triple negative (MDA-MB-231) breast cancer lines. Effects of M1 on proteasome activity were determined by biochemical and cell-based luciferase assays. Effects of M1 on proteasome substrates and the UPR were determined by Western blotting and flow cytometry. Effects of M1 in vivo were determined using a xenograft model.</jats:p>
<jats:p>Results: M1, compared to ritonavir, exhibited a significantly lower IC50 for the T47D, MDA-MB-231 and SKBR3 lines, but a higher IC50 for the non-transformed line MCF10A, indicating M1 selectivity for breast cancer. M1 induced a G0/G1 block and apoptosis in all lines tested. M1 at its IC50 significantly reduced survivin levels in the T47D and MDA-MB-231 lines, and surface HER2 in the SKBR3 line. However, it did not affect the expression of other short half-life antiapoptotic proteins, including MCL-1 and Bcl-2. In vivo, M1 inhibited the MDA-MB-231 xenograft at its maximum tolerated dose (MTD, 20 mg/kg), while ritonavir exhibited no effect at this dosing, which is half of its MTD. 1 h following M1 ip administration, M1 plasma levels were measurable (3.6 ± 2.3 microM). In contrast, ritonavir administration resulted in M1 levels that were at or below the limit of detection, indicating that M1 plasma levels associated with tumor response cannot be achieved with identical dosing of ritonavir. Remarkably, M1 up-regulated the chymotryptic, tryptic and caspase-like activities of the purified 20S proteasome, whereas ritonavir did not. M1 also up-regulated the proteasome chymotryptic site in breast cancer cells. Furthermore, M1 activation of the proteasome was abrogated by lactacystin or MG132. Sp3, a survivin transcription factor that is known to be degraded by the proteasome, was reduced in M1-treated MDA-MB-231 cells (P&lt;0.05). M1 induced the UPR marker GRP78 (BiP) in the MDA-MB-231 line, but not in the T47D line, suggesting that the UPR response did not directly correlate with growth inhibition.</jats:p>
<jats:p>Conclusions: M1 is more potent than ritonavir in vitro and in vivo and, in contrast to ritonavir, is an activator of the proteasome, suggesting a novel mechanism of anticancer activity. Survivin may be an important target of M1 in ER+ and triple negative breast cancer, while HER2 is a target in HER2+ breast cancer. M1, a candidate HIV protease inhibitor derivative, is promising for clinical development in breast cancer.</jats:p>
<jats:p>Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4444.</jats:p>