Inducing differentiation of transformed cells with hybrid polar compounds: a cell cycle-dependent process.
Transformed cells do not necessarily lose their capacity to differentiate. Various agents can induce many types of neoplastic cells to terminal differentiation. Among such inducers, a particularly potent group consists of hybrid polar compounds; hexamethylene bisacetamide (HMBA) is the prototype of this group. 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. This review focuses on HMBA-induced modulation of factors regulating G1-to-S phase progression, including a decrease in the G1 cyclin-dependent kinase cdk4, associated with inhibition of phosphorylation of the retinoblastoma protein pRB and possibly other related proteins that, in turn, sequester factors required for initiation of DNA synthesis; this provides a possible mechanism for HMBA-induced terminal cell division. Evidence that hybrid polar compounds have therapeutic potential for cancer treatment will also be reviewed.
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Program of Cell Biology and Genetics, DeWitt Wallace Research Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Richon
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Kiyokawa
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Rifkind
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D000081:Acetamides / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002461:Cell Line, Transformed; D002986:Clinical Trials as Topic; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute; D051379:Mice; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000081:Acetamides; D000970:Antineoplastic Agents; D016213:Cyclins; D018844:Cyclin-Dependent Kinases; C014026:hexamethylene bisacetamide