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Titolo:
Rationally designed anti-mitotic agents with pro-apoptotic activity
Autore:
Uckun, FM;
Indirizzi:
Parker Hughes Inst, Parker Hughes Canc Ctr, Drug Discovery Program, St Paul, MN 55113 USA Parker Hughes Inst St Paul MN USA 55113 ry Program, St Paul, MN 55113 USA
Titolo Testata:
CURRENT PHARMACEUTICAL DESIGN
fascicolo: 16, volume: 7, anno: 2001,
pagine: 1627 - 1639
SICI:
1381-6128(200111)7:16<1627:RDAAWP>2.0.ZU;2-N
Fonte:
ISI
Lingua:
ENG
Soggetto:
PROTEIN-KINASE-C; BRUTONS-TYROSINE-KINASE; MARINE NATURAL PRODUCT; GROWTH-FACTOR RECEPTOR; BREAST-CANCER CELLS; ACUTE LYMPHOBLASTIC-LEUKEMIA; SPONGE PHORBAS SP; PHORBOXAZOLE-A; MICROTUBULE POLYMERIZATION; TUBULIN POLYMERIZATION;
Tipo documento:
Review
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
87
Recensione:
Indirizzi per estratti:
Indirizzo: Uckun, FM Parker Hughes Inst, Parker Hughes Canc Ctr, Drug Discovery Program, 2665 Long Lake Rd, St Paul, MN 55113 USA Parker Hughes Inst 2665 Long Lake Rd St Paul MN USA 55113 13 USA
Citazione:
F.M. Uckun, "Rationally designed anti-mitotic agents with pro-apoptotic activity", CUR PHARM D, 7(16), 2001, pp. 1627-1639

Abstract

Agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET), targeting the spongistatin binding siteof beta -tubulin, and monotetrahydrofuran compounds (COBRA compounds), targeting a unique binding cavity on alpha -tubulin. At nanomolar concentrations, the SPIKET compound SPIKET-P caused tubulin depolymerization and demonstrated potent cytotoxic activity against cancer cells. COBRA-1 inhibited GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other agents that have shown promise for cancer treatment include phorboxazoles, natural products that are extremely cytostatic towards the National Cancer Institute's panel of 60 tumor cell lines. In standard MTT assays, synthetic phorboxazole A exhibited potent cytotoxicity against NALM-6 acute lymphoblastic leukemia cells (IC50 = 1.7 nM), BT-20 breast cancer cells (IC50 = 3.4 nM), and U373 glioblastoma cells (IC50 = 6.7 nM). Structure-activity studies were reported for seven synthetic analogs of phorboxazole A. Out of these, two showed potent anti-cancer activity. Phorboxazoleanalog 2 was active against NALM-6 cells (IC50 = 4.8 nM), BT-20 cells (IC50 12.6 nM) and U373 cells (IC50 = 27.4 nM), as was analog 3 (NALM-6 IC50 = 5.2 nM, BT-20 IC50 11.3 nM, and U373 IC50 = 29.2 nM). Anticancer activity of the phorboxazole analogs was correlated to the presence of certain structural moieties such as portions of the macrolide group, the central oxazole group, and the polyene side chain, The requirement of more than one structural element for activity suggested that at least bimodal interactions of the natural product with key cellular components may occur. Promising anti-mitotic agents with pro-apoptotic activity include inhibitors of the tyrosinekinase BTK. The leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells (IC50 = 17 muM). Consistent with the anti-apoptotic. function of BTK, treatment of leukemic cells with LFM-A13 enhanced theirsensitivity to chemotherapy-induced apoptosis.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 14:45:11