Antiangiogenic Properties of 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin

Kaur, Gurmeet; Belotti, Dorina; Burger, Angelika M.; Fisher-Nielson, Kirsten; Borsotti, Patrizia; Riccardi, Elena; Thillainathan, Jagada; Hollingshead, Melinda G.; Sausville, Edward A.; Giavazzi, Raffaella

doi:10.1158/1078-0432.ccr-03-0795

Cited by 137 publications

(104 citation statements)

References 21 publications

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“…Some of these proteins have been directly or indirectly associated with angiogenesis in endothelial cells. In addition to Hsp70, a chaperone reported to display down-regulation in HUVECs exposed to VEGF (36, 37), we also found a down-regulation of Hsp90, and some studies show that inhibitors of this protein have antiangiogenic activity in vivo (58,59). Down-regulation of adipose triglyceride lipase is also consistent with a proangiogenic event because this protein acts as a receptor for pigment epithelium-derived factor (57), a strong endogenous inhibitor of angiogenesis (71).…”

Section: O Labelingsupporting

confidence: 62%

Statistical Model to Analyze Quantitative Proteomics Data Obtained by 18O/16O Labeling and Linear Ion Trap Mass Spectrometry

Jorge

Navarro

Martínez-Acedo

et al. 2009

Molecular & Cellular Proteomics

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Section: O Labelingsupporting

confidence: 62%

Statistical Model to Analyze Quantitative Proteomics Data Obtained by 18O/16O Labeling and Linear Ion Trap Mass Spectrometry

Jorge

Navarro

Martínez-Acedo

et al. 2009

Molecular & Cellular Proteomics

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“…An important objective of this study was the detection of target inhibition and modulation in leukemia cells. In seven paired bone marrow samples, Hsp70 induction (a marker of Hsp90 inhibition) 7,8,13 was observed on day 15, suggesting Hsp90 inhibition by alvespimycin. Limited paired marrow samples, however, precluded an accurate determination of the amount of alvespimycin exposure necessary to inhibit Hsp90.…”

Section: Discussionmentioning

confidence: 99%

“…When compared with tanespimycin, alvespimycin has higher potency against Hsp90, longer plasma half-life and oral bioavailability. 7,8 Because of the high incidence of activated Hsp90 client proteins in acute myeloid leukemia (AML), we undertook a phase I study to delineate the safety and biologic profile of alvespimycin in advanced AML.…”

Section: Introductionmentioning

confidence: 99%

Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

et al. 2010

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Heat shock protein 90 (Hsp90) is a molecular chaperone with many oncogenic client proteins. The small-molecule Hsp90 inhibitor alvespimycin, a geldanamycin derivative, is being developed for various malignancies. This phase 1 study examined the maximum-tolerated dose (MTD), safety and pharmacokinetic/pharmacodynamic profiles of alvespimycin in patients with advanced acute myeloid leukemia (AML). Patients with advanced AML received escalating doses of intravenous alvespimycin (8-32 mg/m 2 ), twice weekly, for 2 of 3 weeks. Dose-limiting toxicities (DLTs) were assessed during cycle 1. A total of 24 enrolled patients were evaluable for toxicity. Alvespimycin was well tolerated; the MTD was 24 mg/m 2 twice weekly. Common toxicities included neutropenic fever, fatigue, nausea and diarrhea. Cardiac DLTs occurred at 32 mg/m 2 (elevated troponin and myocardial infarction). Pharmacokinetics revealed linear increases in C max and area under the curve (AUC) from 8 to 32 mg/m 2 and minor accumulation upon repeated doses. Pharmacodynamic analyses on day 15 revealed increased apoptosis and Hsp70 levels when compared with baseline within marrow blasts. Antileukemia activity occurred in 3 of 17 evaluable patients (complete remission with incomplete blood count recovery). The twiceweekly administered alvespimycin was well tolerated in patients with advanced AML, showing linear pharmacokinetics, target inhibition and signs of clinical activity. We determined a recommended phase 2 dose of 24 mg/m 2 .

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“…Furthermore numerous studies indicate that Hsp90 inhibitors block cell migration and angiogenesis. [42][43][44] However, it is important to note that Hsp90 acts as a chaperone for the folding of many proteins besides the myosins, and these agents may affect other cellular functions. Thus, future study is required to determine whether reduced GC UNC-45 function contributes to the cytotoxic effect of Hsp90 inhibition in ovarian cancer cells and to determine whether GC-UNC-45 represents a useful target for developing drugs to slow ovarian cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Myosin II Co-Chaperone General Cell UNC-45 Overexpression Is Associated with Ovarian Cancer, Rapid Proliferation, and Motility

Bazzaro¹,

Santillan²,

Lin

et al. 2007

The American Journal of Pathology

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Both tumor cell proliferation and metastasis are dependent on myosin II. Because UNC-45 is required to chaperone the assembly of a functional myosin II motor, we examined the expression of the general cell (GC) UNC-45 isoform in ovarian tumors. Serous carcinoma expressed elevated levels of GC UNC-45 compared with normal ovarian surface epithelium and benign cystadenoma. High-stage exhibited greater GC UNC-45 expression than low-stage serous carcinoma. Similarly, GC UNC-45 transcripts and protein levels were higher in ovarian cell lines than in immortalized ovarian surface epithelial cells. Elevation of GC UNC-45 levels by ectopic expression enhanced the rate of ovarian cancer cell proliferation, whereas siRNA knockdown of GC UNC-45 suppressed proliferation without altering myosin II levels. GC UNC-45 and myosin II were diffuse within the cytoplasm of confluent interphase cells, but both accumulated together at the cleavage furrow during cytokinesis. GC UNC-45 and myosin II also trafficked to the leading edges of ovarian cancer cells induced to move in a scratch assay. Knockdown of GC UNC-45 reduced the spreading ability of ovarian cancer cells whereas it was enhanced by GC UNC-45 overexpression. In sum, these findings implicate elevated GC UNC-45 protein expression in ovarian carcinoma proliferation and metastasis. Epithelial ovarian cancer is the most lethal gynecological malignancy and the fifth major cause of cancer death among women in the United States. Approximately 70% of ovarian cancer patients are diagnosed with disease that has spread beyond the ovaries when, despite aggressive surgery and chemotherapy, the 5-year survival rate is less than 30%. Ovarian carcinoma rapidly seeds the peritoneal cavity with highly proliferative and invasive cancer cells, and new therapies targeting both of these properties are urgently needed.

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Antiangiogenic Properties of 17-(Dimethylaminoethylamino)-17-Demethoxygeldanamycin

Abstract: ABSTRACT

Cited by 137 publications

References 21 publications

Statistical Model to Analyze Quantitative Proteomics Data Obtained by 18O/16O Labeling and Linear Ion Trap Mass Spectrometry

Statistical Model to Analyze Quantitative Proteomics Data Obtained by 18O/16O Labeling and Linear Ion Trap Mass Spectrometry

Phase I study of the heat shock protein 90 inhibitor alvespimycin (KOS-1022, 17-DMAG) administered intravenously twice weekly to patients with acute myeloid leukemia

Myosin II Co-Chaperone General Cell UNC-45 Overexpression Is Associated with Ovarian Cancer, Rapid Proliferation, and Motility

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