Induced differentiation, the cell cycle, and the treatment of cancer.
Hybrid polar compounds, of which hexamethylene bisacetamide (HMBA) is the prototype, have been shown to be potent inducers of differentiation of many types of transformed cells. With virus-transformed murine erythroleukemia cells as a model, HMBA was shown to cause these cells to arrest in G1 phase and express globin genes. HMBA action involves modulation of factors regulating G1 to S phase progression, including a decrease in the G1 cyclin-dependent kinase 4 accumulation of underphosphorylated retinoblastoma protein, and an increase in the level of both retinoblastoma protein and the related protein, p107. In turn, p107 complexes with transcription factors such as E2F and, presumably, inhibits transcriptional activity of these factors for genes whose products are required for DNA synthesis. This provides a possible mechanism for HMBA-induced terminal cell division of transformed cells. Evidence that hybrid polar compounds have therapeutic potential for cancer treatment is also reviewed.
Rifkind
R A
RA
Dewitt Wallace Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Richon
V M
VM
Marks
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PA
D000081:Acetamides / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002352:Carrier Proteins; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000473:pathology; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D005622:Friend murine leukemia virus; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D016160:Retinoblastoma Protein / Q000378:metabolism; D056465:Retinoblastoma-Binding Protein 1; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000081:Acetamides; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D016160:Retinoblastoma Protein; D056465:Retinoblastoma-Binding Protein 1; D014157:Transcription Factors; D018844:Cyclin-Dependent Kinases; C014026:hexamethylene bisacetamide