Second generation hybrid polar compounds are potent inducers of transformed cell differentiation Journal Article
| Authors: | Richon, V. M.; Webb, Y.; Merger, R.; Sheppard, T.; Jursic, B.; Ngo, L.; Civoli, F.; Breslow, R.; Rifkind, R. A.; Marks, P. A. |
| Article Title: | Second generation hybrid polar compounds are potent inducers of transformed cell differentiation |
| Abstract: | 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 μM, and 4 μM, respectively, compared to 5 mM for HMBA. All three agents induce accumulation of underphosphorylated pRB; increased levels of p21 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. |
| Keywords: | unclassified drug; nonhuman; antineoplastic agents; animal cell; mouse; cytology; animals; mice; cell cycle; gene expression; hemoglobin; cell differentiation; tumor cells, cultured; animalia; cell transformation; murinae; vorinostat; protein p21; oncogene c myb; cell cycle g1 phase; p21; differentiation; cross resistance; c-myb; leukemia, erythroblastic, acute; prb; differentiation therapy; hexamethylenebisacetamide; acetamides; priority journal; article; erythroleukemia cell; 3 carboxycinnamic acid bis(hydroxamide); diethyl bis(pentamethylene n,n dimethylcarboxamide)malonate |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 93 |
| Issue: | 12 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 1996-06-11 |
| Start Page: | 5705 |
| End Page: | 5708 |
| Language: | English |
| DOI: | 10.1073/pnas.93.12.5705 |
| PUBMED: | 8650156 |
| PROVIDER: | scopus |
| PMCID: | PMC39124 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 22 November 2017 -- Source: Scopus |
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