Structure-activity relationships for the induction of differentiation of HL-60 human acute promyelocytic leukemia cells by anthracyclines

Edward L. Schwartz, A. C. Sartorelli

Research output: Contribution to journalArticle

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Abstract

Marcellomycin, a newly developed anthracycline antibiotic with antineoplastic activity, was tested as an inducer of differentiation of the human promyelocytic leukemia cell line HL-60 in vitro. The percentage of cells reducing nitro blue tetrazolium, an indication of a stimulus-induced respiratory burst typical of mature phagocytes, was used as a functional measure of the extent of differentiation. Marcellomycin was a potent inducer of maturation, with 95% of the cells expressing a terminally differentiated state after 10 days of exposure to a concentration of 40 nM anthracycline. Cells exposed to marcellomycin exhibited a 35-fold increase in their total superoxide anion-generating capacity, an 80% increase in acid phosphatase activity, and a loss of myeloperoxidase and chloroacetate esterase activities. In addition, marcellomycin-treated cells stained negatively for α-naphthyl acetate esterase. These findings provided evidence for the granulocytic nature of the mature cells. In contrast, marcellomycin was not an effective inducer of differentiation of Friend murine erythroleukemia cells. Studies on the relationship between structure and the ability to induce differentiation of HL-60 leukemia cells demonstrated that removal from the marcellomycin molecule of the terminal 2-deoxyfucose (musettamycin) or its substitution by cinerulose (aclacinomycin A) did not alter differentiation-inducing capacity. However, removal of the carbomethoxy group from the C-10 position of marcellomycin substantially reduced its potency as an initiator of maturation, and removal of the two terminal 2-deoxyfucose moieties (pyrromycin) decreased both potency and the maximal percentage of differentiated cells produced in the population. The monosaccharide anthracyclines Adriamycin and carminomycin were completely inactive as inducers of HL-60 leukemia cell maturation. The results suggest that certain anthracyclines would be reasonable candidate drugs to use in a clinical trial aimed at reducing the leukemic stem cell burden through maturation rather than through cytodestruction.

Original languageEnglish (US)
Pages (from-to)2651-2655
Number of pages5
JournalCancer Research
Volume42
Issue number7
StatePublished - 1982
Externally publishedYes

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Acute Promyelocytic Leukemia
Anthracyclines
Structure-Activity Relationship
Leukemia
HL-60 Cells
Carubicin
Antineoplastic Antibiotics
Aclarubicin
Acetylesterase
Leukemia, Erythroblastic, Acute
Respiratory Burst
Monosaccharides
Phagocytes
Acid Phosphatase
marcellomycin
Superoxides
Doxorubicin
Peroxidase
Stem Cells
Clinical Trials

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Structure-activity relationships for the induction of differentiation of HL-60 human acute promyelocytic leukemia cells by anthracyclines. / Schwartz, Edward L.; Sartorelli, A. C.

In: Cancer Research, Vol. 42, No. 7, 1982, p. 2651-2655.

Research output: Contribution to journalArticle

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