Indomethacin induces apoptosis and inhibits proliferation in chronic myeloid leukemia cells.

A nonsteroidal anti-inflammatory drug (NSAID)--indomethacin (IN), was found to induce apoptosis and inhibit proliferation of K562 cells and primary culture bone marrow cells from six chronic myelogenous leukemia (CML) patients. IN induced cells apoptosis and inhibited cells proliferation in a dose-and time-dependent manner, the optimum IN concentration and incubation time for eliciting these effects were 400 micromol/l and 72 h, respectively. A synergic effect on Vp-16 (2.5 microg/ml) induced apoptosis was observed when combined with 100 micromol/l IN in K562 cells. RT-PCR results showed that IN down-regulated Bcl-2 mRNA expression, and did not change Bax mRNA expression; Western blot results confirmed that IN inhibited Bcl-2 protein expression, no influence was found on the translative level of bax protein. Our study indicate that IN induce apoptosis of CML cells by down-regulating Bcl-2 expression partially, and there is a potential significance in the treatment of CML.

[1]  T. Mosmann Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. , 1983, Journal of immunological methods.

[2]  G. Jenster,et al.  Acute leukaemia in bcr/abl transgenic mice , 1990, Nature.

[3]  B. Rigas,et al.  Effect of aspirin on induction of apoptosis in HT-29 human colon adenocarcinoma cells. , 1998, Biochemical pharmacology.

[4]  R. Ullrich,et al.  Latent expression of p53 mutations and radiation-induced mammary cancer. , 1995, Cancer research.

[5]  S. Korsmeyer,et al.  Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programed cell death , 1993, Cell.

[6]  C. Bunce,et al.  Potentiation of myeloid differentiation by anti-inflammatory agents, by steroids and by retinoic acid involves a single intracellular target, probably an enzyme of the aldoketoreductase family. , 1996, Biochimica et biophysica acta.

[7]  J. F. Fraumeni,et al.  Incidence of cancer among patients with rheumatoid arthritis. , 1993, Journal of the National Cancer Institute.

[8]  B. Rigas,et al.  Nonsteroidal antiinflammatory drugs inhibit the proliferation of colon adenocarcinoma cells: effects on cell cycle and apoptosis. , 1996, Experimental cell research.

[9]  William L. Smith,et al.  Prostaglandin Endoperoxide H Synthases (Cyclooxygenases)-1 and −2* , 1996, The Journal of Biological Chemistry.

[10]  B. Zehnbauer,et al.  Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia. , 1994, Blood.

[11]  Z. Oltvai,et al.  Bcl-2 functions in an antioxidant pathway to prevent apoptosis , 1993, Cell.

[12]  B. Rigas,et al.  Sulindac sulfide, an aspirin-like compound, inhibits proliferation, causes cell cycle quiescence, and induces apoptosis in HT-29 colon adenocarcinoma cells. , 1995, The Journal of clinical investigation.

[13]  Y. Hannun,et al.  Apoptosis and the dilemma of cancer chemotherapy. , 1997, Blood.

[14]  A. Lichtenstein,et al.  Upregulated expression of BCL-2 in multiple myeloma cells induced by exposure to doxorubicin, etoposide, and hydrogen peroxide. , 1996, Blood.

[15]  M. Melamed,et al.  Induction of DNA strand breaks associated with apoptosis during treatment of leukemias. , 1993, Leukemia.

[16]  D. Alberts,et al.  Antineoplastic drugs sulindac sulfide and sulfone inhibit cell growth by inducing apoptosis. , 1995, Cancer research.

[17]  Ming-chi Wu,et al.  Lipoperoxidation and T‐cell leukemia of childhood. Effects of indomethacin , 1989, Cancer.

[18]  M. Tattersall,et al.  Characteristics of cancer cell death after exposure to cytotoxic drugs in vitro. , 1996, British Journal of Cancer.

[19]  A. Sartorelli,et al.  Induction of the differentiation of HL-60 promyelocytic leukemia cells by nonsteroidal anti-inflammatory agents in combination with low levels of vitamin D3. , 1998, Leukemia research.

[20]  J. Vane,et al.  Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. , 1971, Nature: New biology.

[21]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[22]  E. Montserrat,et al.  Aspirin and salicylate induce apoptosis and activation of caspases in B-cell chronic lymphocytic leukemia cells. , 1998, Blood.

[23]  B. Rigas,et al.  Effects of nonsteroidal anti-inflammatory drugs on proliferation and on induction of apoptosis in colon cancer cells by a prostaglandin-independent pathway. , 1996, Biochemical pharmacology.

[24]  W. El-Deiry,et al.  BCR-ABL-mediated inhibition of apoptosis with delay of G2/M transition after DNA damage: a mechanism of resistance to multiple anticancer agents. , 1995, Blood.