Breast Cancer Research and Treatment

, Volume 75, Issue 2, pp 107–117

Control of Mammary Tumor Cell Growth in Vitro by Novel Cell Differentiation and Apoptosis Agents

  • Qun Zhou
  • Meredith A. McCracken
  • Jeannine S. Strobl
Article

Abstract

The use of breast tumor differentiating agents to complement existing therapies has the potential to improve breast cancer treatment. Previously we showed quinidine caused MCF-7 cells to synchronously arrest in G1 phase of the cell cycle, transition into G0 and undergo progressive differentiation. After 72–96 h cells became visibly apoptotic. Using several analogs of quinidine we determined that MCF-7 cell cycle exit and differentiation are typical of quinoline antimalarial drugs bearing a tertiary amine side chain (chloroquine, quinine, quinidine). Differentiated cells accumulated lipid droplets and mammary fat globule membrane protein. Apoptosis was assayed by a nucleosome release ELISA. Quinidine and chloroquine triggered apoptosis, but not quinine, a quinidine stereoisomer that displayed weak DNA binding. The apoptotic response to quinidine and chloroquine was p53-dependent. A 4–15-fold induction of p21(WAF1) protein was observed in cells treated with quinidine or chloroquine prior to apoptosis, but p21(WAF1) was not increased in cells that differentiated in response to quinine. Chloroquine was most active in stimulating MCF-7 apoptosis, and quinine was most active in promoting MCF-7 cell differentiation. We conclude, distinct mechanisms are responsible for breast tumor cell differentiation and activation of apoptosis by quinoline antimalarials. Alkylamino-substituted quinoline ring compounds represented by quinidine, quinine, and chloroquine will be useful model compounds in the search for more active breast tumor differentiating agents.

apoptosis breast cancer cell differentiation agents chloroquine MCF-7 quinidine quinine 

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Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • Qun Zhou
    • 1
  • Meredith A. McCracken
    • 2
  • Jeannine S. Strobl
    • 1
    • 2
  1. 1.Department of Biochemistry and Molecular PharmacologyWest Virginia UniversityMorgantownUSA
  2. 2.Genetics and Developmental Biology ProgramWest Virginia UniversityMorgantownUSA

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