Control of Mammary Tumor Cell Growth in Vitro by Novel Cell Differentiation and Apoptosis Agents
- 109 Downloads
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.
Unable to display preview. Download preview PDF.
- 1.Webster Jr LT: Drugs used in the chemotherapy of protozoal infections: malaria. In: Goodman AG, Goodman LS, Rall TW, Murad F (eds) The Pharmacological Basis of Therapeut-ics. 7th edn MacMillan Publishing Company, NY, 1985, pp 1029–1048Google Scholar
- 5.Melkoumian ZK, Martirosyan AR, Strobl JS: Myc protein is differentially sensitive to quinidine in tumor versus immortalized breast epithelial cells. Int J Cancer (in revision)Google Scholar
- 8.Udenfriend S: Drugs and toxic agents. In: Fluorescence Assay in Biology and Medicine. Vol 1, Academic Press, NY, 1962, pp 400–443Google Scholar
- 9.Hahn FE: Chloroquine. In: Corcoran JW, Hahn FE, (eds) Antibiotics, Vol III, Mechanism of Action of Antimicrobial and Antitumor Agents. Springer-Verlag Press, NY, 1975, pp 58–78Google Scholar
- 11.Bancroft JD, Cook HC: Manual of Histological Techniques. Churchill Livingstone, Edinburgh 1984, pp 132–133Google Scholar
- 16.Kim YB, Ki SW, Yoshida M, Horinouchi S: Mechanism of cell cycle arrest caused by histone deacetylase inhibitors in human carcinoma cells. J Antibiot (Tokyo) 53(10): 1191–1200, 2000Google Scholar
- 19.Vogelstein B, Kinzler KW: Has the breast cancer gene been found? Cell 79(1): 1–3, 1994Google Scholar
- 21.O'Brien RL, Allision JL, Hahn FE: Evidence for intercalation of chloroquine into DNA. Biochim Biophys Acta 129(3): 622–624, 1966Google Scholar
- 28.Yoshida M, Furumai R, Nishiyama M, Komatsu Y, Nishino N, Horinouchi S: Histone deacetylase as a new target for cancer chemotherapy. Cancer Chemother Pharmacol (suppl 1): S20–26, 2001Google Scholar