Second generation hybrid polar compounds are potent inducers of transformed cell differentiation
| Autor: | B Jursic, Victoria M. Richon, Terry L. Sheppard, Yael Webb, F Civoli, Richard A. Rifkind, R Merger, Paul A. Marks, Ronald Breslow, Lang Ngo |
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| Rok vydání: | 1996 |
| Předmět: |
Stereochemistry
Cellular differentiation Cell Antineoplastic Agents Biology Mice chemistry.chemical_compound Differentiation therapy hemic and lymphatic diseases Acetamides Tumor Cells Cultured medicine Animals Inducer Multidisciplinary Cell Cycle Cell Differentiation Cell cycle medicine.disease Molecular biology Leukemia medicine.anatomical_structure Malonate chemistry Toxicity Leukemia Erythroblastic Acute Research Article |
| Zdroj: | Proceedings of the National Academy of Sciences. 93:5705-5708 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.93.12.5705 |
| Popis: | Hybrid polar compounds, of which hexamethylenebisacetamide (HMBA) is the prototype, are potent inducers of differentiation of murine erythroleukemia (MEL) cells and a wide variety of other transformed cells. HMBA has been shown to induce differentiation of neoplastic cells in patients, but is not an adequate therapeutic agent because of dose-limiting toxicity. We report on a group of three potent second generation hybrid polar compounds, diethyl bis-(pentamethylene-N,N-dimethylcarboxamide) malonate (EMBA), suberoylanilide hydroxamic acid (SAHA), and m-carboxycinnamic acid bis-hydroxamide (CBHA) with optimal concentrations for inducing MEL cells of 0.4 mM, 2 microM, and 4 microM, respectively, compared to 5 mM for HMBA. All three agents induce accumulation of underphosphorylated pRB; increased levels of p2l protein, a prolongation of the initial G1 phase of the cell cycle; and accumulation of hemoglobin. However, based upon their effective concentrations, the cross-resistance or sensitivity of an HMBA-resistant MEL cell variant, and differences in c-myb expression during induction, these differentiation-inducing hybrid polar compounds can be grouped into two subsets, HMBA/EMBA and SAHA/CBHA. This classification may prove of value in selecting and planning prospective preclinical and clinical studies toward the treatment of cancer by differentiation therapy. |
| Databáze: | OpenAIRE |
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